Patent Publication Number: US-9422231-B2

Title: Method for inhibiting Trypanosoma cruzi

Description:
RELATED APPLICATIONS 
     This application is a U.S. National Stage Application filed under 35 U.S.C. §371 of International Application PCT/US2012/048616, filed Jul. 27, 2012, designating the United States, which claims priority from U.S. Provisional Application 61/512,232, filed Jul. 27, 2011, the complete disclosures of which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present inventions relate to methods for inhibiting  Trypanosoma cruzi  using an imido-substituted 1,4-napthoquinone compound and certain novel imido-substituted 1,4-napthoquinones. 
     BACKGROUND OF THE INVENTION 
     Chagas disease is a vector-transmitted tropical disease caused by  Trypanosoma cruzi.    
     Historically, Chagas disease has been regarded as largely affecting people living in rural areas of Latin America, primarily rural areas of Central and South America. The symptoms of the disease are silent and can appear many years after infection. 
     Chagas disease is expanding beyond its endemic area as a result of migration from and to the endemic countries (Hotez, 2008; Schofield and Kabayo, 2008). In addition, the World Health Organization (WHO) reports that blood donations and poor safety in blood banks have led to infections with Chagas disease in countries outside Latin America as some people who may be unaware they carry the infection have donated their blood to the national blood supply. As a result, the disease has now appeared in several countries in Europe and various parts of the United States of America. 
     A hematophagous insect (such as a triatomine insect) takes a blood meal from a vertebrate host infected with  Trypanosoma cruzi  and becomes a vector for Chagas disease. The insect ingests trypomastigotes from an infected vertebrate host, which proliferate and transform into the epimastigote form and then transform into the metacyclic trypmastigote form. The feces from the vector contain metacyclic trypomastigotes that can contaminate a bite or wound and pass into a vertebrate host (a mammalian “reservoir,” which can be a human). The metacyclic trypomastigotes penetrate various cells at the bite or wound site and transform into amastigotes, which multiply by binary fission in cells of infected tissue. The intracellular amastigotes transform into trypomastigotes that then burst from the cells into the bloodstream. Clinical manifestations can result from the repetitive infective cycle in an infected vertebrate host. 
     Once an individual has contracted Chagas disease, the infection may remain relatively dormant, in some cases for decades. Many people who have the disease do not know they are infected. Chagas disease is a silent killer that causes the slow swelling of its victims&#39; internal organs causing their eventual death. Most people later develop cardiac complications, resulting in disability and even death. Intestinal complications are also known to develop in patients resulting in an enlarged oesophagus or colon which make it difficult for the person to eat normally or pass stool. 
     There are currently two drugs used in the treatment of Chagas disease, benznidazole and nifurtimox. Where Chagas disease is endemic one of the two is used to treat disease victims. WHO has reported the two drugs (nifurtimox and benznidazole) are currently used to treat early stages of Chagas disease and that studies are being conducted for efficacy in treating later states of the disease. More recent literature reports the two drugs may be used to treat the acute phase of the infection where parasites (trypomastigotes) are detectable in the peripheral blood (Andrade et al., 2004; Schofield and Kabayo, 2008). 
     Nifurtimox is a 5-membered nitrofuran compound that is orally administered for 30 to 60 days. Benznidazole is an orally administered antiparasitic medication formerly marketed under the brand names Rochagan and Radanil. Benznidazole is reportedly effective in the acute or early chronic stage of infection with decreased effectiveness during late chronic phase. Recently, the emergence of  Trypanosoma cruzi  strains resistant to benznidazole have been reported. Both drugs have gastrointestinal and neurological side effects which may worsen as the patient ages. There are problems of non-compliance and there is no prescribed approved pediatric formulation. 
     Treatment is complicated due to high costs and side effects. Therapy mostly depends on the two known drugs developed decades ago that require long term administration, and are not available to all patients due to their high cost. 
     Consequently, there is a search for alternative drugs with efficacy against  Trypanosoma cruzi  and, in particular, drugs having a more selective mode of action. In the on-going search for alternatives, several classes of drug-like molecules have been considered. For instance, the naturally occurring lapachol ( FIG. 1 ), and some of its derivatives reportedly show trypanocidal activity against  T. cruzi  (Salas et al., 2008). Use of naphthofuranquinones synthesized from 2-hydroxy-3-allyl-1,4-naphthoquinone against the epimastigote and trypomastigote forms of  T. cruzi  has been reported (Silva et al., 2006). A study involving 2,3-diphenyl-1,4-naphthoquinone against  T. cruzi  epimastigotes at a low micromolar concentration (LD50=2.5 μM) by inhibiting  T. cruzi  lipoamide dehydrogenase (TcLipDH) has been reported (Ramos et al., 2009). Still other efforts are focusing on other structurally diverse compounds, including other natural products (canthinones, catechin, hinokinin, as examples) and pyrimidine derivatives (fenarimol, as an example), and additional structurally diverse compounds. Other literature includes Menna-Barreto et al., 2009. 
     Despite a number of efforts, relating the structure and efficacy and selectivity of compounds for treating Chagas disease remains elusive and results can be unpredicatable. 
     In particular, there remains a need for appropriate chemotherapeutic treatment that can be used in  Trypanosoma cruzi -infected patients, especially for slowing the progress of Chagas disease and for arresting development of severe forms of Chagas disease. 
     This situation establishes the unfulfilled need for new chemotherapeutic agents against  Trypanosoma cruzi.    
     SUMMARY OF THE INVENTION 
     In its broadest aspect, a method for treating a mammalian patient at risk or suffering from a disease caused by a kinetoplastid parasite comprises administering to such subject an effective kinetoplasticidal amount of an imido-substituted 1,4-naphthoquinone to inhibit the kinetoplastid. 
     In an important aspect, a method of inhibiting  Trypanosoma cruzi  comprises administering to a patient for prophylaxis or to a patient in need of treatment an antitrypanosomal effective amount of an imido-substituted 1,4-naphthoquinone. 
     In another important aspect, a method of inhibiting  Trypanosoma cruzi  comprises administering to a patient for prophylaxis or to a patient in need of treatment an antitrypanosomal effective amount of an imido-substituted 1,4-naphthoquinone represented by the general formula: 
                         
wherein X is alkyl, such as lower alkyl, alkoxy, benzyloxy aryloxy, trifluoro methyl, H, or halogen, as examples; and Q represents the imido-substituent bonded to the 1,4-napthoquinone moiety through the imido nitrogen.
 
     In an aspect, a method of inhibiting tubulin polymerization in  Trypanosoma cruzi  in a patient in need of treatment comprises administering to the patient, in an amount effective for inhibiting tubulin polymerization, an imido-substituted 1,4-naphthoquinone represented by the above general formula. 
     In an aspect of the method, in the general formula, X is —OR 1  and R 1  is alkyl. 
     In an aspect of the method, in the general formula, X is —OR 1  (alkoxy) and R 1  is lower alkyl. 
     In an aspect of the method, when X is —OR, R 1  is cycloalkyl or a straight or branched alkyl, including for example C 1  to C 10  alkyl, preferably C 1  to C 6  alkyl. 
     In an aspect of the method, in the general formula, X is —OR 1  and R 1  is aryl. 
     In an aspect of the method, in the general formula, X is halogen. 
     In an aspect of the method, in the general formula X is bromo, chloro, fluoro or iodo. 
     In an aspect of the method, in the general formula, X is bromo or chloro. 
     In an aspect of the method, Q is represented by: 
                         
wherein in Q each R is, independently, a substituted or unsubstituted hydrocarbon, provided that one R can, optionally, be hydrogen, and provided that, optionally, R can include at least one hetero atom.
 
     In an aspect of the method, Q is represented by: 
                         
wherein in Q each R is, independently, cyclic or acyclic, substituted or unsubstituted, or the R groups in formula (1) bond together to form a cyclic imido-substituent.
 
     In an aspect of the method, when Q is represented by: 
                         
wherein each R is independent of the other, and
         (a) R is an optionally substituted straight, branched or cyclic alkyl group, wherein the substitution is, for example, halogen, alkoxy or acetoxy,   (b) the R groups bond together to form an alkylene group whereby Q is a cyclic imido-substituent,   (c) the R groups bond together to form an alkylene group having a hetero atom, or   (d) R is aryl or substituted aryl, wherein the substitutent(s) include, for example, alkoxy or halogen.
 
When R is cycloalkyl or aryl, each ring can include 0, 1, 2, 3, 4, or 5 substituents. Each R is independent of the other. In principle, one R can be hydrogen.
       

     In an aspect of the method, in an imido-substituted 1,4-naphthoquinone Q is an aryl-imido substituent. 
     In an aspect of the method, the imido-substituted 1,4-naphthoquinone in the general formula is represented by: 
                         
wherein each R is, independently, an optionally halo-substituted straight or branched C 1  to C 10  alkyl, preferably a C 1  to C 6  alkyl. X is alkyl, alkoxy (cyclic or alicyclic), trifluoro methyl, aryloxy, benzyloxy, hydrogen or halogen. X can be substituted alkyl or substituted alkoxy, aryloxy or benzyloxy.
 
     In an aspect of the method, in an imido-substituted 1,4-naphthoquinone Q in the general formula is represented by: 
                         
wherein the symbol ( ) designates —(CH 2 )— and n is 1 to 3. Preferably n is 1 or 2.
 
     In an aspect of the method, Q is represented by: 
                         
wherein the aryl ring may, optionally, be substituted, such as substituted with halogen.
 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone is represented by: 
                         
wherein X is hydrogen, halogen, alkoxy (cyclic or alicyclic), trifluoro methyl, aryloxy, or benzyloxy, to mention examples; each Y, independently, represents hydrogen, halogen, alkoxy (cyclic or alicyclic), trifluoro methyl or alkyl, and each m, independent of the other, is 0, 1, 2, 3, 4 or 5.
 
