# A Review on Platensimycin: A Selective FabF Inhibitor

Authors: Manik Das; Partha Sakha Ghosh; Kuntal Manna
Journal: International Journal of Medicinal Chemistry
 (2016)

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## Abstract

Emerging resistance to existing antibiotics is an inevitable matter of concern in the treatment of bacterial infection. Naturally occurring unique class of natural antibiotic, platensimycin, a secondary metabolite fromStreptomyces platensis, is an excellent breakthrough in recent antibiotic research with unique structural pattern and significant antibacterial activity. β-Ketoacyl-(acyl-carrier-protein (ACP)) synthase (FabF) whose Gram-positive bacteria need to biosynthesize cell membranes is the target of inhibition of platensimycin. So, isolation, retrosynthetic analysis, synthesis of platensimycin, and analogues of platensimycin synthesized till today are the objectives of this review which may be helpful to further investigate and to reveal untouched area on this molecule and to obtain a potential antibacterial lead with enhanced significant antibacterial activity.


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## Body

## 1. Introduction

The majority of the “illness” lies in the fact that when immune system is defeated, it is in war with pathogens. Development starting from ethnic to modern synthetic approaches in drug discovery mainly provides better weapons to combat and survive against pathogens. In contrast to medical development, pathogens also have acquired protection called “resistance.” More or less all classes of antibiotics are resistant to bacteria; hence a novel process to the discovery of antibiotic with new mechanism of action is essential [1, 2]. Microbial and chemical groups at Merck in the year 2006 have found three novel chemical classes, using antisense technology, from their older microbial screening library [3]. Two compounds, platensimycin and platencin, were found as potent inhibitors of fatty acid biosynthesis. Platensimycin selectively inhibits fatty acid acyl carrier protein synthase II (FabF). Platensin is a balanced dual inhibitor of both FabF and FabH (fatty acid acyl carrier protein synthase III) [4]. The third compound lucensimycin A was found to inhibit ribosomal protein synthesis. FabF is one of the enzymes which catalyze the biosynthesis of fatty acids in bacteria. It makes FabF an essential target for inhibiting bacterial growth in resistant bacteria. Previously two classes of inhibitor, cerulenin [5] and thiolactomycin [6–8], were reported, but inhibitory activity was poor (IC50 ranges within 1.3–13 μg/mL) with poor antimicrobial activity (Streptococcus aurous, MIC—64 μg/mL) [9]. On the other hand, platensimycin had shown selective FabF inhibitory activity onS. aurous andE. coli with IC50 value of 48 nM and 68 nM [3]. The ability of this class of compounds to bind and inhibit FabF enzyme has given a new class of antibiotics. Among them platensimycin and platencin are most promising and need further investigation. There might be an argument that if fatty acid synthesis is an attractive target for antibacterials, why there have not many drugs or natural inhibitors targeting this pathway been isolated? One of the reasons may be that theStreptomyces and relatedActinomyces, the organisms that have delivered most of the existing antibiotics, are constrained in their ability to produce fatty acid synthesis inhibitors by the adjacent relationship between the synthetic pathways of fatty acids and polyketides. These pathways share many chemical, mechanistic, and structural features, and, thus, fatty acid synthesis inhibitors recurrently inhibit polyketide synthesis (e.g., cerulenin is a powerful inhibitor of polyketide synthesis). An organism producing a fatty acid synthesis inhibitor must retain not only a resistant form of the fatty acid synthetic enzyme but also a resistant form of the antibiotic-producing polyketide synthase. Furthermore, if several polyketides are needed for survival of the organism in its ecological niche, then resistant forms of each of these pathways would be prerequisite. Such precincts seem likely to severely narrow the opportunities to evolve fatty acid synthesis inhibitors and may account for the scarceness of such antibiotics. However, variousStreptomyces produce analogues of thiolactomycin, which has not been reported to block polyketide synthesis, thus demonstrating that development of fatty acid synthesis inhibitors by this organism is conceivable [10].


## 2. Isolation of Platensimycin

Platensimycin was isolated by Wang et al. in 2006 at concentration of 2 to 4 mg/L from fermentation broth ofS. platensis (MA7327 and MA7331) using SephadexLH20 liquid chromatography medium by reversed-phase HPLC chromatography [3]. In a subsequent study, three-step isolation was modified by Singh et al. and they established two-step method eliminating the SephadexLH20 step [11]. It was also isolated fromStreptomyces platensis (MA7327), recovered from soil samples collected in Eastern Cape, South Africa [12].


## 3. Structure of Platensimycin

Platensimycin (Figure1) consists of a benzoic acid moiety substituted at ortho and para with hydroxyl group and in meta position is conjugated with a unique pentacyclic ketolide by an amide linkage [13]. The structure was established by combination of DQ-COSY and TOCSY correlations (2D NMR), UV, and IR spectroscopy and confirmed by X-ray crystallography [14].Figure 1
Structure of platensimycin.


## 4. Synthesis of Platensimycin

Platensimycin consists of an aromatic acid conjugated with aliphatic moiety by an amide linkage. The effective synthetic strategy is to synthesize the aromatic and aliphatic parts separately and then combine them by amide linkage. Many synthetic methods are available for the synthesis of those two building blocks.


### 4.1. First Total Synthesis of Platensimycin

Nicolaou et al. in the year 2006 first reported the total synthesis of platensimycin [26].


#### 4.1.1. Retrosynthetic Analysis of Platensimycin

Using retrosynthetic analysis (Scheme1) they separated the aromatic amine2 and the carboxylic acid3 by disconnection of amide linkage. The carboxylic acid was further simplified to a simplified enyne in successive three retrosynthetic steps. This resulted in two target molecules to synthesize the tetracyclic carboxylic acid and the aromatic amine from simplified starting material.Scheme 1
Retrosynthetic analysis of platensimycin.


#### 4.1.2. Synthesis of Tetracyclic Cage

The simplified enone generated from 3-ethoxycyclohex-2-enone which was used as a starting material (Scheme2). Allylic bromide9 [27] (LDA, 92%) and propargyl bromide (LDA, 97%) were used as reagents of choice to generate the bis-alkylated enone10 from8. Reduction followed by acidic hydrolysis and reintroduction of the TBS ether produced enone11 from enone10 (yield 84%). Spirocycle12 was generated by cycloisomerization of11 [28, 29]. Oxidation of12 produced bis-enone13 [30] which upon acid hydrolysis gave desired aldehyde6. Secondary alcohol14 was prepared by addition of samarium(II) iodide in a dilute solution of aldehyde6 HFIP in THF/HMPA followed by NH4Cl solution. Esterification of14 with TEA resulted in the formation of cage-like structure4 which on treatment with KHMDS and MeI followed by KHMDS and allyl iodide produced olefin16. Vinyl pinacol boronate and16 reacted in presence of the Grubbs second generation catalyst to produce vinyl boronate19 which on reacting with trimethylamine N-oxide gave20. Following Pinnick protocol20 was converted to desired carboxylic acid3.Scheme 2
Synthesis of tetracyclic cage. (i) LDA, (ii) LDA, (iii) DIBAL-H, then HCl, (iv) TBSCL, (v) [CpRu(MeCN)3]PF6, (vi) LiHMDS, TMSCl, (vii) Pd(OAc)2, (viii) HCl aq., (ix) Sml2, HFlP, (x) TFA, (xi) KHMDS, MeI, (xii) KHMDS, (xiii) Me3NO, and (xiv) NaClO2.


