Synthesis of Bis-substituted Amidinobenzothiazoles as Potential Anti-HIV Agents (2001)

In the multistep syntheses of the title compounds we obtained some new cyano-substituted heterocycles (1a, 1b, 2a, and 2b) as intermediates.Starting from dinitriles (2a and 2b) as well as from two formerly prepared dinitriles, substituted bisamidines (3a, 3b, 5a, 5b, 7a, and 7b) and amidino dihydrochlorides (4a, 4b, 6a, 6b, 8a, 8b, 9a, and 9b) have been synthesized.2][3] The amidine group at the termini of the molecules seemed to contribute significantly to the dications and the DNA 4,5 complex stability.A number of aromatic bisamidines have been shown to bind in minor groove on DNA at AT-rich sites and to be affective against many opportunistic organisms. 6,7veral hypotheses have been proposed to explain the mode of action of these compounds.The important factors in minor groove binding are hydrogen-bonding, electrostatic interactions, van der Waals interactions, and the radius of curvature of the observed molecule. 8 connection with our studies on new bisamidines, 9 the preparation of the new bisamidine compounds containing benzothiazole and furan or thiophene nuclei (3a, 3b-9a, and 9b) was achieved by using the multistep synthesis according to Scheme 1 and Scheme 2. As the key precursors of the bisamidino compounds the corresponding dinitriles were used.According to the Scheme 1 the starting compound was p-aminobenzoic acid, which was diazotized and the obtained diazonium salt was used for arylation of 2-furancarbonitrile and 2-thiophenecarbonitrile.The arylation of 2-furancarbonitrile takes place with better yield (24.7 %) than arylation of 2thiophenecarbonitrile (12.4 %).Such difference between reactivities of furan and thiophene compounds was observed earlier. 10,11The new compounds 5-(4-carboxyphenyl)-2-furancarbonitrile (1a) and 5-(4carboxyphenyl)-2-thiophenecarbonitrile (1b) were condensed with 4-amino-3-mercaptobenzonitrile 11 yielding 2-[4-(6-cyanobenzothiazol-2-yl)phenyl]-5-furancarbonitrile (2a) and 2-[4-(6-cyanobenzothiazol-2-yl)phenyl]-5-thiophenecarbonitrile (2b), the key precursors for bisamidino compounds.The classical Pinner method 12,13 was used to transform the cyano into amidino group.The imidate esters hydrochlorides generated as intermediate products were immediately converted, with the appropriate amine or bisamine, to the desired bisamidines (3a, 3b, 5a, and 5b).The conversion of the free bases into appropriate bishydrochlorides (4a, 6a, and 6b) was achieved by treatment with gaseous hydrochloric acid, while the salt (4b) was obtained using concentrated hydrochloric acid.The synthetic steps for obtaining dicationic compounds (8a, 8b, 9a and 9b) are outlined in Scheme 2. This bisamidines as hydrochloric salts were synthesized from appropriate bisnitriles 11 using also the classical Pinner-type approach for conversion of the cyano function into the amidino one.The attempt to employ fusion of the 2-(4-cyanophenyl)-5-(6-cyanobenzothiazol-2-yl)furan with the hydrochloride salt of the ethylenediamine 14 gave very low yield of the 2-[4-(imidazolin-2-yl)phenyl]-5-[6-(imidazolin-2yl)benzothiazol-2-yl]furan (7a), while the 2-(4-cyanophenyl)-5-(6-cyanobenzothiazol-2-yl)thiophene didn't react at all.From 2-(4-cyanophenyl)-5-(6-cyanobenzothiazol-2-yl)furan and 2-(4-cyanophenyl)-5-(6-cyanobenzothiazol-2-yl)thiophene 11 , using Pinner method, free bases 2-[4-(imidazolin-2-yl)phenyl]-5-[6-(imidazolin-2-yl)benzothiazol-2-yl]furan (7a) and 2-[4-(imidazolin-2-yl)phenyl]-5-[6-(imidazolin-2yl)benzothiazol-2-yl]thiophene (7b) are obtained.Treating the solution of free base (7a) in 2methoxyethanol with gaseous hydrochloric acid, the corresponding bishydrochloride (8a) was obtained.From the free base (7b) the bishydrochloride (8b) was obtained with concentrated hydrochloric acid.Bishydrochlorides (9a, and 9b) were obtained from corresponding imidate esters hydrochloride in the reaction with isopropylamine.Inspite of the excess of isopropylamine the hydrochloric salts (9a, and 9b) were isolated from reaction mixture.It seems that the reason for it is the difference in the basicity of the isopropylamine and corresponding amidine.The structure of the new compounds was confirmed by elemental analysis, IR, 1 H NMR and in some cases 13 C NMR spectra.Due to a very low solubility of most compounds in appropiate solvent it was impossible to record some of the 13 C NMR spectra.The examination of biological activity of the compounds (4a, 4b, 6a, 6b, 8a, 8b, 9a, and 9b) are in course.