     In an aspect of the method, on one of the aryl rings each Y can be hydrogen. 
     In an aspect of the method, when each m is 0, an imido-substituted 1,4-naphthoquinone is represented by: 
                         
wherein each Y is hydrogen.
 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone is represented by: 
                         
wherein X is hydrogen, halogen, alkoxy (cyclic or alicyclic), trifluoro methyl, aryloxy or benzyloxy, and each Y, independently, is alkoxy, aryloxy or halogen, and each m is 1. Y is ortho, meta or para-substituted. In another aspect, Y is meta-substituted. In a further aspect of this method, one Y can be hydrogen.
 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone is represented by: 
                         
wherein X is hydrogen, halogen, alkoxy (cyclic or alicyclic), trifluoro methyl, aryloxy, or benzyloxy and each Y, independently, is halogen. X and Y are independent of each other. In a further aspect, Y is ortho, meta or para-substituted. In another aspect, Y is meta-substituted. In a further aspect of this method, one Y can be hydrogen.
 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone having in vitro toxicity against  Trypanosoma cruzi  greater than nifurtimox is administered to a patient in need of treatment. 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone having a selectivity index against  Trypanosoma cruzi  greater than nifurtimox is administered to a patient in need of treatment. 
     In an aspect of the method, an imido-substituted 1,4-naphthoquinone having an IC 50  cytoxicity value greater than 100 μM is administered to a patient in need of treatment against  Trypanosoma cruzi.    
     In an aspect of the method, an anti-trypanosomal effective amount of a compound selected from the group consisting of IMDNQ1, IMDNQ2, IMDNQ3, IMDNQ4, IMDNQ5, IMDNQ6, IMDQ7, IMDNQ8, IMDNQ9, IMNDQ10, and IMNDQ11 is administered to a patient to inhibit  Trypanosoma cruzi.    
     In an aspect of the method, an anti-trypanosomal effective amount of a compound selected from the group consisting of IMDNQ1, IMDNQ 2, IMDNQ 3, and IMDNQ10 is administered to a patient. 
     In an aspect of the method, an anti-trypanosomal effective amount of IMDNQ10 is administered to a patient. 
     In an aspect, the method of inhibiting includes a method for treating a disease caused by  Trypanosoma cruzi.    
     In an aspect, the method comprises treating a patient in need of treatment for Chagas disease with a therapeutically effective amount of an active ingredient that is a compound represented by the general formula. 
     In an aspect, the method comprises treating a patient in need of treatment for Chagas disease with a therapeutically effective amount of an active ingredient that is a compound selected from the group consisting of IMDNQ1, IMDNQ2, IMDNQ3, IMDNQ4, IMDNQ5, IMDNQ6, IMDQ7, IMDNQ8, IMDNQ9, IMNDQ10, and IMNDQ11. 
     In an aspect, the method comprises treating a patient in need of treatment for Chagas disease with a therapeutically effective amount of an active ingredient that is a compound selected from the group consisting of IMDNQ1, IMDNQ 2, IMDNQ 3, and IMDNQ10. 
     In an aspect, the method comprises treating a patient in need of treatment for Chagas disease by administering a therapeutically effective amount of an active ingredient that is IMDNQ10. 
     In an aspect, the method comprises prophylaxis against  Trypanosoma cruzi  by administering an effective anti-trypanosomal amount of a compound represented by general formula to a patient. 
     In an aspect, the method comprises prophylaxis against  Trypanosoma cruzi  by administering an effective anti-trypanosomal amount of an active ingredient that is a compound selected from the group consisting IMDNQ1, IMDNQ2, IMDNQ3, IMDNQ4, IMDNQ5, IMDNQ6, IMDQ7, IMDNQ8, IMDNQ9, IMNDQ10, and IMNDQ11. 
     In an aspect, the method comprises prophylaxis against  Trypanosoma cruzi  by administering an effective anti-trypanosomal amount of a compound selected from the group consisting of IMDNQ1, IMDNQ 2, IMDNQ 3, and IMDNQ10. 
     In an aspect, the method comprises prophylaxis against  Trypanosoma cruzi  by administering an effective anti-trypanosomal amount of a compound represented by of an active ingredient that is IMDNQ10 or a derivative thereof. 
     In an aspect, the method comprises inhibiting tublin polymerization in  Trypanosoma cruzi  by administering an effective anti-tublin polymerization amount of an imido-substituted 1,4-naphthoquinione compound. In a further aspect the compound is represented by the general formula. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  shows the structures of nifurtimox, benznidazole and the naturally occurring lapachol. 
         FIG. 2  shows the structures for the imido-substituted 1,4-naphthoquinones according to Examples 1-29. 
         FIG. 3  is a bar graph showing the trypanocidal effects of certain imido-substituted 1,4-naphthoquinones on  Trypanosoma cruzi . Results were expressed as means±S.E. of three experiments. *P&lt;0.05, **P&lt;0.01, ***P&lt;0.001 compared with Nifurtimox. 
         FIG. 4  is bar graph showing the cytotoxicity of certain imido-substituted 1,4-naphthoquinones on Balb/C 3T3 mouse fibroblasts. Results were expressed as means±S.E. of three experiments. ***P&lt;0.0001 compared with Nifurtimox. 
         FIG. 5  is a bar graph showing the selectivity indices of certain imido-substituted 1,4-naphthoquinones. Results were expressed as means±S.E. of three experiments. **P&lt;0.01, ***P&lt;0.0001 compared with Nifurtimox. 
         FIGS. 6A through 6X  show structures of exemplary acid halide compounds useful in preparing imido-substituted 1,4-naphthoquinones. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The methods described herein advantageously utilize imido-substituted 1,4-naphthoquinones as a novel class of anti-trypanosomal agents to inhibit proliferation of  Trypanosoma cruzi . The methods can provide prophylaxis or treatment for a vertebrate against  Trypanosoma cruzi . The methods can provide treatment against the various stages of  Trypanosoma cruzi . Thus, administering an imido-substituted 1,4-naphthoquinone can provide prophylaxis or treatment to a patient against the proliferation of  Trypanosoma cruzi.    
     In particular, the method can provide treatment for a human against Chagas disease. 
     Administering an imido-substituted 1,4-naphthoquinone to a patient in a stage of infection with  Trypanosoma cruzi  can treat against metacyclic trypomastigotes. 
     Administering an imido-substituted 1,4-naphthoquinone to a patient in a stage of infection with  Trypanosoma cruzi  can treat against amastigotes. 
     Administering an imido-substituted 1,4-naphthoquinone to a patient in a stage of infection with  Trypanosoma cruzi  can treat against trypomastigotes that have burst from infected cells into the bloodstream. 
     Administering can be used to treat an acute phase of  Trypanosoma cruzi  infection where parasites (trypomastigotes) are detectable in the peripheral blood. 
     Administering for prophylaxis may help break the cycle of Chagas disease and reduce the patient&#39;s chances of becoming infected or infecting another through a vector. 
     Administering an imido-substituted 1,4-naphthoquinone to a patient can, in principle, lead to inhibiting proliferation of  Trypanosoma cruzi , such as epimastigotes, in the disease vector. Once a vector ingests blood from the patient whose blood plasma contains a imido-substituted 1,4-naphthoquinone, further development of  Trypanosoma cruzi  in the vector may be inhibited. 
     The imido-substituted 1,4-naphthoquinones include 3-imido 2-alkoxy 1,4-napthoquinones, 3-imido 2-aryloxy 1,4-naphthoquinones, and 3-imido 2-halo-1,4-naphthoquinones. 
     An aspect of the method is inhibiting proliferation of  Trypanosoma cruzi  in a patient in need of treatment by administering an imido-substituted 1,4-naphthoquinone, especially a 3-imido 2-alkoxy 1,4-naphthoquinone, to the patient. 
     An aspect of the method is inhibiting proliferation of  Trypanosoma cruzi  in a patient in need of treatment by administering an imido-substituted 1,4-naphthoquinone, especially a 3-imido 2-aryloxy 1,4-naphthoquinone, to the patient. 
     An aspect of the method is inhibiting proliferation of  Trypanosoma cruzi  in a patient in need of treatment by administering an imido-substituted 1,4-naphthoquinone, especially a 3-imido-substituted 2-halo 1,4-naphthoquinone, to the patient. 
     An aspect of the method is inhibiting proliferation of  Trypanosoma cruzi  in a patient in need of treatment by administering a cyclic-imido-substituted 1,4-naphthoquinone, to the patient. 
     An aspect of the method is inhibiting proliferation of  Trypanosoma cruzi  in a patient in need of treatment by administering an acyclic-imido-substituted 1,4-naphthoquinone, to the patient. 
     Administering includes sublingual administration, oral administration, and, in principle, intravenous administration. A pharmaceutical composition can contain the active pharmaceutical ingredient and may additionally comprise a pharmaceutically acceptable vehicle or adjuvant. A pharmaceutical composition can be in the form of a solid pharmaceutical dosage form (tablet, caplet, capsule, or deliverable from an osmotic pump as examples) or syrup. Remington, The Science and Practice of Pharmacy, provides general information regarding pharmaceutical dosage forms. 
     An anti-trypanosomal effective amount of the imido-substituted 1,4 naphthoquinone refers to an amount effective in inhibiting proliferation of  Trypanosoma cruzi  and includes an trypanocidal amount against  Trypanosoma cruzi.    
     A therapeutically effective amount means an amount of the imido 1,4-naphthoquinone that can provide a therapeutic benefit to a patient against  Trypanosoma cruzi.    
     Patient includes human. A patient in need of treatment includes a human patient in need of treatment against  Trypanosoma cruzi . Thus, methods of treating a mammal other than human (veterinary treatments) against  Trypanosoma cruzi  are also within the scope of our inventions. 
     A method for inhibiting proliferation of  Trypanosoma cruzi  with imido-substituted 1,4-naphthoquinones, such as imido-substituted 2-halo 1,4-napthoquinones, can exhibit greater antitrypanosomal efficacy against  Trypanosoma cruzi  than the presently clinically used nifurtimox. For example, compared to nifurtimox (IC 50 =10.67 μM), representative imido-naphthoquinone analogs (IMDNQ1-IMDNQ11, as examples) are significantly more potent against  Trypanosoma cruzi  with IC 50  values ranging from 0.7 μM to 6.1 μM (P&lt;0.05,  FIG. 3 ). Thus, in one of its aspects the method for inhibiting proliferation of  Trypanosoma cruzi  comprises administering an imido-substituted 1,4-napthoquinone, such as an imido-substituted 2-halo 1,4-napthoquinone, having an acceptable IC 50  value, preferably an IC 50  value equal to or better than nifurtimox. 
     A method for inhibiting proliferation of  Trypanosoma cruzi  with an imido-substituted 1,4-naphthoquinone, especially an imido-substituted 2-halo 1,4-napthoquinone, can exhibit greater selectivity against  Trypanosoma cruzi  than the presently clinically used nifurtimox. The representative compounds IMDNQ 1-11 described herein are significantly more selective in inhibiting the parasite&#39;s growth than nifurtimox. For example, representative imido-naphthoquinone analogs (IMDNQ1, IMDNQ2, IMDNQ3 and IMDNQ10, as examples) unexpectedly significantly exhibited in vitro selectivity indices of at least about 300% greater than nifurtimox. Thus, in another of its aspects the method for inhibiting proliferation of  Trypanosoma cruzi  comprises administering an imido-substituted 1,4-naphthoquinone, such as an imido-substituted 2-halo 1,4-napthoquinone, having an acceptable selectivity index, preferably a selectivity index better than nifurtimox. 
     A method for inhibiting proliferation of  Trypanosoma cruzi  with an imido-substituted 1,4-naphthoquinone, such as an imido-substituted 2-halo 1,4-napthoquinone, can exhibit good cytotoxicity characteristics. In vitro testing has demonstrated representative imido-naphthoquinone analogs were relatively non-cytotoxic to Balb/C 3T3 mouse fibroblast cell line with IC 50  values of well over 100 μM. For example, cytotoxicity study on Balb/C 3T3 mouse fibroblast cell line showed that IMDNQ1, IMDNQ2, and IMDNQ10 are far less cytotoxic than nifurtimox ( FIG. 4 ). Thus, in yet another of its aspects the method for inhibiting proliferation of  Trypanosoma cruzi  comprises administering an imido-substituted 1,4-naphthoquinone, such as an imido-substituted 2-halo 1,4-napthoquinone, having an acceptable cytotoxicity value, preferably a value better than nifurtimox. 
     In the synthesis of the imido-substituted 1,4-naphthoquiniones, compounds represented by the formula: 
                         