#### 4.1.3. Synthesis of Aromatic Amine

The synthesis of the aromatic amine2 was started from 2-nitroresorcinol21 by protecting with MOM ether, followed by catalytic hydrogenation,24 was formed (Scheme 3). Again protecting the amino group and followed by silylation, lithiation, and quenching with methyl cyanoformate24 was carboxylated and by unprotecting amino group using thermolysis, desired aniline2 was synthesized.Scheme 3
Synthesis of aromatic amine and platensimycin. (i) NaH, MOMCL, (ii) H2, Pd/C cat., (iii) Boc2O, (iv) nBuLi, and (v) 205°C.


#### 4.1.4. Synthesis of Platensimycin Core

The total synthesis of platensimycin was completed by the coupling of carboxylic acid3 with aniline2 which was achieved by treatment with HATU followed by hydrolysis with LiOH (Scheme 3).


### 4.2. Another Approach for Synthesizing Tetracyclic Cage by Nicolaou et al.

After successfully reporting the first total synthetic strategy of platensimycin, Nicolaou et al. [31] report a new synthetic strategy that starts from the readily available and inexpensive (R)-(−)-carvone to the tetracyclic enone2.


#### 4.2.1. Retrosynthetic Strategy of Tetracyclic Enone

A five-step retrosynthetic disconnection approach was shown to generate commercially available (R)-(−)-carvone31 from26 (Scheme 4).Scheme 4
Retrosynthetic analysis of platensimycin.


#### 4.2.2. Synthesis of Tetracyclic Enone

(R)-(−)-carvone31 on reaction with Grignard’s reagent32 using CeCl3 [32] and by oxidizing with PCC gave the corresponding enone33. Enone33 was treated with Hg(OAc)2 and later on with NaBH4 to generate approximately 1 : 1 mixture of exo- and endotertiary alcohol, which on dehydration using Martin’s sulfurane reagent produced exocyclic alkene35 which was treated with TMSCl and HMDS and followed by an electrophilic quench with PhSeCl and subsequent oxidative elimination (H2O2) to give enone36. Enone37 was treated with SmI2 for radical cyclization, and by adding mentioned reagent (Scheme 5) in subsequent 8 steps of tetracyclic cage26 was synthesized.Scheme 5
Synthesis of tetracyclic cage. (i) CeCl3, (ii) PCC, and (iii) Hg(OAc)2, then NaBH4, (iv) Martin’s sulfurane, (v) TMSCl, Lil HMDS, and then PhSeCl, (vi) H2O2, Py, (vii) AcOH, MW, (ix) Sml2, (x) DIAD, ArCO2H, PPh3, Ar=p-NO2C6H4, (xi) KOH, (xii) L-selectride (H3O+), (xiii) PCC, (xiv) TMSCl, Lil HMDS, and (xv) IBX or Pd(OAc)2.


### 4.3. Matsuo’s Synthesis of Tetracyclic Cage

#### 4.3.1. Retrosynthetic Analysis of Tetracyclic Cage

Matsuo et al. [33] offered another route for stereocontrolled synthesis of tetracyclic enone4. They expected that the transannular radical cyclization of44 will produce enone4. A four-step retrosynthetic analysis is producing enone47 and siloxydiene48. The key feature of plan is that all stereocenters in4 are controlled by the stereochemistry presented in47 (Scheme 6).Scheme 6
Retrosynthetic analysis of platensimycin.


#### 4.3.2. Synthesis of Tetracyclic Cage

O-TBS andO-benzoyl-protected enones47a and47b were prepared from 1,3-cyclohexadiene49 through allylboration, selective oxidation, and utilizing the Dess-Martin oxidation, with the yield of (97%). Diels-Alder reaction in between47a and47b and siloxydienes produced two stereogenic mixtures46a,46b and46c,46d. The mixture of two inseparable diastereomers (46b and46d) was employed in the next step. Following Noyori’s procedure [26] followed by hydrolysis of the benzoyl group and separation of diastereomers53 was given which upon catalytic oxidation using palladium(II) chloride and copper(II) acetate produced54a and54b in 10 : 1 ratio. Vinyl triflate55 was produced from54 and reduced to56 which was transformed to57. Transannular radical cyclization of monothioacetal57 gave desired4 (Scheme 7).Scheme 7
Synthesis of tetracyclic cage. (i) allylBBr2, then HOOH NaOH, (ii) t-BuOOH, VO(sese)2, (iii) Dess-Martin, periodinane, (iv) Silica gel, (v) TBSCl imidazole/BzCl, Py, (vi) PMSOTf (cat.) (TMSOCH2)2, (vii) aqNaOH separation of diastereomers, (viii) PdCl2 Cu(OAc)2 DMA, O2, (ix) KHMDS, (x) Pd(OAc)2(PPh3)2 HCOOH, Bu3N, (xi) PhSH, (xii) Bu3SnH AIBN toluene, reflux, and (xiii) 1N aq HCL.


### 4.4. Kaliappan’s Synthesis of Tetracyclic Cage

#### 4.4.1. Retrosynthetic Analysis of Tetracyclic Cage

Kaliappan and Ravikumar [34] showed seven-step retrosynthetic analysis using a 5-exo-trig radical cyclization strategy [35, 36] to generate Wieland-Miescher ketone64 (Scheme 8).Scheme 8
Retrosynthetic analysis of platensimycin.


#### 4.4.2. Synthesis of Tetracyclic Cage

Synthesis was started from Wieland-Miescher ketone64 [37], a chiral starting material, which on two-step reduction yielded an inseparable diastereomeric mixture of alcohols66 [38]. Corresponding aldehyde68 containing oxoethylene group was synthesized from alcohols66 by Mandai protocol [39]. Using Ohira-Bestmann reagent74 [40, 41], enyne69 was formed which was treated with AIBN intert-BuOH and PPTS to initiate the radical cyclization resulting formation of tetracyclic cage72. L-Selectride, THF, and TFA/CH2Cl2 were consecutively added with72 to produce the desired enone58 (Scheme 9).Scheme 9
Synthesis of tetracyclic cage. (i) NaBH4, ETOH, 00C, 2 h, (ii) TBSCI, Im, DMF, r.t., 2 h, (iii) DIBAL-H CH2Cl2, (iv) NaH, cat. KHTHF, r.t., 12 h, (v) Decalin, 180°C, 5d, (vi) K2CO3, MeOH, (vii) TBAF, THF, reflux, (viii) IBX PhF/DMSO 65°C, (ix) TBTH, AIBN t-BuOH, reflux, 12 h, (x) PPTS, CH2Cl2, r.t., 6 h, (xi) L-selectride, THF, −78°C to r.t., and (xii) TFA/CH2Cl2, 0°C, 2 h.


### 4.5. Corey’s Synthetic Strategy

#### 4.5.1. Synthesis of Tetracyclic Cage

Lalic and Corey [42] used methoxy α-naphthol75 as the starting material which upon reaction with bistrifluoroacetoxyiodobenzene and ethylene glycol in acetonitrile at 0°C produced 6-methoxy-1,4-naphthoquinone-4-ethylene ketal76. An enantioselective conjugation of 2-propenyl group to ketal76 using 2-propenyl trifluoroborate, Rh-BINAP, BF4 catalyst, and triethylamine [43–45] produced the chiral ketone77.cis-tetralin78 was generated from77 by reduction of the carbonyl group, hydroxyl protection, and reductive cleavage of the ethylene ketal subunit. Demethylation of78 produced phenol79 which was converted to tricyclic80 by etherification followed by reaction with Br2 in CH2Cl2. Heating with tetra-n-butylammonium fluoride in THF at 130°C, tetracyclic cage81 was produced which on catalytic diastereoselective hydrogenation produced tetrahydro derivative82. The saturated ketone82 was transformed into the corresponding α,β-enone4 using the 2-iodoxybenzoic acid sequence (Scheme 10) [46, 47].Scheme 10
Synthesis of tetracyclic cage. (i) PhI(O2CCF3)2, OHCH2CH2OH, MeCN, 0°C, 2 h. (ii) (S)-BINAP, [Rh(cod)2]BF4, C7H8, H2O, Et3N, CH3-CH(BF3K)=CH2. (iii) (1) NaBH4, MeOH, (2) MEMCl, i-Pr2NEt, CH2Cl2, (3) TsOH, Me2CO, 0°C, (4)i-Bu2AIH, CH2Cl2, 0°C, (5) Et3SiH, (CF3CO)2O, CH2Cl2, −20°C. (iv) PhSH, Cs2CO3, DMF, D 170°. (v) (1)i-Pr3SiCl, imidazole, CH2Cl2, 23°C, 12 h and (2) Br2, CH2Cl2, −78°C. (vi)n-Bu4NF, THF, D 130°C. (vii) [Rh(cod)2]BF4, (R,R)-DIOP, H2 600 psi, CH2Cl2, 16 h. (viii) (1) TMSOTf, Me3N, CH2Cl2 and (2) IBX, MPO, DMSO.


### 4.6. Yamamoto’s Synthetic Strategy

#### 4.6.1. Retrosynthetic Analysis of Tetracyclic Core

Li et al. [47] used an intramolecular Robinson annulation approach [48] in the retrosynthetic analysis presented in (Scheme 11). The bicyclic compound84 to give the tetracyclic core structure4 is key step in the retrosynthesis by Robinson annulation event.Scheme 11
Retrosynthetic analysis of platensimycin.


#### 4.6.2. Synthesis of Tetracyclic Core

The bicyclic ketone84 can be synthesized from known lactone85 which could be generated from ketone86, through a Baeyer-Villiger oxidation/rearrangement sequence [49, 50] and by utilizing Bronsted acid assisted chiral Lewis acid catalyzed Diels-Alder reaction, and subsequent N-nitrosoaldol addition/decarboxylation, ketone86 could be easily prepared from inexpensive, commercially available starting materials (Scheme 12).Scheme 12
Synthesis of tetracyclic cage. (i) CH2Cl2, −78°C, 14 h, (ii) LDA, THF, −78°C, then PhNO, −78°C, 2 h, and then LiOH dioxane/H2O 30°C, 20 h, (iii) H2O2/NaOH Et2O/H2O 0°C to r.t., 45 min, (iv) CuBr·Me2S, CH2CMgBr THF/Me2S, −40°C to r.t., (v) 4.5 mol% HNTf2, CH2ClCH2Cl, 70°C, 45 min, (vi) DIBAL-H, toluene, −78°C, 30 min, then Et2AlCN BF3·OET2, 20 min, (vii) DIBAL-H/n-BuLi, −78°C to 0°C, 25 min, (viii) NaH, CH3COCH2P(O)(OET)2, THF, 0°C, 20 min, (ix) 2.02 eq NaIO4, 3.5 mol% RuCl3 6 : 1 CH3CN/H2O r.t., 3 h, and (x) 1 eq pyrrolidine-2-carboxylic acid, DMF, r.t., 5 days, then 2N NaOH(aq) 0°C to r.t., 40 min.Diels-Alder reaction between methyl acrylate87 and methyl cyclopentadiene88 produced adduct89. The reaction was catalyzed by BLA and carbon-based Bronsted acid [51]. Ketone90 was obtained in one pot reaction from adduct89 using lithium enolate and lithium hydroxide in dioxane. Baeyer-Villiger oxidation in basic condition [52] of ketone90 gave lactone85. Vinyl lactone91 was obtained from lactone85 using cuprate reagent [53] and trifluoromethanesulfonimide [54, 55]. DIBAL-H reduction followed by cyanation produced cyanide92a,92b, which was reduced and subjected to Wadsworth-Emmons conditions [56] to give enone93; ruthenium-catalyzed oxidation [57] produced aldehyde84. Using L-proline as the chiral control element followed by sodium hydroxide treatment gave the desired tetracyclic core structure4.


## 4.1. First Total Synthesis of Platensimycin

Nicolaou et al. in the year 2006 first reported the total synthesis of platensimycin [26].


### 4.1.1. Retrosynthetic Analysis of Platensimycin

Using retrosynthetic analysis (Scheme1) they separated the aromatic amine2 and the carboxylic acid3 by disconnection of amide linkage. The carboxylic acid was further simplified to a simplified enyne in successive three retrosynthetic steps. This resulted in two target molecules to synthesize the tetracyclic carboxylic acid and the aromatic amine from simplified starting material.Scheme 1
Retrosynthetic analysis of platensimycin.