wherein X is hydrogen, halogen, alkoxy (cyclic or alicyclic), trifluoro methyl, benzyloxy or aryloxy are suitable starting materials that provide the 1,4-napthoquinone skeleton. For example, a 2-amino-3-halo-1,4-naphthoquinone is a suitable starting material for preparing imido-substituted 1,4, naphthoquiones having a 2-halo 1,4-naphthoquinone skeleton. The 2-amino-3-chloro-1,4-naphthoquinone is commercially available. It can also be facilely obtained from 2,3-dichloro-1,4-naphthoquinone and ammonia in a mixture of concentrated ammonium hydroxide and ethanol. A 2-amino-3-bromo-1,4-naphthoquinone starting material can be prepared by refluxing commercially available 2,3-dibromo-1,4-naphthoquinone with ammonia/ammonium hydroxide mixture in ethanol. A 2-amino-3-iodo-1,4-naphthoquinone starting material can be prepared as described in Perez et al., Synthesis of Iodinated Naphthoquinones Using Morpholine-Iodine Complex, Synthetic Communications, 34(18):3389-3397 (2004) (compound (4)), the complete disclosure of which is incorporated herein by reference. For imido-substituted 1,4, naphthoquiones having a 2-alkoxy 1,4-naphthoquinone skeleton, a 2-amino-3-alkoxy-1,4-naphthoquinone or 2-amino 3-aryloxy-1,4-naphthoquinone are representative classes of starting material. Synthesis includes Examples 12-13. It will be appreciated that X can also be halo-alkyl, such as trifluoro methyl, or halo-alkoxy, such as trifluoromethoxy.
 
     A starting material where X is alkoxy or aryloxy can be synthesized by adapting procedures in Examples 12 and 13. In Example 12, a 2,3-dichloro 1,4-naphthoquinone is used as a representative 2,3-dihalo 1,4-napthoquinone in the synthesis of 2,3-dimethoxy-1,4-naphthoquinone. In Example 12, NaOMe is used as a representative reactant. When X is another alkoxy, aryloxy or benzyloxy, to mention examples, another suitable starting material is selected instead of NaOMe. Examples 14-19 describe 2-imido-substituted 3-methoxy 1,4-naphthoquinone compounds and it will be appreciated that X is not limited to methoxy when X is alkoxy. 
     X can be alkoxy or aryloxy, and is represented by —OR 1  where R 1  represents alkyl or aryl. R 1  represents straight or branched chain alkyl or cycloalkyl. X can be methoxy, ethoxy, propyloxy, butoxy, pentoxy, and hexyloxy, as examples. When X is cycloalkoxy, R 1  can be cyclopentyl or cyclo hexyl as examples. X can be branched alkoxy when R 1  is a branched alkyl such as isopropyl, isobutyl, t-butyl, iso-hexyl or isoamyl, as examples. X can be aryloxy in the general formula. X can be benzyloxy. X can also be a substituted alkoxy group, such as trifluoro alkoxy (trifluoro methoxy is an example), or a halo-alkyl, such as trifluoro methyl as an example. 
     The above-mentioned starting materials are suitable for reacting with a selected acid halide(s) to obtain the imido-substituted 1,4-naphthoquinone compound. Exemplary acid halides are shown in  FIG. 6 . 
     In the following description, the imido substitutent may be shown as being ‘symmetrical’ for illustrative purposes and it should be understood that the imido substitutent can be mixed. For example, in a “mixed” imido compound useful in the present methods, the “R” groups in the imido substitutent can be the same or different, and each Y can be the same or different, in which case an “unsymmetrical” or mixed imido substituent is provided. 
     In the following description, various syntheses and compounds are shown in which X is chloro. It will be appreciated that X is not restricted to chloro. X can be a halogen other than chloro, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryloxy substituted aryloxy, benzyloxy, or substituted benzyloxy, to mention examples. 
     In an aspect of the method, Q is represented by: 
                         
wherein in Q each R is, independently, a substituted or unsubstituted hydrocarbon, provided that one R can, optionally, be hydrogen, and provided that, optionally, R can include at least one hetero atom.
 
     A sub-class of imido-substituted 1,4-naphthoquinones includes those represented by the formula: 
                         
In general, each R is independently a cyclic or acyclic group. Each R includes acyclic, such as straight chain alkyl —(CH 2 ) n CH 3 ) or branched alkyl, or cyclic, such as cyclo alkyl, or aryl. The expression open-chain imide derivative connotes the case where R is straight or branched alkyl. In another aspect, R can include unsaturation, e.g, an alkenyl. R can be cyclo alkyl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. By preference, cyclo alkyl is a C 5  to C 7  cyclo alkyl. The R groups may be bonded to each other to form an alkylene bridge, such as a divalent alkylene bridge, although it will be appreciated that the R groups can, together, comprise a polycyclic moiety.
 
     Depending on the R group, the imido compounds can adapt an anti-conformation. For instance, when R is acyclic, the acyclic imido groups can adapt anti-orientation or are capable of some form of staggered orientation, whereas when R is cyclic, the imido groups tend to adapt the syn orientation. 
     Compounds represented by the foregoing formula can be synthesized by adapting the following representative reaction scheme: 
                         
wherein RCOCl is selected to provide the desired R group, and purification of the reaction product yields the intended compound(s) within the general formula for the imido-substituted 1,4-naphthoquinone. Although X is chloro in the example, it will be appreciated that by selecting the appropriate starting material, X can be, for instance, another substituent.
 
     When R is a straight chain alkyl —(CH 2 ) n CH 3 , n is generally 0 to 10, preferably 2 to 5, including methyl, ethyl, propyl, butyl, pentyl, and hexyl, such as 
                         
as examples. Longer R groups are possible. Although X is chloro in the example, it will be appreciated that by selecting the appropriate starting material, X can be, for instance, another substituent.
 
     When R is branched the branching can be along the chain or can be terminal branching. For terminal branching, an R group can be represented by —(CH 2 ) n CH(CH 3 ) 2  as an example, where n is from 0 to 6, preferably from 1 to 4, such as 
                         
as an example. Although X is chloro in the example, it will be appreciated that by selecting the appropriate starting material, X can be, for instance, another substituent.
 
     Within the foregoing sub-classes of the above imido-substituted 1,4-naphthoquinones are those in which the open chain imido derivatives have halogen substitution. In one aspect, in a halo-substituted alkylene derivative according to formula (1), the R groups have terminal halo-substitution, such as IMDNQ11. Suitable compounds can be synthesized as shown in the following representative exemplary reaction scheme: 
                         
An exemplary chloroacyl chloride reagent is shown for illustrative purposes. Other suitable reagents, such as another acyl dihalide can be selected so that the alkyl group has different halo-substitution, such as a terminally bromo-substituted alkyl group (such as by using bromoacetyl bromide). Mono-halogenation is illustrated but it will be appreciated that other multi-halogenated derivatives are included within the scope of the present methods. Other suitable acyl halides include 2-bromopropionyl chloride, 2-chloropropionyl chloride, 2,3-dibromopropionyl chloride, 2,3-dichloropropionyl chloride, bromoacetyl chloride, 3-bromopropionyl chloride, 4-chloropropionyl chloride, 4-bromopropionyl chloride, 4-bromobutryl chloride, 4-chlorobutryl chloride, 2,4-dibromobutryl chloride, 5-chlorovaleroyl chloride, 5-bromovaleroyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, 6-chloroheanoyl chloride, as the like by as examples. Although X is chloro in the example, it will be appreciated that by selecting the appropriate starting material, X can be, for instance, another substituent.
 
     The R groups can also be bonded together to form an alkylene bridge —(CH2) n - in which case n is an integer of 1 to 3, preferably n is 2 or 3, so that Q represents a cyclic imido-substitutent (a nitrogen-containing ring having dione substitution) such as 
                         
to mention examples. The 3-cyclic-imido-substituted 2-halo 1,4-napthoquinone compounds can be synthesized by adapting the following representative reaction scheme:
 
                         
wherein ( ) designates —(CH 2 )— and n is an integer of 1 to 3. 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone is obtained when n is 1. As shown, the succinimidyl derivative (IMDNQ1) has a surprisingly beneficial combination of properties. 2-chloro-3-(N-glutaimidyl)-1,4-napthoquinone is obtained when n is 2. Although X is shown as chloro in the exemplary formulas and in the representative synthesis, it will be appreciated that by selecting the appropriate starting material, X can be, for instance, another substitutent.
 
     A further sub-class of 2-imido-substituted 1,4-naphthoquinones includes derivatives in which the 2-imido-substitution comprises a heterocyclic ring having dione substitution in which the additional hetero atom is preferably oxygen. For instance, the ring can be a five or six member ring with oxygen as an additional hetero atom. An exemplary derivative is a morpholine dione analog, such as IMDNQ4. Morpholine dione analogs can be synthesized as shown in the following exemplary reaction scheme: 
     
       
         
         
             
             
         
       
     
     X is not restricted to chloro. X can be another halogen, alkoxy, aryloxy or benzyloxy, to mention examples. When X is halogen, the microwave treatment can vary in duration and intensity, as seen from Berhe, S., et al., Microwave-assisted synthesis of imido-substituted 2-chloro-1,4-naphthoquinone derivatives and their cytotoxic activities on three human prostate cancer cell lines,  Lett. Drug Des. Discov.,  5, 485-488 (2008), but typically on lab scale synthesis the duration is on the order of minutes. 
     A sub-class of imido-substituted 1,4-naphthoquinones includes phthalimidyl derivatives. The compound IMDNQ2 is an example. 
     A sub-class of imido-substituted 1,4-naphthoquinones includes the cyclic imido-substituted derivatives, which include diarylimido-substituted derivatives. Diarylimido-substituted derivatives, which may be optionally substituted, include those represented by the formula: 
                         
wherein X is halogen, hydrogen, alkyl, substituted alkyl, alkoxy (cyclic or alicyclic), trifluoro methyl, substituted alkoxy, aryloxy, substituted aryloxy, benzyloxy, or substituted benzyloxy, as examples; each Y, independently, is hydrogen, halogen, alkoxy, alkyl, halo-alkyl, or halo-alkoxy and m is 0, 1, 2, 4, or 5 or 3. When an m=0, Y is hydrogen. X and Y are independent of each other.
 