### 4.1.2. Synthesis of Tetracyclic Cage

The simplified enone generated from 3-ethoxycyclohex-2-enone which was used as a starting material (Scheme2). Allylic bromide9 [27] (LDA, 92%) and propargyl bromide (LDA, 97%) were used as reagents of choice to generate the bis-alkylated enone10 from8. Reduction followed by acidic hydrolysis and reintroduction of the TBS ether produced enone11 from enone10 (yield 84%). Spirocycle12 was generated by cycloisomerization of11 [28, 29]. Oxidation of12 produced bis-enone13 [30] which upon acid hydrolysis gave desired aldehyde6. Secondary alcohol14 was prepared by addition of samarium(II) iodide in a dilute solution of aldehyde6 HFIP in THF/HMPA followed by NH4Cl solution. Esterification of14 with TEA resulted in the formation of cage-like structure4 which on treatment with KHMDS and MeI followed by KHMDS and allyl iodide produced olefin16. Vinyl pinacol boronate and16 reacted in presence of the Grubbs second generation catalyst to produce vinyl boronate19 which on reacting with trimethylamine N-oxide gave20. Following Pinnick protocol20 was converted to desired carboxylic acid3.Scheme 2
Synthesis of tetracyclic cage. (i) LDA, (ii) LDA, (iii) DIBAL-H, then HCl, (iv) TBSCL, (v) [CpRu(MeCN)3]PF6, (vi) LiHMDS, TMSCl, (vii) Pd(OAc)2, (viii) HCl aq., (ix) Sml2, HFlP, (x) TFA, (xi) KHMDS, MeI, (xii) KHMDS, (xiii) Me3NO, and (xiv) NaClO2.


### 4.1.3. Synthesis of Aromatic Amine

The synthesis of the aromatic amine2 was started from 2-nitroresorcinol21 by protecting with MOM ether, followed by catalytic hydrogenation,24 was formed (Scheme 3). Again protecting the amino group and followed by silylation, lithiation, and quenching with methyl cyanoformate24 was carboxylated and by unprotecting amino group using thermolysis, desired aniline2 was synthesized.Scheme 3
Synthesis of aromatic amine and platensimycin. (i) NaH, MOMCL, (ii) H2, Pd/C cat., (iii) Boc2O, (iv) nBuLi, and (v) 205°C.


### 4.1.4. Synthesis of Platensimycin Core

The total synthesis of platensimycin was completed by the coupling of carboxylic acid3 with aniline2 which was achieved by treatment with HATU followed by hydrolysis with LiOH (Scheme 3).


## 4.1.1. Retrosynthetic Analysis of Platensimycin

Using retrosynthetic analysis (Scheme1) they separated the aromatic amine2 and the carboxylic acid3 by disconnection of amide linkage. The carboxylic acid was further simplified to a simplified enyne in successive three retrosynthetic steps. This resulted in two target molecules to synthesize the tetracyclic carboxylic acid and the aromatic amine from simplified starting material.Scheme 1
Retrosynthetic analysis of platensimycin.


## 4.1.2. Synthesis of Tetracyclic Cage

The simplified enone generated from 3-ethoxycyclohex-2-enone which was used as a starting material (Scheme2). Allylic bromide9 [27] (LDA, 92%) and propargyl bromide (LDA, 97%) were used as reagents of choice to generate the bis-alkylated enone10 from8. Reduction followed by acidic hydrolysis and reintroduction of the TBS ether produced enone11 from enone10 (yield 84%). Spirocycle12 was generated by cycloisomerization of11 [28, 29]. Oxidation of12 produced bis-enone13 [30] which upon acid hydrolysis gave desired aldehyde6. Secondary alcohol14 was prepared by addition of samarium(II) iodide in a dilute solution of aldehyde6 HFIP in THF/HMPA followed by NH4Cl solution. Esterification of14 with TEA resulted in the formation of cage-like structure4 which on treatment with KHMDS and MeI followed by KHMDS and allyl iodide produced olefin16. Vinyl pinacol boronate and16 reacted in presence of the Grubbs second generation catalyst to produce vinyl boronate19 which on reacting with trimethylamine N-oxide gave20. Following Pinnick protocol20 was converted to desired carboxylic acid3.Scheme 2
Synthesis of tetracyclic cage. (i) LDA, (ii) LDA, (iii) DIBAL-H, then HCl, (iv) TBSCL, (v) [CpRu(MeCN)3]PF6, (vi) LiHMDS, TMSCl, (vii) Pd(OAc)2, (viii) HCl aq., (ix) Sml2, HFlP, (x) TFA, (xi) KHMDS, MeI, (xii) KHMDS, (xiii) Me3NO, and (xiv) NaClO2.


## 4.1.3. Synthesis of Aromatic Amine

The synthesis of the aromatic amine2 was started from 2-nitroresorcinol21 by protecting with MOM ether, followed by catalytic hydrogenation,24 was formed (Scheme 3). Again protecting the amino group and followed by silylation, lithiation, and quenching with methyl cyanoformate24 was carboxylated and by unprotecting amino group using thermolysis, desired aniline2 was synthesized.Scheme 3
Synthesis of aromatic amine and platensimycin. (i) NaH, MOMCL, (ii) H2, Pd/C cat., (iii) Boc2O, (iv) nBuLi, and (v) 205°C.


## 4.1.4. Synthesis of Platensimycin Core

The total synthesis of platensimycin was completed by the coupling of carboxylic acid3 with aniline2 which was achieved by treatment with HATU followed by hydrolysis with LiOH (Scheme 3).


## 4.2. Another Approach for Synthesizing Tetracyclic Cage by Nicolaou et al.

After successfully reporting the first total synthetic strategy of platensimycin, Nicolaou et al. [31] report a new synthetic strategy that starts from the readily available and inexpensive (R)-(−)-carvone to the tetracyclic enone2.


### 4.2.1. Retrosynthetic Strategy of Tetracyclic Enone

A five-step retrosynthetic disconnection approach was shown to generate commercially available (R)-(−)-carvone31 from26 (Scheme 4).Scheme 4
Retrosynthetic analysis of platensimycin.


### 4.2.2. Synthesis of Tetracyclic Enone

(R)-(−)-carvone31 on reaction with Grignard’s reagent32 using CeCl3 [32] and by oxidizing with PCC gave the corresponding enone33. Enone33 was treated with Hg(OAc)2 and later on with NaBH4 to generate approximately 1 : 1 mixture of exo- and endotertiary alcohol, which on dehydration using Martin’s sulfurane reagent produced exocyclic alkene35 which was treated with TMSCl and HMDS and followed by an electrophilic quench with PhSeCl and subsequent oxidative elimination (H2O2) to give enone36. Enone37 was treated with SmI2 for radical cyclization, and by adding mentioned reagent (Scheme 5) in subsequent 8 steps of tetracyclic cage26 was synthesized.Scheme 5
Synthesis of tetracyclic cage. (i) CeCl3, (ii) PCC, and (iii) Hg(OAc)2, then NaBH4, (iv) Martin’s sulfurane, (v) TMSCl, Lil HMDS, and then PhSeCl, (vi) H2O2, Py, (vii) AcOH, MW, (ix) Sml2, (x) DIAD, ArCO2H, PPh3, Ar=p-NO2C6H4, (xi) KOH, (xii) L-selectride (H3O+), (xiii) PCC, (xiv) TMSCl, Lil HMDS, and (xv) IBX or Pd(OAc)2.


## 4.2.1. Retrosynthetic Strategy of Tetracyclic Enone

A five-step retrosynthetic disconnection approach was shown to generate commercially available (R)-(−)-carvone31 from26 (Scheme 4).Scheme 4
Retrosynthetic analysis of platensimycin.


## 4.2.2. Synthesis of Tetracyclic Enone

(R)-(−)-carvone31 on reaction with Grignard’s reagent32 using CeCl3 [32] and by oxidizing with PCC gave the corresponding enone33. Enone33 was treated with Hg(OAc)2 and later on with NaBH4 to generate approximately 1 : 1 mixture of exo- and endotertiary alcohol, which on dehydration using Martin’s sulfurane reagent produced exocyclic alkene35 which was treated with TMSCl and HMDS and followed by an electrophilic quench with PhSeCl and subsequent oxidative elimination (H2O2) to give enone36. Enone37 was treated with SmI2 for radical cyclization, and by adding mentioned reagent (Scheme 5) in subsequent 8 steps of tetracyclic cage26 was synthesized.Scheme 5
Synthesis of tetracyclic cage. (i) CeCl3, (ii) PCC, and (iii) Hg(OAc)2, then NaBH4, (iv) Martin’s sulfurane, (v) TMSCl, Lil HMDS, and then PhSeCl, (vi) H2O2, Py, (vii) AcOH, MW, (ix) Sml2, (x) DIAD, ArCO2H, PPh3, Ar=p-NO2C6H4, (xi) KOH, (xii) L-selectride (H3O+), (xiii) PCC, (xiv) TMSCl, Lil HMDS, and (xv) IBX or Pd(OAc)2.


## 4.3. Matsuo’s Synthesis of Tetracyclic Cage

### 4.3.1. Retrosynthetic Analysis of Tetracyclic Cage

Matsuo et al. [33] offered another route for stereocontrolled synthesis of tetracyclic enone4. They expected that the transannular radical cyclization of44 will produce enone4. A four-step retrosynthetic analysis is producing enone47 and siloxydiene48. The key feature of plan is that all stereocenters in4 are controlled by the stereochemistry presented in47 (Scheme 6).Scheme 6
Retrosynthetic analysis of platensimycin.


### 4.3.2. Synthesis of Tetracyclic Cage

O-TBS andO-benzoyl-protected enones47a and47b were prepared from 1,3-cyclohexadiene49 through allylboration, selective oxidation, and utilizing the Dess-Martin oxidation, with the yield of (97%). Diels-Alder reaction in between47a and47b and siloxydienes produced two stereogenic mixtures46a,46b and46c,46d. The mixture of two inseparable diastereomers (46b and46d) was employed in the next step. Following Noyori’s procedure [26] followed by hydrolysis of the benzoyl group and separation of diastereomers53 was given which upon catalytic oxidation using palladium(II) chloride and copper(II) acetate produced54a and54b in 10 : 1 ratio. Vinyl triflate55 was produced from54 and reduced to56 which was transformed to57. Transannular radical cyclization of monothioacetal57 gave desired4 (Scheme 7).Scheme 7
Synthesis of tetracyclic cage. (i) allylBBr2, then HOOH NaOH, (ii) t-BuOOH, VO(sese)2, (iii) Dess-Martin, periodinane, (iv) Silica gel, (v) TBSCl imidazole/BzCl, Py, (vi) PMSOTf (cat.) (TMSOCH2)2, (vii) aqNaOH separation of diastereomers, (viii) PdCl2 Cu(OAc)2 DMA, O2, (ix) KHMDS, (x) Pd(OAc)2(PPh3)2 HCOOH, Bu3N, (xi) PhSH, (xii) Bu3SnH AIBN toluene, reflux, and (xiii) 1N aq HCL.


## 4.3.1. Retrosynthetic Analysis of Tetracyclic Cage

Matsuo et al. [33] offered another route for stereocontrolled synthesis of tetracyclic enone4. They expected that the transannular radical cyclization of44 will produce enone4. A four-step retrosynthetic analysis is producing enone47 and siloxydiene48. The key feature of plan is that all stereocenters in4 are controlled by the stereochemistry presented in47 (Scheme 6).Scheme 6
Retrosynthetic analysis of platensimycin.


## 4.3.2. Synthesis of Tetracyclic Cage

O-TBS andO-benzoyl-protected enones47a and47b were prepared from 1,3-cyclohexadiene49 through allylboration, selective oxidation, and utilizing the Dess-Martin oxidation, with the yield of (97%). Diels-Alder reaction in between47a and47b and siloxydienes produced two stereogenic mixtures46a,46b and46c,46d. The mixture of two inseparable diastereomers (46b and46d) was employed in the next step. Following Noyori’s procedure [26] followed by hydrolysis of the benzoyl group and separation of diastereomers53 was given which upon catalytic oxidation using palladium(II) chloride and copper(II) acetate produced54a and54b in 10 : 1 ratio. Vinyl triflate55 was produced from54 and reduced to56 which was transformed to57. Transannular radical cyclization of monothioacetal57 gave desired4 (Scheme 7).Scheme 7
Synthesis of tetracyclic cage. (i) allylBBr2, then HOOH NaOH, (ii) t-BuOOH, VO(sese)2, (iii) Dess-Martin, periodinane, (iv) Silica gel, (v) TBSCl imidazole/BzCl, Py, (vi) PMSOTf (cat.) (TMSOCH2)2, (vii) aqNaOH separation of diastereomers, (viii) PdCl2 Cu(OAc)2 DMA, O2, (ix) KHMDS, (x) Pd(OAc)2(PPh3)2 HCOOH, Bu3N, (xi) PhSH, (xii) Bu3SnH AIBN toluene, reflux, and (xiii) 1N aq HCL.


## 4.4. Kaliappan’s Synthesis of Tetracyclic Cage

### 4.4.1. Retrosynthetic Analysis of Tetracyclic Cage

Kaliappan and Ravikumar [34] showed seven-step retrosynthetic analysis using a 5-exo-trig radical cyclization strategy [35, 36] to generate Wieland-Miescher ketone64 (Scheme 8).Scheme 8
Retrosynthetic analysis of platensimycin.