     Exemplary diarylimido derivatives having Y halogen substitution include those when m is 1 represented by the formula: 
                         
Examples include those compounds denoted herein as IMDNQ5 through IMDNQ10.
 
     Mono-halogen-substituted diarylimido derivatives can be synthesized as shown in the following exemplary reaction scheme: 
                         
In the exemplary reaction scheme, X is halogen, hydrogen, alkyl, substituted alkyl, alkoxy (cyclic or alicyclic), trifluoro methyl, substituted alkoxy, aryloxy, substituted aryloxy, benzyloxy, or substituted benzyloxy, as examples; and each Y, independently, is H, halogen, alkyl or alkoxy. Co-produced is a mixed imido compound having R hydrogen and the other R is an aryl-imido substituent. X includes bromo, chloro, fluoro, and iodo. Bromo, chloro and fluoro may be preferred when X is halogen. Y may be at the meta, ortho and/or para position of the aryl ring. Meta-halogen substitution on each aryl ring in the imido moiety may be preferred when Y is halogen. Y includes bromo, chloro, fluoro, and iodo. More particularly, Y can be bromo, chloro or fluoro. When Y is a halogen, Y may preferably be chloro or fluoro, with chloro being preferred. IMDNQ10 is a member of this sub-class of imido-substituted 1,4-naphthoquinones. Y can be alkyl, including branched alkyl, or alkoxy as shown in the Examples. When Y is hydrogen, benzoyl chloride can be used.
 
     In general, for the compounds in which an arylimido group is (are) substituted with one or more Y substituent, a synthesis, such as a synthesis above or in the Examples, can be adapted and 
                         
may be used where m is 1, 2, 3, 4 or 5. Acyl halides include 3,5-bis(trifluoromethyl)benzoyl chloride, 2-bromobenzoyl chloride, 2-chlorobenzoyl chloride, 2-fluorobenzoyl chloride, 2-iodobenzoyl chloride, 2-methoxybenzoyl chloride, 2-ethoxybenzoyl chloride, 2-(trifluoromethoxy)benzoyl chloride, 2,4-difluorobenzoyl chloride, 2,6-difluorobenzoyl chloride, 2,4-dichlorobenzyol chloride, 2,6-dichlorobenzyol chloride, O-acetylsalicyloyl chloride, 2-methoxybenzoyl chloride, 2,6-dimethoxybenzoyl chloride, 2-(trifluoromethyl)benzoyl chloride, 3-bromobenzoyl chloride, 3-chlorobenzoyl chloride, 3-fluorobenzoyl chloride, 3-iodobenzoyl chloride, 3,4-bromobenzoyl chloride, 3,4-di-chlorobenzoyl chloride, 3-methoxybenzoyl chloride, 3,4-dimethoxybenzoyl chloride, 3,4-dimethylbenzoyl chloride, 3,4-difluorobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, 3-(trifluoro)benzoyl chloride, 3-(chloromethyl)benzoyl chloride, 4-bromobenzoyl chloride, 4-chlorobenzoyl chloride, 4-fluorobenzoyl chloride, 4-iodobenzoyl chloride, 4-methoxybenzoyl chloride, 4-ethoxybenzoyl chloride, 4-butoxybenzoyl chloride, 4-(hexyloxy)benzoyl chloride, 4-(heptyloxy)benzoyl chloride, 4-(trifluoromethyl)benzoyl chloride, 4-(tert-butyl)benzoyl chloride, 4-(trifluoromethoxy)benzoyl chloride, 4-ethoxybenzoyl chloride, 4-propylbenzoyl chloride, 4-butylbenzoyl chloride, 5-pentylbenzoyl chloride, 4-hexylbenzoyl chloride, 4-heptylbenzoyl chloride, 3,5-dichlorobenzoyl chloride, 2,3-dichlorobenzoyl chloride, 2,3-difluorobenzoyl chloride, 2,5-dichlorobenzoyl chloride, 2,5-difluorobenzoyl chloride, 3,5-dimethoxybenzoyl chloride, 2,4,6-trimethylbenzoyl chloride, 2,4,6,-trichlorobenzoyl chloride, 2,4,6,-trifluorobenzoyl chloride, 2,4,5-trifluorobenzoyl chloride, 2,3,4-trifluorobenzoyl chloride, 2,4-dimethoxybenzoyl chloride, 2,5-dimethoxybenzoyl chloride, 2-fluoro-3-(trifluoromethyl)benzoyl chloride, 2-fluoro-4-(trifluoromethyl)benzoyl chloride, 2-fluoro-5-(trifluoromethyl)benzoyl chloride, 3-fluoro-5-(trifluoromethyl)benzoyl chloride, 4-fluoro-2-(trifluoromethyl)benzoyl chloride, 4-fluoro-3-(trifluoromethyl)benzoyl chloride, 5-fluoro-2-(trifluoromethyl)benzoyl chloride, 2-fluoro-6-(trifluoromethyl)benzoyl chloride, 2,4-bis(trifluoromethyl)benzoyl chloride, 2,6-bis(trifluoromethyl)benzoyl chloride, 3-(trifluoromethoxy)benzoyl chloride, 2,3,4,5-fluorobenzoyl chloride, 2,4-dichloro-5-fluorobenzoyl chloride, 3-(dichloromethyl)benzoyl chloride, 2,3,5-trifluorobenzoyl chloride, 3,4,5-trifluorobenzoyl chloride, 2-chloro-6-fluorobenzoyl chloride, 3-chloro-4-fluorobenzoyl chloride, 4-chloro-2,5-difluorobenzoyl chloride, 5-fluoro-2-methylbenzoyl chloride, 3-fluoro-4-methylbenzoyl chloride, 2,6-difluoro-3-methylbenzoyl chloride, 3-chloro-2-6-(trifluoromethyl)benzoyl chloride, 5-chloro-2-(trifluoromethyl)benzoyl chloride, and 2-chloro-6-fluoro-3-methylbenzoyl chloride, 6-chloro-2fluoro-3-methylbenzoyl chloride, 2-chloro-5-fluorobenzoyl chloride, 4-fluoro-3-methyl chloride, 5-chloro-2-fluorobenzoyl chloride, 2-chloro-3,6-fluorobenzoyl chloride, 3-chloro-2,4-fluorobenzoyl chloride, 3-chloro-2-fluoro-5(trifluoromethyl)benzoyl chloride, 4-methoxy-3-(trifluoromethyl)benzoyl chloride, 4-methyl3-(trifluoromethyl)benzoyl chloride, 2-chloro-5-(trifluoromethyl)benzoyl chloride, 2,3-difluoro-4-methylbenzoyl chloride, 3,5-dichloro-4-methoxybenzoyl chloride, 2,4,5-trifluoro-3-methoxybenzoyl chloride, 2,3,4,6-tetrafluorobenzoyl chloride, 5-bromo-2,3,4-trimethylbenzoyl chloride, 4-bromo-2,6-difluorobenzoyl chloride, 2-fluoro-5-iodobenzoyl chloride, 2-fluoro-6-iodobenzoyl chloride, 4-bromo-2-fluorobenzoyl chloride, and 2-bromo-6-chlorobenzoyl chloride by way of example.
 
     Other imido-substituted 1,4-naphthoquinones with different Q moieties can be obtained with other acid halides, including those disclosed in  FIG. 6 , such as, for example, O-acetylmandelic chloride, phenoxyacetyl chloride, 4-chlorophenoxyacetyl chloride, phenylacetyl chloride, cinnamoyl chloride, hydrocinnamoyl chloride, 2-chloro-2,2diphenylacetyl chloride, alpha-chlorophenylacetyl chloride, 1-napthoyl chloride, 2-napthoyl chloride, 3,4(dimethoxy)benzoylacetyl chloride, 3-methoxyphenylacetyl chloride, 3-phenoxyproprionyl chloride, 2-(1-naphthyl)ethanoyl chloride, and 2-(3,5-difluorophenyl)ethanoyl chloride, 2-bromophenylacetyl chloride, 3-acetoxy-2-methylbenzoyl chloride, by way of alternative aryl groups. It will thus be appreciated that when an R group is aryl or aryloxy or cyclo alkyl (which includes polycyclic alkyl), there may be an intervening linking group (sometimes called a spacer group) between the aryl or aryloxy or cyclo alkyl group to the imido-functional group. An exemplary such linking group would be an alkylene group, as an example. 
     In each of the various aspects of the present inventions, a Y substituent can be substituted alkyl, such as halogen-substituted alkyl, including trifluoro methyl, or substituted alkoxy, such as halogen-substituted alkoxy, including trifluoromethoxy, to mention examples. 
     The imido-substituted 1,4-naphthoquinone compound can be symmetrical or mixed, such as shown in the Examples. An exemplary reaction scheme for preparing a sub-class of imido-substituted 1,4-naphthoquinones having mixed Y group(s) can be represented as follows: 
     
       
         
         
             
             
         
       
     
     It will be appreciated that an unsymmetrical imido substituent, e.g., “mixed” as to an aryl ring(s), the Y substituent(s), and/or in the position(s) of a Y substituent(s) may be achieved by selecting a desired member from the class of acid chlorides from the class of benzoyl chlorides for the first step, and a different member for the second step. It will also be appreciated that a “mixed” imido-substituted 1,4-naphthoquinone is obtained in the first step wherein, for instance, the imido-nitrogen is bonded to hydrogen (one of the R groups) and the other R is substituted aryl. Other “mixed” compounds are obtained by adapting an appropriate synthesis and using an appropriate acid halide, which includes the exemplary acid chlorides in  FIG. 6 . For instance, other “mixed” imido-substituted 1,4-naphthoquinione compounds include an R being other than hydrogen and the other R being a different substituted or unsubstituted hydrocarbon. 
     Another sub-class of imido-substituted 1,4-naphthoquinones have unsymmetrical substitution with alkyl and aryl in the imido moiety (Q group), and can be synthesized by adapting the following representative reaction scheme. An amino-naphthoquinone analog is first converted to the alkyl amido derivative which is subsequently reacted with an aryl acid chloride in the presence of an alkali hydride, such as sodium hydride, in anhydrous THF to furnish the imido-substituted 1.4-naphthoquinone derivative having Unsymmetrical substitution with alkyl and aryl in the imido moiety: 
     
       
         
         
             
             
         
       
     
     An R group can be alkyl, such as described elsewhere herein, which includes C 1 -C 6  alkyl. The other R group can be an aromatic group, such as an aryl group, such as described elsewhere herein. X can be a substitutent as described elsewhere herein, which includes, for example, hydrogen, halogen, akyl, alkoxy (such as lower alkoxy, methoxy or the like). 
     A 1,4-naphthoquinone starting material as shown in various reaction schemes herein is chloro substituted (X=chloro) only for illustrative purposes. It will be appreciated that the 1,4-naphthoquinone starting material can have a 2-substitution so that X in the general formula and in the various formulas can be other than chloro. 
     In the general formula for the imido-substituted 1,4-naphthoquinones, the selection of X as halogen may not drastically affect activity and selectivity towards  Trypanosoma cruzi  in compounds as seen from Examples 1-11. For example, it appears that when X is bromo instead of X is chloro on the 1,4-naphthoquinone ring may not drastically affect the activities and selectivity indices of the compounds according to Examples 1-11. This is shown by the activity and selectivity of compound IMDNQ6 versus IMDNQ8, and also compound IMDNQ5 versus IMDNQ9 (Table 1,  FIG. 2 ). A slight increase in antitrypanosomal activity against  Trypanosoma cruzi  may arise when the 3-chloro-group is substituted with a 3-bromo group as seen in compounds IMDNQ9 (IC 50 =4.07 μM) and IMDNQ5 (IC 50 =2.27 μM) and in compounds IMDNQ8 (IC 50 =2.67 μM) and IMDNQ6 (IC 50 =1.51 μM). When the 3-chloro-group is substituted with a 3-bromo group a slight increase in cytotoxicity on Balb/C 3T3 mouse fibroblast cell line is seen in compounds IMDNQ9 (IC 50 =21.83 μM) versus IMDNQ5 (IC 50 =12.83 μM); and compound IMDNQ8 (IC 50 =26.50 μM) versus IMDNQ6 (IC 50 =14.17 μM). 
     The ratio between the toxic dose and the therapeutic dose of a drug is a selectively index. It is used as a measure of the relative safety of the drug for a particular treatment. The selectivity index (SI) herein is the ratio of IC 50  for fibroblast cells/IC 50  for parasites and was calculated to compare the toxicity for mammalian cells and the activity against  T. cruzi . The presently prescribed nifurtimox has a selectivity index of 10.86. In vitro testing demonstrates that the present method can be significantly and unexpectedly more selective against  Trypanosoma cruzi . In one aspect of the method, the selectivity index is at least about 300% greater than the selectivity index for nifurtimox. For example, the IMDNQ1, IMDNQ2, IMDNQ3 and IMDNQ10 compounds exhibited selectivity indices of 60.25, 53.97, 31.83 and 275.3, respectively, in in vitro testing against  Trypanosoma cruzi . Further, in an aspect of the invention, representative compounds are relatively non-cytotoxic to Balb/C 3T3 mouse fibroblast cell line with IC 50  values of well over 100 μM. 
     The in vitro testing shows the present method should have in vivo efficacy in inhibiting proliferation of  Trypanosoma cruzi , and thus indicating a disease caused by the trypanosome can be treated by administering a compound according to the general formula. 
     Inhibitory concentration is typically evaluated at the 50% inhibitory concentration (IC 50 ). Inhibition of proliferation may be attained at a lower concentration in practice, but an IC 50  concentration may be desirable. 
     Representative imido-substituted 1,4-napthoquinone compounds, and their synthesis, are described in Bakare, O., et al, Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.  Bioorg. Med. Chem.,  11, 3165-3170 (2003); Berhe, S., et al., Microwave-assisted synthesis of imido-substituted 2-chloro-1,4-naphthoquinone derivatives and their cytotoxic activities on three human prostate cancer cell lines,  Lett. Drug Des. Discov.,  5, 485-488 (2008); Akinboye et al., Acta Cryst. E65, o24 (2009), and Akinboye et al., Acta Cryst. E65, o277 (2009), the complete disclosures of which are incorporated herein by reference. 
     A patient in need of treatment may be diagnosed by testing and by physical examination. Testing includes serological tests, immunoassays and PCR methods to diagnose for the presence of  Trypanosoma cruzi  infection in an individual. The testing is sometimes performed in tandem. Serological testing of blood samples from an individual can yield negative and positive sero results. A so-called sero-positive result is indicative of infection. So-called sero-negative results may or may not indicate the absence of infection. Sero-negative results may be useful in assessing possible cure after an individual has completed treatment for  Trypanosoma cruzi . However, due to the disease progression more than a single test with a single sero-negative result is preferred. PCR methods can be used in determining a patient in need of treatment, and such methods include those described in Galvão et al., PCR Assay for Monitoring  Trypanosoma cruzi  Parasitemia in Childhood after Specific Chemotherapy, J. Clin. Microbiology, 5066-70 (November 2003); Gomes et al., Chagas disease diagnosis: comparative analysis of parasitologic, molecular and serological methods, Am. J. Trp. Med. Hyg. 60:205-210 (1999). Since  Trypanosoma cruzi  releases antigenic material, including tubulin, in an infected mammalian host, monitoring for the presence of tubulin in urine may assist in early diagnosis of Chagas disease. Microscopic examination of fresh anticoagulated blood samples may also be useful. A combination of tests can be useful in monitoring the progress of treatment. 
     Diagnosis of a patient in the acute phase of Chagas disease who is in need of treatment may include physical examination. The acute stage may extend for a few weeks or months following initial infection. Many symptoms may not be unique to Chagas disease. However, a commonly recognized marker of the acute stage is Romaña&#39;s sign, which includes swelling of eyelids on the side of the patient&#39;s face nearest the bite or where feces from the vector were deposited or rubbed into the eye. 
     The methods described herein advantageously utilize an active ingredient selected from 3-imido-substituted 1,4-naphthoquinones, such as 3-imido-substituted 2-alkoxy 1,4-napthoquinones and 3-imido-substituted 2-halo-1,4-naphthoquinones, as a novel class of selective antitrypanosomal agents effective against  Trypanosoma cruzi.    
     The expression imido-substituted 1,4-naphthoquinone includes a compound according to the general formula. 
     Those skilled in the art will recognize that modifications and variations may be made without departing from the true spirit and scope of the invention. The invention, therefore, is not to be limited to the embodiments described and illustrated in the following non-limiting examples but is to be determined from the appended claims. 
     EXAMPLES 
     In the Examples, reactions were carried out using laboratory grade materials and solvents. Melting points were determined in open capillary tubes on a Mel-Temp melting point apparatus and are uncorrected. The IR spectra were recorded on a Perkin Elmer PE 100 spectrometer with an Attenuated Total Reflectance (ATR) window. The  1 H- and  13 C-NMR spectra were obtained on a Bruker Avance 400 MHz spectrometer in deuterated chloroform (CDCl 3 ). Chemical shifts are in δ units (ppm) with TMS (0.00 ppm) or CHCl 3  (7.26 ppm), as internal standard for  1 H-NMR, and CDCl 3  (77.00 ppm) for  13 C-NMR. Electrospray ionization mass spectrometry was recorded on a Thermo LTQ Orbitrap XL mass spectrometer and compounds dissolved in acetonitrile with 0.1% formic acid. The known intermediates were prepared according to procedures that are reported in the literature. 2-Amino-3-bromo-1,4-naphthoquinone was prepared by refluxing commercially available 2,3-dibromo-1,4-naphthoquinone with ammonia/ammonium hydroxide mixture in ethanol. 
     Examples 1-3 
     The succinimidyl (IMDNQ1), phthalimidyl (IMDNQ2) and dibutytryl (IMDNQ3) derivatives were synthesized from 2-amino-3-chloro-1,4-naphthoquinone and the appropriate acid chloride in accordance with Bakare, O., et al, Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.  Bioorg. Med. Chem.,  11, 3165-3170 (2003); and Berhe, S., et al., Microwave-assisted synthesis of imido-substituted 2-chloro-1,4-naphthoquinone derivatives and their cytotoxic activities on three human prostate cancer cell lines,  Lett. Drug Des. Discov.,  5, 485-488 (2008). 
     Example 4 
     The morpholine dione analog (IMDNQ4) was synthesized by microwave irradiation of a mixture of 2-amino-3-chloro-1,4-naphthoquinone and diglycolyl chloride as depicted in scheme 1 in Berhe, S., et al., Microwave-assisted synthesis of imido-substituted 2-chloro-1,4-naphthoquinone derivatives and their cytotoxic activities on three human prostate cancer cell lines,  Lett. Drug Des. Discov.,  5, 485-488 (2008). 
     Examples 5-10 
     A general procedure for the synthesis of arylimido-substituted 1,4-naphthoquinones represented by the formula 
                         
wherein X is halogen and Y is halogen is exemplified with respect to IMDNQ5-IMDNQ10, respectively in Examples 5 through 10. 2-Amino-3-chloro-1,4-naphthoquinone (1.47 mmol) or the 3-bromo-analog was dissolved in THF (15 mL). NaH (3.08 mmol) was added and the mixture stirred at room temperature for 15 min. Appropriate acid chloride (3.08 mmol) was added drop wise, and the resulting mixture stirred at room temperature for 24 hours. The THF was then evaporated under vacuum and ice-cooled water added to the residual mixture. The resulting aqueous mixture was extracted with CH 2 Cl 2  (2×30 mL) and the combined organic phase washed with water (3×15 mL), saturated NaCl solution (15 mL) and dried over anhydrous MgSO 4 . The crude product was purified by triturating in hot ethanol followed by recrystallization in ethyl acetate and/or column chromatography on silica gel.
 