### 4.4.2. Synthesis of Tetracyclic Cage

Synthesis was started from Wieland-Miescher ketone64 [37], a chiral starting material, which on two-step reduction yielded an inseparable diastereomeric mixture of alcohols66 [38]. Corresponding aldehyde68 containing oxoethylene group was synthesized from alcohols66 by Mandai protocol [39]. Using Ohira-Bestmann reagent74 [40, 41], enyne69 was formed which was treated with AIBN intert-BuOH and PPTS to initiate the radical cyclization resulting formation of tetracyclic cage72. L-Selectride, THF, and TFA/CH2Cl2 were consecutively added with72 to produce the desired enone58 (Scheme 9).Scheme 9
Synthesis of tetracyclic cage. (i) NaBH4, ETOH, 00C, 2 h, (ii) TBSCI, Im, DMF, r.t., 2 h, (iii) DIBAL-H CH2Cl2, (iv) NaH, cat. KHTHF, r.t., 12 h, (v) Decalin, 180°C, 5d, (vi) K2CO3, MeOH, (vii) TBAF, THF, reflux, (viii) IBX PhF/DMSO 65°C, (ix) TBTH, AIBN t-BuOH, reflux, 12 h, (x) PPTS, CH2Cl2, r.t., 6 h, (xi) L-selectride, THF, −78°C to r.t., and (xii) TFA/CH2Cl2, 0°C, 2 h.


## 4.4.1. Retrosynthetic Analysis of Tetracyclic Cage

Kaliappan and Ravikumar [34] showed seven-step retrosynthetic analysis using a 5-exo-trig radical cyclization strategy [35, 36] to generate Wieland-Miescher ketone64 (Scheme 8).Scheme 8
Retrosynthetic analysis of platensimycin.


## 4.4.2. Synthesis of Tetracyclic Cage

Synthesis was started from Wieland-Miescher ketone64 [37], a chiral starting material, which on two-step reduction yielded an inseparable diastereomeric mixture of alcohols66 [38]. Corresponding aldehyde68 containing oxoethylene group was synthesized from alcohols66 by Mandai protocol [39]. Using Ohira-Bestmann reagent74 [40, 41], enyne69 was formed which was treated with AIBN intert-BuOH and PPTS to initiate the radical cyclization resulting formation of tetracyclic cage72. L-Selectride, THF, and TFA/CH2Cl2 were consecutively added with72 to produce the desired enone58 (Scheme 9).Scheme 9
Synthesis of tetracyclic cage. (i) NaBH4, ETOH, 00C, 2 h, (ii) TBSCI, Im, DMF, r.t., 2 h, (iii) DIBAL-H CH2Cl2, (iv) NaH, cat. KHTHF, r.t., 12 h, (v) Decalin, 180°C, 5d, (vi) K2CO3, MeOH, (vii) TBAF, THF, reflux, (viii) IBX PhF/DMSO 65°C, (ix) TBTH, AIBN t-BuOH, reflux, 12 h, (x) PPTS, CH2Cl2, r.t., 6 h, (xi) L-selectride, THF, −78°C to r.t., and (xii) TFA/CH2Cl2, 0°C, 2 h.


## 4.5. Corey’s Synthetic Strategy

### 4.5.1. Synthesis of Tetracyclic Cage

Lalic and Corey [42] used methoxy α-naphthol75 as the starting material which upon reaction with bistrifluoroacetoxyiodobenzene and ethylene glycol in acetonitrile at 0°C produced 6-methoxy-1,4-naphthoquinone-4-ethylene ketal76. An enantioselective conjugation of 2-propenyl group to ketal76 using 2-propenyl trifluoroborate, Rh-BINAP, BF4 catalyst, and triethylamine [43–45] produced the chiral ketone77.cis-tetralin78 was generated from77 by reduction of the carbonyl group, hydroxyl protection, and reductive cleavage of the ethylene ketal subunit. Demethylation of78 produced phenol79 which was converted to tricyclic80 by etherification followed by reaction with Br2 in CH2Cl2. Heating with tetra-n-butylammonium fluoride in THF at 130°C, tetracyclic cage81 was produced which on catalytic diastereoselective hydrogenation produced tetrahydro derivative82. The saturated ketone82 was transformed into the corresponding α,β-enone4 using the 2-iodoxybenzoic acid sequence (Scheme 10) [46, 47].Scheme 10
Synthesis of tetracyclic cage. (i) PhI(O2CCF3)2, OHCH2CH2OH, MeCN, 0°C, 2 h. (ii) (S)-BINAP, [Rh(cod)2]BF4, C7H8, H2O, Et3N, CH3-CH(BF3K)=CH2. (iii) (1) NaBH4, MeOH, (2) MEMCl, i-Pr2NEt, CH2Cl2, (3) TsOH, Me2CO, 0°C, (4)i-Bu2AIH, CH2Cl2, 0°C, (5) Et3SiH, (CF3CO)2O, CH2Cl2, −20°C. (iv) PhSH, Cs2CO3, DMF, D 170°. (v) (1)i-Pr3SiCl, imidazole, CH2Cl2, 23°C, 12 h and (2) Br2, CH2Cl2, −78°C. (vi)n-Bu4NF, THF, D 130°C. (vii) [Rh(cod)2]BF4, (R,R)-DIOP, H2 600 psi, CH2Cl2, 16 h. (viii) (1) TMSOTf, Me3N, CH2Cl2 and (2) IBX, MPO, DMSO.