     N-(3-Bromo-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-fluoro-N-(4-fluorobenzoyl)-benzamide (IMDNQ 5): Yellow solid (66%). Mp: 170-172° C. IR (cm −1 ) 1719.23, 1670.56, 1596.69, 1505.57.  1 H NMR (CDCl 3 ) 7.05 (t, 4H, J=12.0 Hz), 7.77-7.88 (m, 6H), 8.08-8.15 (m, 1H), 8.21-8.27 (m, 1H).  13 C NMR (CDCl 3 ) 115.57, 115.79, 127.4, 127.71, 130.18, 130.30, 130.33, 130.85, 131.35, 131.44, 134.46, 134.50, 138.52, 146.90, 165.03, 169.91, 176.96, 177.97. ESI MS m/z 517.9785 ([M+Na] +  calcd 517.9815). 
     N-(3-Bromo-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-chloro-N-(2-chlorobenzoyl)-benzamide (IMDNQ 6): Yellow crystal (34%). Mp 232-234° C. IR (cm −1 ) 1728.78, 1688.76, 1671.10, 1588.22, 1468.70.  1 H NMR (CDCl 3 ) 7.13 (□□d, 2H, J=7.9 Hz), 7.21 (□□dd, 2H, J=1.6, 7.9 Hz), 7.28 (dd, 2H, J=1.3, 7.5 Hz), 7.78-7.86 (m, 2H), 7.94 (d, 2H, 5.2 Hz), 8.15-8.21 (m, 1H), 8.22-8.28 (m, 2H).  13 C NMR (CDCl 3 ) 126.65, 127.66, 128.08, 129.63, 130.49, 130.81, 131.23, 132.25, 134.68, 134.80, 140.78, 145.81, 167.57, 177.26, 177.81. ESI MS m/z 549.9240 ([M+Na] +  calcd 549.9224). 
     4-Chloro-N-(4-chlorobenzoyl)-N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-benzamide (IMDNQ 7): Yellow solid. (27%). Mp 212-213° C. IR (cm −1 ) 1737.38, 1714.75, 1696.91, 1673.62, 1589.20, 1571.10.  1 H NMR (CDCl 3 ) 7.33-7.36 (m, 4H), 7.68-7.72 (m, 4H), 7.79-7.85 (m, 2H), 8 09-8.11 (m, 1H), 8.20-8.22 (m, 1H).  13 C NMR (CDCl 3 ) 127.72, 127.80, 129.18, 130.34, 130.50, 131.32, 132.52, 134.92, 134.95, 139.67, 142.46, 143.87, 170.40, 177.05, 178.59. ESI MS m/z 505.975 ([M+Na] +  calcd 505.973). 
     2-Chloro-N-(2-chlorobenzoyl)-N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-benzamide (IMDNQ 8): Yellow solid. (49%). Mp 217-218° C. IR (cm −1 ) 1720.19, 1681.22, 1618.00, 1588.02.  1 H NMR (CDCl 3 ) 7.10-7.16 (m, 2H), 7.21-7.31 (m, 4H), 7.79-7.89 (m, 4H), 8.17-8.20 (m, 1H), 8.20-8.26 (m, 1H).  13 C NMR (CDCl 3 ) 126.76, 126.93, 127.60, 127.80, 129.69, 130.54, 130.85, 131.37, 132.36, 132.52, 132.56, 132.75, 134.14, 134.75, 134.91, 142.65, 144.43, 177.13, 178.22. ESI MS m/z 505.9741 ([M+Na] +  calcd 505.9730). 
     N-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-fluoro-N-(4-fluorobenzoyl)-benzamide (IMDNQ 9): Yellow solid. (56%). Mp 284-286° C. IR (cm −1 ) 3074.94, 1719.61, 1689.97, 1672.75, 1591.10.  1 H NMR (CDCl 3 ) 7.00-7.06 (m, 1H), 7.75-7.85 (m, 1H), 8.10-8.12 (m, 6H), 8.20-8.22 (m, 4H).  13 C NMR (CDCl 3 ) 115.97, 116.19, 116.41, 126.65, 126.96, 127.67, 127.77, 130.53, 130.57, 130.58, 131.35, 131.62, 131.71, 132.75, 134.88, 142.42, 144.13, 164.14, 166.68, 170.33, 177.13, 178.63. ESI MS m/z 474.034 ([M+Na] +  calcd 474.032). 
     3-Chloro-N-(3-chlorobenzoyl)-N-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-benzamide (IMDNQ 10): Yellow solid. (31%). Mp 258-260° C. IR (cm −1 ) 3075.36, 1713.64, 1698.11, 1672.50, 1591.48, 1571.31.  1 H NMR (CDCl 3 ) 7.27-7.31 (t, J=7.85 Hz, 2H), 7.42-7.45 (ddd, J=1.03, 2.09, 8.07 Hz, 2H), 7.60-7.63 (td, J=1.07, 7.68 Hz, 2H), 7.70-7.71 (t, J=1.82, 2H), 7.80-7.85 (m, 2H), 8.11-8.14 (m, 1H), 8.21-8.23 (m, 1H).  13 C NMR (CDCl 3 ) 127.02, 127.93, 128.03, 129.34, 130.21, 130.75, 131.55, 133.29, 135.14, 135.21, 136.06, 143.00, 143.84, 170.20, 177.25, 178.66. ESI MS m/z 505.9741 ([M+Na] +  calcd 505.9730). 
     Example 11 
     The bis-(chloroacetyl)-derivative (IMDNQ11) was prepared by heating 2-amino-3-chloro-1,4-naphthoquinone in excess 2-chloroacetyl chloride at high temperatures as shown in scheme 1 in Bakare, O., et al, Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.  Bioorg. Med. Chem.,  11, 3165-3170 (2003) (2003); and Berhe, S., et al., Microwave-assisted synthesis of imido-substituted 2-chloro-1,4-naphthoquinone derivatives and their cytotoxic activities on three human prostate cancer cell lines,  Lett. Drug Des. Discov.,  5, 485-488 (2008). 
     Example 12 
     Synthesis of 2,3-dimethoxy-1,4-naphthoquinone is shown below: 
     
       
         
         
             
             
         
       
     
     A mixture of 2,3-dichloro1,4-naphthoquinone (4.960 g, 0.022 mol) and NaOMe (3.582 g, 0.066 mol) was refluxed at 80° C. for 5 hrs in anhydrous MeOH (100 mL). A second amount of NaOMe (2.365 g, 0.044 mol) was added and the mixture was refluxed for 1 hr. The reaction mixture was concentrated, filtered and the residue was repeatedly washed with ice-cold water to obtain a yellow solid. (3.463 g, 72.7%). 
     For a different alkoxy or aryloxy substitution on the 2,3 positions of the 1,4-naphthoquinone, an appropriate alkali alkoxide can be selected. In turn, this will lead to X being a different alkoxy or aryloxy subtitutent than reported in Examples 13-19. 
     Example 13 
     Synthesis of 2-amino-3-methoxy-1,4-naphthoquinone is shown below: 
     
       
         
         
             
             
         
       
     
     NH 3  was continuously bubbled through a mixture of 1 (305 mg, 1.40 mmol) and (NH 4 ) 2 CO 3  (439 mg, 4.57 mmol) in anhydrous MeOH (70 mL). The reaction mixture was refluxed at 50° C. for 2 hrs. Another (NH 4 ) 2 CO 3  (418 mg, 4.35 mmol) was added to the cooled solution and the mixture was again refluxed for 1 hr. Argon was bubbled through the cooled solution for 10 mins. The solution was evaporated to dryness in vacuo, ice-cold water (20 mL) was added and precipitate was filtered to obtain a red solid. (226 mg). 
     Examples 14 to 19 
     Synthesis of 2-imido-3-methoxy 1,4-napthoquniones (3)-(8), respectively Examples 14 to 19, is shown below: 
     
       
         
         
             
             
         
       
     
     A solution of 2,3-dimethoxy-1,4-naphthoquinone (200 mg, 0.984 mmol) in anhydrous THF (20 mL) was stirred at room temperature. NaH (54 mg, 2.26 mmol) was added and the resulting mixture was stirred at room temperature for 30 mins. The respective acid chlorides (2.3 mole ratio) were added and the reaction was stirred at room temperature for 24 hrs. The reaction mixture was concentrated under vacuum and ice-water mixture (20 mL) was added. The aqueous layer was extracted with dichloromethane (4×10 mL) and the combined organic layer washed with water (3×15 mL), saturated sodium chloride solution and dried over anhydrous MgSO 4 . The solvent was removed in vacuo and the residue triturated in ethanol (2 mL) and filtered. Further purification was done by recrystallization in EtOH or EtOAc and column chromatography on silica gel with 100% DCM. 
     Variants of compound 8 are possible, and instead of a t-butyl substituent, other reactants represented the formula: 
                         
can be used wherein Y represents a substituent other than t-butyl. For example, the substituent Y can be alkyl. The alkyl can be lower alkyl. Exemplary alkyls include C 1 -C 5  alkyl, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, iso-amyl, as examples.
 
     Examples 20 to 26 
     2-amino-3-chloro-1,4-naphthoquinone or 2-amino-3-bromo-1,4-naphthoquinone was dissolved in THF (15 mL). NaH was added and the mixture was stirred at room temperature for 15 mins. The appropriate acid chloride was added, drop wise, and the mixture was stirred for 24 hours. (Mole ratio of Substrate:NaH:Acid Chloride (1:2.3:2.3)) THF was evaporated under vacuum and the mixture was washed with ice-water (10 g ice and 10 mL water). The ice-water mixture was extracted with CH 2 Cl 2  (30 mL, 20 mL consecutively) and the combined organic phase washed with water (3×20 mL), saturated NaCl solution (3×20 mL), then dried over anhydrous MgSO 4 . The crude was purified via triturating in hot ethanol, recrystallization in ethyl acetate and/or via column chromatography. 
     2-Dibenzoylamino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtained a yellow solid. (61.3%). Mp 294-297° C. IR (cm −1 ) 3328.00, 1698.21, 1672.91, 1618.25, 1590.78, 1573.45.  1 H NMR (DMSO-d 6 ) 7.35-7.39 (t, J=7.5 Hz, 4H), 7.46-7.50 (tt, J=1.2, 7.5 Hz, 2H), 7.65-7.67 (m, 4H), 7.83-7.90 (m, 2H), 7.94-7.96 (dd, J=1.7, 7.4 Hz, 1H), 8.04-8.06 (dd, J=1.3, 8.2 Hz, 1H).  13 C NMR (CDCl 3 ) 127.61, 127.64, 128.59, 129.11, 130.69, 131.37, 132.90, 134.45, 134.68, 134.73, 142.32, 144.33, 171.59, 177.29, 178.59. 
     2-Dibenzoylamino-3-bromo-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtained a yellow solid. (53.1%). Mp 234-238° C. IR (cm −1 ) 3087.51, 1693.21, 1671.24, 1588.29, 1570.41.  1 H NMR (CDCl 3 ) 7.30-7.34 (t, J=7.40 Hz, 4H), 7.41-7.45 (tt, J=1.21, 7.49 Hz, 2H), 7.77-7.81 (m, 6H), 8.10-8.12 (m, 1H), 8.20-8.22 (m, 1H).  13 C NMR (CDCl 3 ) 127.72, 127.96, 128.58, 129.22, 130.65, 131.22, 132.89, 134.58, 134.68, 134.70, 138.75, 147.47, 171.55, 177.48, 178.30. 
     2-bis-(3-chlorobenzoyl)amino-3-bromo-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtained a yellow solid (25.9%) Mp 204-206° C. IR (cm −1 ) 3074.53, 1698.10, 1671.33, 1589.07, 1566.99.  1 H NMR (CDCl 3 ) 7.28 (t, 2H, J=7.90), 7.38-7.46 (m, 2H), 7.60-7.66 (m, 2H), 770-7.5 (t, 2H, J=1.8 Hz), 7.78-7.85 (m, 2H), 8.09-8.15 (m, 1H), 8.19-8.26 (m, 2H).  13 C NMR (CDCl 3 ) 127, 128.09, 128.40, 129.49, 130.25, 130.78, 131.49, 133.32, 135.15, 135.18, 135.24, 136.25, 139.56, 147.05, 170.21, 177.50, 178.43. 
     2-bis-(4-chlorobenzoyl)amino-3-bromo-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain a yellow solid. (34.3%). Mp 266-269° C. IR (cm −1 ) 3096.94, 1703.69, 1661.23, 1586.85.  1 H NMR (CDCl 3 ) 7.33-7.36 (dd, J=2.16, 8.47 Hz, 4H), 7.70-7.73 (dd, J=2.37, 8.53 Hz, 4H), 7.79-7.82 (m, 2H), 8.08-8.11 (m, 1H), 8.20-8.22(m, 1H).  13 C NMR (CDCl 3 ) 127.80, 128.09, 129.13, 130.41, 130.46, 131.17, 132.66, 134.84, 134.90, 138.94, 139.61, 146.98, 170.32, 177.21, 178.28. 
     2-bis-(4-tert-butylbenzoyl)amino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain yellow solid. (27.9%). Mp 257-260° C. IR (cm −1 ) 2965.11, 2901.26, 2868.04, 1701.21, 1673.45, 1603.90, 1592.73, 1572.41.  1 H NMR (CDCl 3 ) 8.22-8.18 (m, 1H), 8.13-809 (m, 1H), 7.81-7.78 (m, 2H), 7.69-7.67 (dd, 4H, J=8.57, 1.86 Hz), 7.32-7.30 (dd, 4H, J=8.53, 1.81 Hz), 1.25 (s, 18H).  13 C NMR (CDCl 3 ) 30.96, 35.06, 125.51, 127.60, 127.65, 129.14, 130.82, 131.45, 131.71, 134.62, 134.68, 142.09, 144.58, 156.57, 171.66, 177.51, 178.67. 
     2-bis-(4-methoxybenzoyl)amino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain a yellow solid. (47.9%). Mp 283-287° C. IR (cm −1 ) 3019.56, 1698.7, 1668.81, 1599.28, 1574.26, 1508.65.  1 H NMR (CDCl 3 ) 3.81 (s, 6H), 6.80-6.84 (td, J=2.86, 8.95 Hz, 4H), 7.73-7.82 (m, 6H), 8.09-8.11 (m, 1H), 8.19-8.21 (m, 1H).  13 C NMR (CDCl 3 ) 55.48, 113.98, 114.21, 126.76, 127.57, 127.64, 130.38, 130.79, 131.41, 131.48, 134.61, 134.66, 141.69, 144.95, 163.34, 171.03, 177.48, 178.77. 
     2-bis-(3,4,5-trimethoxybenzoyl)amino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain orange crystals (51.6%). Mp 171-172° C. IR (cm −1 ) 3015.37, 2939.81, 2838.40, 1704.21, 1675.26, 1586.02, 1122.75.  1 H NMR (CDCl 3 ) 3.81 (s, 12H), 3.84 (s, 6H), 7.02 (s, 4H), 7.81-7.84 (m, 2H), 8.12-8.14 (m, 1H), 8.22-8.24 (m, 1H).  13 C NMR (CDCl 3 ) 56.27, 56.35, 60.93, 127.62, 127.77, 129.31, 130.69, 131.39, 134.86, 142.06, 142.27, 144.45, 153.01, 171.08, 177.27, 178.84. 
     Example 27 
     An unsymmetrical analog was also synthesized either by first forming the amide derivative via heating 2-amino-3-chloro-1,4-naphthoquinone in p-chlorobenzoyl chloride, or reacting 2-amino-3-chloro-1,4-naphthoquinone, sodium hydride and p-chlorobenzoyl chloride for 5 min at room temperature. Subsequent reaction of the isolated pure amide with NaH followed by addition of benzoyl chloride furnished the unsymmetrical analog in 43% yield. 
     A syntheses is described for 2-(N-Benzoyl-N-(4-chlorobenzoyl))-amino-3-chloro-1,4-naphthoquinone: 
                         
2-Amino-3-chloro-1,4-naphthoquinone (302 mg, 1.45 mmol) was dissolved in THF (15 mL). NaH (104 mg, 4.33 mmol) was added to the solution and the mixture was stirred at room temperature for 30 mins. p-Chlorobenzoyl chloride (0.27 mL, 375 mg, 2.14 mmol) was added and the mixture was stirred for 5 mins. THF was removed under vacuum and the mixture was washed with ice-water (10 g ice and 10 mL water). The ice-water mixture was washed with CH 2 Cl 2  (30 mL) and the organic layer was washed with water (3×15 mL) and saturated NaCl (3×15 mL) then dried over Na 2 SO 4 . The crude was recrystallized in 100% EtOH (20 mL) then triturated in 100% ethyl acetate to obtain the 2(p-chlorobenzylamido)-3-chloro-1,4-naphthoquinone. The 2-(p-chlorobenzylamido)-1,4-naphthoquinone (101 mg, 0.292 mmol) was dissolved in THF (15 mL). NaH (14 mg, 0.583 mmol) was added followed by the addition of benzoyl chloride (84.84 mg, 0.604 mmol). The resulting mixture was stirred at room temperature for 26 hours. THF was removed under vacuum and the mixture was washed with ice-water (10 g ice and 10 mL water). The ice-water mixture was washed with CH 2 Cl 2  (30 mL) and the organic layer was washed with water (3×15 mL) and saturated NaCl (3×15 mL) then dried over Na 2 SO 4 . The crude was purified by column chromatography with silica gel in 100% CH 2 Cl 2  to obtain a yellow solid. (57 mg, 43.2%). Mp 200-210° C. IR (cm −1 ) 3093.23, 1705.87, 1693.46, 1673.22, 1587.07, 1571.70, 1521.92.  1 H NMR (CDCl 3 ) 7.30-7.33 (td, J=1.89, 6.72 Hz, 2H), 7.33-7.37 (t, J=7.98 Hz, 2H), 7.45-7.47 (tt, 7.46 Hz, 1H), 7.69-7.72 (td, J=1.96, 8.60 Hz, 2H), 7.73-7.76 (td, J=1.41, 8.49 Hz, 2H), 7.79-7.82 (m, 1H), 8.10-8.13 (m, 1H), 8.20-8.22 (m, 1H).  13 C NMR (CDCl 3 ) 127.68, 127.73, 128.76, 129.00, 129.06, 130.63, 131.37, 133.21, 134.82, 124.84, 171.34, 177.19, 178.60.
 
     Other unsymmetrical imides such as depicted in the structure below can be obtained in similar manner. In these compounds the aryl groups on the imido moiety are different (“unsymmetrical” or “mixed”) as follows: 
                         
wherein each Y, independent of the other, can be halogen, alkyl, alkoxy, trifluoromethyl. Although the structure illustrated includes one Y in the para position, it should be understood that each Y can be the same or different, and in the same or different positions on their respective aryl rings. Positions in this context means ortho-, meta- or para-positions on each aryl aryl ring in the imido moiety. Thus, each Y can be the same and in the same positions; each Y can be the same but in different positions; each Y can be different but in the same positions; or each Y can be different and in different positions.
 
     Still further, in another aspect, each aryl ring can have multiple substituents, e.g., (Y) m  where m is an integer from 0 to 5, and the various Y substituents can differ based on the acid chlorides from the class of benzoyl chlorides used in the synthesis. It will be appreciated that the acid chloride is not restricted to being selected from the class of benzoyl chlorides when an R group is other than aryl or substituted aryl. 
     In Example 27 and in its accompanying illustrative formulas, X is chloro but it will be appreciated that X is not restricted to chloro. 
     Example 28 
     2-amino-3-chloro-1,4-naphthoquinone was dissolved in THF (15 mL). NaH was added and the mixture was stirred at room temperature for 15 mins. The 4-methoxybenzoyl chloride was added, drop wise, and the mixture was stirred for 24 hours. (Mole ratio of Substrate:NaH:Acid Chloride (1:2.3:2.3)) THF was evaporated under vacuum and the mixture was washed with ice-water (10 g ice and 10 mL water). The ice-water mixture was extracted with CH 2 Cl 2  (30 mL, 20 mL consecutively) and the combined organic phase washed with water (3×20 mL), saturated NaCl solution (3×20 mL), then dried over anhydrous MgSO 4 . The crude was purified via triturating in hot ethanol, recrystallization in ethyl acetate and/or via column chromatography. 
     2-bis-(4-methoxybenzoyl)amino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain a yellow solid. (47.9%). Mp 283-287° C. IR (cm −1 ) 3019.56, 1698.7, 1668.81, 1599.28, 1574.26, 1508.65.  1 H NMR (CDCl 3 ) 3.81 (s, 6H), 6.80-6.84 (td, J=2.86, 8.95 Hz, 4H), 7.73-7.82 (m, 6H), 8.09-8.11 (m, 1H), 8.19-8.21 (m, 1H).  13 C NMR (CDCl 3 ) 55.48, 113.98, 114.21, 126.76, 127.57, 127.64, 130.38, 130.79, 131.41, 131.48, 134.61, 134.66, 141.69, 144.95, 163.34, 171.03, 177.48, 178.77. 
     Example 29 
     2-amino-3-chloro-1,4-naphthoquinone was dissolved in THF (15 mL). NaH was added and the mixture was stirred at room temperature for 15 mins. The 3,4,5-(trimethoxy)benzoyl chloride was added, drop wise, and the mixture was stirred for 24 hours. (Mole ratio of Substrate:NaH:Acid Chloride (1:2.3:2.3)) THF was evaporated under vacuum and the mixture was washed with ice-water (10 g ice and 10 mL water). The ice-water mixture was extracted with CH 2 Cl 2  (30 mL, 20 mL consecutively) and the combined organic phase washed with water (3×20 mL), saturated NaCl solution (3×20 mL), then dried over anhydrous MgSO 4 . The crude was purified via triturating in hot ethanol, recrystallization in ethyl acetate and/or via column chromatography. 
     2-bis-(3,4,5-trimethoxybenzoyl)amino-3-chloro-1,4-naphthoquinone 
     
       
         
         
             
             
         
       
     