## 4.5.1. Synthesis of Tetracyclic Cage

Lalic and Corey [42] used methoxy α-naphthol75 as the starting material which upon reaction with bistrifluoroacetoxyiodobenzene and ethylene glycol in acetonitrile at 0°C produced 6-methoxy-1,4-naphthoquinone-4-ethylene ketal76. An enantioselective conjugation of 2-propenyl group to ketal76 using 2-propenyl trifluoroborate, Rh-BINAP, BF4 catalyst, and triethylamine [43–45] produced the chiral ketone77.cis-tetralin78 was generated from77 by reduction of the carbonyl group, hydroxyl protection, and reductive cleavage of the ethylene ketal subunit. Demethylation of78 produced phenol79 which was converted to tricyclic80 by etherification followed by reaction with Br2 in CH2Cl2. Heating with tetra-n-butylammonium fluoride in THF at 130°C, tetracyclic cage81 was produced which on catalytic diastereoselective hydrogenation produced tetrahydro derivative82. The saturated ketone82 was transformed into the corresponding α,β-enone4 using the 2-iodoxybenzoic acid sequence (Scheme 10) [46, 47].Scheme 10
Synthesis of tetracyclic cage. (i) PhI(O2CCF3)2, OHCH2CH2OH, MeCN, 0°C, 2 h. (ii) (S)-BINAP, [Rh(cod)2]BF4, C7H8, H2O, Et3N, CH3-CH(BF3K)=CH2. (iii) (1) NaBH4, MeOH, (2) MEMCl, i-Pr2NEt, CH2Cl2, (3) TsOH, Me2CO, 0°C, (4)i-Bu2AIH, CH2Cl2, 0°C, (5) Et3SiH, (CF3CO)2O, CH2Cl2, −20°C. (iv) PhSH, Cs2CO3, DMF, D 170°. (v) (1)i-Pr3SiCl, imidazole, CH2Cl2, 23°C, 12 h and (2) Br2, CH2Cl2, −78°C. (vi)n-Bu4NF, THF, D 130°C. (vii) [Rh(cod)2]BF4, (R,R)-DIOP, H2 600 psi, CH2Cl2, 16 h. (viii) (1) TMSOTf, Me3N, CH2Cl2 and (2) IBX, MPO, DMSO.


## 4.6. Yamamoto’s Synthetic Strategy

### 4.6.1. Retrosynthetic Analysis of Tetracyclic Core

Li et al. [47] used an intramolecular Robinson annulation approach [48] in the retrosynthetic analysis presented in (Scheme 11). The bicyclic compound84 to give the tetracyclic core structure4 is key step in the retrosynthesis by Robinson annulation event.Scheme 11
Retrosynthetic analysis of platensimycin.


### 4.6.2. Synthesis of Tetracyclic Core

The bicyclic ketone84 can be synthesized from known lactone85 which could be generated from ketone86, through a Baeyer-Villiger oxidation/rearrangement sequence [49, 50] and by utilizing Bronsted acid assisted chiral Lewis acid catalyzed Diels-Alder reaction, and subsequent N-nitrosoaldol addition/decarboxylation, ketone86 could be easily prepared from inexpensive, commercially available starting materials (Scheme 12).Scheme 12
Synthesis of tetracyclic cage. (i) CH2Cl2, −78°C, 14 h, (ii) LDA, THF, −78°C, then PhNO, −78°C, 2 h, and then LiOH dioxane/H2O 30°C, 20 h, (iii) H2O2/NaOH Et2O/H2O 0°C to r.t., 45 min, (iv) CuBr·Me2S, CH2CMgBr THF/Me2S, −40°C to r.t., (v) 4.5 mol% HNTf2, CH2ClCH2Cl, 70°C, 45 min, (vi) DIBAL-H, toluene, −78°C, 30 min, then Et2AlCN BF3·OET2, 20 min, (vii) DIBAL-H/n-BuLi, −78°C to 0°C, 25 min, (viii) NaH, CH3COCH2P(O)(OET)2, THF, 0°C, 20 min, (ix) 2.02 eq NaIO4, 3.5 mol% RuCl3 6 : 1 CH3CN/H2O r.t., 3 h, and (x) 1 eq pyrrolidine-2-carboxylic acid, DMF, r.t., 5 days, then 2N NaOH(aq) 0°C to r.t., 40 min.Diels-Alder reaction between methyl acrylate87 and methyl cyclopentadiene88 produced adduct89. The reaction was catalyzed by BLA and carbon-based Bronsted acid [51]. Ketone90 was obtained in one pot reaction from adduct89 using lithium enolate and lithium hydroxide in dioxane. Baeyer-Villiger oxidation in basic condition [52] of ketone90 gave lactone85. Vinyl lactone91 was obtained from lactone85 using cuprate reagent [53] and trifluoromethanesulfonimide [54, 55]. DIBAL-H reduction followed by cyanation produced cyanide92a,92b, which was reduced and subjected to Wadsworth-Emmons conditions [56] to give enone93; ruthenium-catalyzed oxidation [57] produced aldehyde84. Using L-proline as the chiral control element followed by sodium hydroxide treatment gave the desired tetracyclic core structure4.


## 4.6.1. Retrosynthetic Analysis of Tetracyclic Core

Li et al. [47] used an intramolecular Robinson annulation approach [48] in the retrosynthetic analysis presented in (Scheme 11). The bicyclic compound84 to give the tetracyclic core structure4 is key step in the retrosynthesis by Robinson annulation event.Scheme 11
Retrosynthetic analysis of platensimycin.


## 4.6.2. Synthesis of Tetracyclic Core

The bicyclic ketone84 can be synthesized from known lactone85 which could be generated from ketone86, through a Baeyer-Villiger oxidation/rearrangement sequence [49, 50] and by utilizing Bronsted acid assisted chiral Lewis acid catalyzed Diels-Alder reaction, and subsequent N-nitrosoaldol addition/decarboxylation, ketone86 could be easily prepared from inexpensive, commercially available starting materials (Scheme 12).Scheme 12
Synthesis of tetracyclic cage. (i) CH2Cl2, −78°C, 14 h, (ii) LDA, THF, −78°C, then PhNO, −78°C, 2 h, and then LiOH dioxane/H2O 30°C, 20 h, (iii) H2O2/NaOH Et2O/H2O 0°C to r.t., 45 min, (iv) CuBr·Me2S, CH2CMgBr THF/Me2S, −40°C to r.t., (v) 4.5 mol% HNTf2, CH2ClCH2Cl, 70°C, 45 min, (vi) DIBAL-H, toluene, −78°C, 30 min, then Et2AlCN BF3·OET2, 20 min, (vii) DIBAL-H/n-BuLi, −78°C to 0°C, 25 min, (viii) NaH, CH3COCH2P(O)(OET)2, THF, 0°C, 20 min, (ix) 2.02 eq NaIO4, 3.5 mol% RuCl3 6 : 1 CH3CN/H2O r.t., 3 h, and (x) 1 eq pyrrolidine-2-carboxylic acid, DMF, r.t., 5 days, then 2N NaOH(aq) 0°C to r.t., 40 min.Diels-Alder reaction between methyl acrylate87 and methyl cyclopentadiene88 produced adduct89. The reaction was catalyzed by BLA and carbon-based Bronsted acid [51]. Ketone90 was obtained in one pot reaction from adduct89 using lithium enolate and lithium hydroxide in dioxane. Baeyer-Villiger oxidation in basic condition [52] of ketone90 gave lactone85. Vinyl lactone91 was obtained from lactone85 using cuprate reagent [53] and trifluoromethanesulfonimide [54, 55]. DIBAL-H reduction followed by cyanation produced cyanide92a,92b, which was reduced and subjected to Wadsworth-Emmons conditions [56] to give enone93; ruthenium-catalyzed oxidation [57] produced aldehyde84. Using L-proline as the chiral control element followed by sodium hydroxide treatment gave the desired tetracyclic core structure4.


## 5. Pharmacology of Platensimycin

Bacterial cell wall synthesis, protein synthesis, and DNA replication are the predominant targets for widely used antibiotics. But the emergence of resistance to antibiotics demands new antibacterial targets. Fatty acid synthase (FAS) pathway is now an attractive target for antibacterial agents because, as a new target, FAS inhibition will not suffer from bacterial resistance immediately and biosynthesis pathway of bacteria, plants, and parasites (FAS II in which component proteins are dissociated) is different from mammals (FAS I in which component proteins are generally single-chain, multidomain homodimers or two-chain heterodimers carrying all proteins of the pathway) in subcellular organization of components which demonstrate a target specificity for the FAS II inhibitors. A general scheme for type II fatty acid biosynthesis is shown in Figure2[9]. A recent development in finding inhibitors of fatty acid biosynthesis is the discovery of platensimycin which shows broad-spectrum Gram-positive antibacterial activity (Staphylococcus aureus (MRSA) andEnterococci (VRE), MIC < 1.0 μg mL−1) by selectively inhibiting cellular lipid biosynthesis [58]. The mechanism of action is the selective inhibition of elongation of FabF (a condensing enzyme) in the bacterial fatty acid synthetic pathway by intercalating with the malonyl binding site of the catalytic triad of FabF acyl enzyme intermediate. Inverse correlation of FabF expression levels with the sensitivity ofS.aureus to the drug platensimycin confirms that FabF is the useful target for antibacterial action. Platensimycin exhibited an IC50 of 48 nM and 160 nM against FabF inS.aureus andE.coli, respectively. But the drug shows weak inhibition against FabH with an IC50 value of 67 mM. Further studies have shown thatin vitro binding of platensimycin with FabF is relatively weak, which leads to the discovery of its binding with acyl-thioester intermediate of the FabF pathway. From a crystal structure of a Cys-163-Gln FabF mutant, which simulates acyl-thioester intermediate, it was found that platensimycin bind with the active site of FabF with the carboxylic acid group lying in the malonate-binding site coplanar with the amide side chain of Gln163 [59].Figure 2
Fatty acid biosynthesis pathway of bacteria (FAS II).Though Brinster et al. [60] explained an alternative hypothesis that FAS II inhibition is not a suitable target forStreptococcus agalactiae (lactobacillales). The need for synthesized fatty acid by their own (streptococci, pneumococci, enterococci, and staphylococci) reduces in the presence of exogenous fatty acid in bothin vitro andin vivo conditions. Human serum has a high composition of fatty acids, so FAS II inhibitor may not affect at all Gram-positive pathogensin vivo. But the findings withS. agalactiae can be reasonably extended to all Gram-positive bacteria, which has started a vigorous debate. Also there is no clear explanation how bacteria incorporates exogenous fatty acids into their cell [61, 62]. Platensimycin exhibited antibacterial activity against efflux-negativeEscherichia coli (tolC), but not against wild-typeE. coli, specifying that efflux mechanisms, and not compound specificity, limit the effectiveness of platensimycin inE. coli and possibly other Gram-negative bacteria [3].


## 6. Platensimycin Analogues

The major drawback to most natural products, including platensimycin, is poor pharmacokinetic properties and negligible oral bioavailability. Only the continuous infusion of a high platensimycin dose showed effectiveness in mice infected withS. aureus [3]. For the improvement of pharmacokinetic profile, many researchers have developed platensimycin analogues (Table 1); however potent antimicrobial activity than that of platensimycin is yet to get.Table 1
Antimicrobial activity of synthesized platensimycin analogue.
Sl. number
Analogues name
Analogues structure
Antimicrobial activity
Reference
1
(−)-Platencin
Inhibits both FabF and FabH  with similar potency
[12]
2
7-Phenylplatensimycin
MIC againstS. aureus (MSSA), 0.25 μg/mL
[15]
3
11-Methyl-7-phenylplatensimycin
MIC againstS. aureus (MSSA), <0.25 μg/mL
[15]
4
Sulfonamide analogues of platensimycin
Not tested
[16]
5
Oxazinidinyl platensimycin
MIC of 90μg/mL against S. aureus, S. agalactiae, and B.  subtilis
[17]
6
Isoplatencin
MIC againstS. aureus (MSSA), 0.4 μg/mL
[18]
7
Cl-iso-platencin
MIC againstS. aureus (MSSA), >25.6 μg/mL
[18]
8
Cl-platencin
MIC againstS. aureus (MSSA), >25.6 μg/mL
[18]
9
Dehydrohomoplatencin
MIC againstS. aureus (MSSA), 0.4 μg/mL
[19]
10
Isoplatensimycin
MIC againstS. aureus (MSSA), 128 μg/mL
[20]
11
Carbaplatensimycin
MIC againstS. aureus, 0.4–1.1 μg/mL
[21]
12
Platensimycin B1 and B3
Not tested
[22]
13
Platensimide A
Not tested
[22]
14
Homoplatensimide A and homoplatensimide A methyl ester
Not tested
[22]
15
Dialkylamino-2,4-dihydroxybenzoic acids analogues of Platensimycin
Out of 18 Synthesized derivatives, four derivatives which have the substitution 1, 2, 3, and 4, respectively, have shown potential activity againstB. subtilis (MIC 2–8 μg/mL)
[23]
16
(−)-nor-platencin
MIC againstS. aureus (MSSA), 5 μg/mL
[24]
17
Adamantaplatensimycin
MIC of (−)-adamantaplatensimycin  againstS. aureus (MSSA), 1.3–1.8 μg/mL; MIC of (+)-adamantaplatensimycin  against S. aureus (MSSA), >88 μg/mL
[25]


## 7. Conclusion

Development of bacterial resistance to the existing antibiotics is an alarming situation in the 20th century. Finding new target for bacterial demolition is essential. Platensimycin serving as a potential antibiotic interacting with FabF may bypass bacterial resistance. It should be noted that starting from 2006 till now a huge number of scientists provided many synthetic strategies and derivatives which are very encouraging. Though some evidence like incorporation of exogenous fatty acid inside bacteria when supplied makes the hope regarding platensimycin is uncertain, overall, isolation of platensimycin as a selective FabF inhibitor, complex synthesis of tetracyclic cage, and enhancement of its pharmacokinetic properties by its derivative synthesis are the excellent works in the era of medicinal chemistry. It is expected that this review might be helpful for the medicinal chemist.



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*Source: 9706753-2016-01-28.xml*