     Obtain orange crystals (51.6%). Mp 171-172° C. IR (cm −1 ) 3015.37, 2939.81, 2838.40, 1704.21, 1675.26, 1586.02, 1122.75.  1 H NMR (CDCl 3 ) 3.81 (s, 12H), 3.84 (s, 6H), 7.02 (s, 4H), 7.81-7.84 (m, 2H), 8.12-8.14 (m, 1H), 8.22-8.24 (m, 1H).  13 C NMR (CDCl 3 ) 56.27, 56.35, 60.93, 127.62, 127.77, 129.31, 130.69, 131.39, 134.86, 142.06, 142.27, 144.45, 153.01, 171.08, 177.27, 178.84. 
     Comparison 
     Nifurtimox is one of two commercial drugs for Chagas disease and was used as a reference drag. 
     In Vitro Testing 
     The antitrypanosomal activity against  Trypanosoma cruzi  was assayed.  Trypanosoma cruzi  epimastigotes (Tulahuen CL98 strain) were cultured in liver infusion trypose (LIT) medium supplemented with 10% fetal bovine serum (FBS) at 28° C., with an inoculum of 1×10 5  cells/ml. Different concentrations ranging from 0.39-100 μM of the compounds were added. All assays were carried out in triplicate. Parasites were counted after 48 h using hemocytometers and the concentration that inhibits the parasite&#39;s proliferation by 50% (IC 50 ) was calculated for each compound. 
     A cytotoxicity assay was performed with representive analogs IMNDQ1 through IMNDQ11. The cytotoxic effects of the 2-imido-substituted 1,4-naphthoquinones on Balb/C 3T3 mouse fibroblasts (clone A31) were quantitatively assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. MTT is a yellow tetrazolium salt that is reduced to purple formazan crystals by metabolically active cells. Cells (2.2×10 4  cells/well) were seeded in 96-well plate in Improved Minimum Essential Medium (IMEM). Serial dilutions (0.39-100 μM) of the compounds were added. After 48 h incubation at 37° C. in the presence 5% CO 2 , the medium was aspirated and the cells washed twice to remove traces of chemical compounds. IMEM without phenol containing 10% (v/v) of 3 mg/ml MTT were added to each well. The plates were incubated for 4 h at 37° C. followed by aspiration. The plates were dried for 1 h in a 37° C. incubator. 100 μl of 0.04 N HCl in isopropanol were added to each well and incubated at room temperature (27° C.) in the dark for 2 h to dissolve the formazan crystals. The absorbance was measured spectrophotometrically at 570 nm in a plate reader. The concentration that reduces cell viability by 50% (IC 50 ) was calculated for each compound. The toxicity for mammalian cells and the activity against  T. cruzi  were compared by calculating the selectivity index (SI), the ratio of IC 50  for fibroblast cells/IC 50  for parasites. 
     The data were subjected to statistical analysis. All experiments were done in triplicate, the means and standard errors (S.E.) were determined. Data were analyzed by one way ANOVA and Tukey&#39;s multiple comparison test using GraphPad PRISM software version 5.00. P&lt;0.05 was considered significant. 
     The antitrypanocidal activity against  Trypanosoma cruzi , cytotoxicity, and selectivity indices of the eleven imido-substituted 1,4-naphthoquinones and nifurtimox are summarized in Table 1. Each value represents the mean±S.E. of three experiments 
     Testing established 2-imido-substituted 1,4-napthoquinones in Examples 1-11 were more potent antitrypanosomal agents against  T. Cruzi  than nifurtimox. For example, in vitro testing the cyclic and acyclic 2-imido-substituted 3-halo 1,4-naphthoquinone derivatives revealed potent antitrypanosomal properties against  Trypanosoma cruzi  thus demonstrating efficacy in inhibiting proliferation of  Trypanosoma cruzi.    
     Certain of the compounds unexpectedly additionally exhibited relatively low cytotoxicity against mammalian cells. Cyclic imido-substituted 1,4-naphthoquinones may have relatively low cytotoxicity. For instance, the IMDNQ1 analog surprisingly was relatively non-cytoxic to the Balb/C 3T3 mouse fibroblast cell line with IC 50  values of well over 100 μM. The phthalimidyl-substituted 1,4-napthoquinones may have relatively low cytoxicity. For instance, the IMDNQ2 analog surprisingly was relatively non-cytoxic to the Balb/C 3T3 mouse fibroblast cell line with IC 50  values of well over 100 μM. Meta-halogenated aryl imido-substituted 1,4-naphthoquinones may have relatively low cytotoxicity. For instance, the IMDNQ10 analog surprisingly was relatively non-cytoxic to the Balb/C 3T3 mouse fibroblast cell line with IC 50  values of well over 100 μM. 
     Representative compounds additionally can exhibit an in vitro selectivity index significantly greater than nifurtimox (selectivity index of 10.86), making them significantly more selective in inhibiting the growth and proliferation of  Trypanosoma cruzi . Comparison of the antitryponosomal activities with cytotoxicity on Balb/C 3T3 mouse fibroblast cell line shows certain of these compounds show far better selectivity than nifurtimox as seen from the selectivity indices values (Table 1 and  FIG. 5 ), such as seen for a cyclic imido-substituted 1,4-naphthoquinone, a phthalimidyl-substituted 1,4-napthoquinone, an open-chain imido-substituted 1,4-napthoquinione and a meta-halogenated aryl imido-substituted 1,4-naphthoquinone. For instance, the selectivity indices for IMDNQ1, IMDNQ2, IMDNQ3 and IMDNQ10 were 60.25, 53.97, 31.83 and 275.3, respectively. While the dibutyrylamino derivative (IMDNQ3) is the most potent with an IC 50  value of 0.7 μM against  Trypanosoma cruzi , and is more cytotoxic to the mouse fibroblast cells (IC 50 =21.67 μM), its potent activity in vitro gives it a good selectivity index of 31.83, which is approximately 300% better than Nifurtimox. A cyclic imido-substituted 1,4-naphthoquinone can show potent antitrypanosomal activity while being relatively non-toxic, as seen from IMDNQ1 (potency IC 50 =2.77 μM for IMDNQ1 and non-toxicity to mouse fibroblast cell, IC 50  value of 165.9 μM for IMDNQ1). A phthalimidyl-substituted 1,4-naphthoquinone can show potent antitrypanosomal activity while being relatively non-toxic, as seen from IMDNQ2 (potency IC 50 =4.89 μM for IMDNQ2 and non-toxicity to mouse fibroblast cell, IC 50  value of 253.7 μM for IMDNQ2). 
     A diaryl imido analog in which each aryl ring has meta-halo substitution in the diarylimido moiety may be preferred. IMDNQ10 is a diaryl imido analog with a meta-chloro-substituent on each of the aryl groups and thus significantly differs structurally from the cyclic imido-substituted derivative IMDNQ1, the phthalimidyl-substituted derivative IMDNQ2 and the open chain imido-substituted 1,4-naphthoquinone derivative IMDNQ3. IMDNQ10 exhibited an unexpected combination of useful properties. The IMDNQ10 analog exhibited potent antitrypanosomal activity with an IC 50  value of 2.23 μM against  Trypanosoma cruzi , was non-cytotoxic to the mouse fibroblast cell (IC 50  value of 610.9 μM), and yielded a calculated selectivity index of 275.3, which was unexpectedly about 25 times better than nitfurtimox. 
                                     TABLE 1                       Antitrypanocidal   Cytotoxicity   Selectivity Index           activity IC 50  (μM)   IC 50  (μM)   (Cytotoxicity/Activity)                                                    Nifurtimox   10.67 ± 1.01    114.0 ± 1.03   10.86 ± 093        IMDNQ1   2.77 ± 0.15   165.9 ± 1.24   60.25 ± 2.79       IMDNQ2   4.83 ± 0.60   253.7 ± 1.87   53.97 ± 5.95       IMDNQ3   0.70 ± 0.10   21.67 ± 1.45   31.83 ± 3.17       IMDNQ4   4.93 ± 0.64   35.50 ± 1.76    7.43 ± 0.97       IMDNQ5   2.27 ± 0.15   12.83 ± 0.73    5.70 ± 0.06       IMDNQ6   1.51 ± 0.01   14.17 ± 1.42    9.43 ± 0.94       IMDNQ7   1.27 ± 0.15   17.83 ± 2.21   14.23 ± 1.62       IMDNQ8   2.67 ± 0.33   26.50 ± 1.61   10.17 ± 0.97       IMDNQ9   4.07 ± 0.23   21.83 ± 1.88    5.43 ± 0.69       IMDNQ10   2.23 ± 0.15    610.9 ± 10.27    275.3 ± 13.73       IMDNQ11   6.10 ± 0.38   19.67 ± 3.71    3.20 ± 0.44                    
Tublin Assembly Assay
 
     In principle, a mode of action (mechanism of action against  Trypanosoma cruzi ) of the imido-substituted 1,4-naphthoquinone compounds is by tublin polymerization inhibition. It may not be the exclusive mode of action. A higher tubulin polymerization inhibition IC 50  value compared to antitrypanosomal activity IC50 value against  Trypanosoma cruzi  suggests other mechanisms in addition to tubulin inhibition may be responsible for the differences. 
     Tubulin assembly assays were conducted to assess tubulin polymerization inhibition. The assays were conducted in a 96-well microplate. Assembly reactions were conducted in a buffer containing 0.1 M PIPES (pH 6.9), 1 mM EGTA, 5 mM Mgcl, 1.2 mg/ml purified  Trypanosoma cruzi  tublin, at concentrations (0.6-40 μM) of the imido-substituted 1,4-naphthoquinone (IMDNQ 1-IMDNQ 11). Components of the reaction mixtures were added to the microplate and assembly was initiated by the addition of 1 mM GTP. The assembly reactions were assayed photometrically by measuring the absorbance at 405 nm using a microplate reader at 30° C. 
     The results of the tubulin assembly assay for IMDNQ 1, 2, 3, 10 and 11 are presented in Table 2. 
     
       
         
           
               
               
             
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                 Tubulin 
               
               
                   
                 polymerization 
               
               
                   
                 Inhibition IC 50 (μM) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Nifurtimox 
                   
               
               
                   
                 IMDNQ1 
                 6 
               
               
                   
                 IMDNQ2 
                 12 
               
               
                   
                 IMDNQ3 
                 3.2 
               
               
                   
                 IMDNQ10 
                 8 
               
               
                   
                 IMDNQ11 
                 &gt;40 
               
               
                   
                   
               
            
           
         
       
     
     The eleven representative imido-substituted 1,4-napthoquinones IMDNQ1 through IMDNQ11 can inhibit tubulin polymerization. 
     In general, a lower value for Tubulin polymerization Inhibition IC 50 (μM) is indicative of greater inhibition of tublin polymerization. The data appear consistent with the antitrypanocidal activity against  Trypanosoma cruzi  reported in Table 1. 
     REFERENCES 
     The complete disclosure of each of the following references is incorporated herein by reference:
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     While the invention has been described in terms of preferred embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims.