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Stereoselective synthesis of the potentially biologically valuable 5beta-lanosteroidal-type backbone is achieved by anionic cycloaddition. Results reveal that the use of a chiral ring A precurosr with a dimethylphenyl silyl group imparts a complete stereocontrol for the anionic cycloaddition reaction.

Reactivemetabolites (RMs) have been implicated as causal factorsin many drug-associated idiosyncratic toxicities. This study aimsat identification and mitigation of an RM liability associated withaminoimidazole and amino(aza)benzimidazole structural motifs froman antimalarial project. Nineteen compounds with different structuralmodifications were studied in rat and human liver microsomes usingglutathione (GSH) and N-acetyl cysteine (NAC) astrapping agents for RM. Metabolite profiling of aminoimidazole compoundsin initial studies revealed the presence of dihydrodiol metabolitessuggestive of reactive epoxide precursors, confirmed by the identificationof a dihydrohydroxy GSH conjugate in GSH supplemented incubations.Substitution of methyl group at a potential site of metabolism blockedthe epoxidation; however, formation of an imine-methide RM was suspected.Masking the site of metabolism via benzimidazole and 4/7-azabenzimidazoleresulted in the possible formation of quinone-imine intermediatesas a product of bioactivation. Further, substitutions with electronwithdrawing groups and steric crowding did not address this liability.Mitigation of bioactivation was achieved with 5/6-azabenzimidazoleand with CF3substitution at the 6-position of the 7-azabenzimidazolering. Moreover, compounds devoid of imidazole -NH2do notundergo bioactivation. This study, therefore, establishes aminoimidazoleand amino(aza)benzimidazoles as potential toxicophores and describesways to mitigate this bioactivation liability by chemical modification. [ABSTRACT FROM AUTHOR]

Fromthe phenotypic screening of the AstraZeneca corporate compoundcollection, N-aryl-2-aminobenzimidazoles have emergedas novel hits against the asexual blood stage of Plasmodiumfalciparum(Pf). Medicinal chemistry optimizationof the potency against Pfand ADME properties resultedin the identification of 12as a lead molecule. Compound 12was efficacious in the P. berghei(Pb) model of malaria. This compound displayed an excellentpharmacokinetic profile with a long half-life (19 h) in rat blood.This profile led to an extended survival of animals for over 30 daysfollowing a dose of 50 mg/kg in the Pbmalaria model.Compound 12retains its potency against a panel of Pfisolates with known mechanisms of resistance. The fastkilling observed in the in vitroparasite reductionratio (PRR) assay coupled with the extended survival highlights thepromise of this novel chemical class for the treatment of malaria. [ABSTRACT FROM AUTHOR]

A novel pyrazolopyridone class ofinhibitors was identified fromwhole cell screening against Mycobacterium tuberculosis(Mtb). The series exhibits excellent bactericidality in vitro, resultingin a 4 log reduction in colony forming units following compound exposure.The significant modulation of minimum inhibitory concentration (MIC)against a Mtb strain overexpressing the Rv3790genesuggested the target of pyrazolopyridones to be decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1). Genetic mapping of resistancemutation coupled with potent enzyme inhibition activity confirmedthe molecular target. Detailed biochemical characterization revealedthe series to be a noncovalent inhibitor of DprE1. Docking studiesat the active site suggest that the series can be further diversifiedto improve the physicochemical properties without compromising theantimycobacterial activity. The pyrazolopyridone class of inhibitorsoffers an attractive non-nitro lead series targeting the essentialand vulnerable DprE1 enzyme for the discovery of novel antimycobacterialagents to treat both drug susceptible and drug resistant strains ofMtb. [ABSTRACT FROM AUTHOR]

Stereoselective synthesis of the potentially biologically valuable 5β-lanosteroidal-type backbone was achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40 and their cycloaddition with chiral cyclohexenone 25 and further functional group manipulations resulted in highly functionalized tetracyclic intermediates 28 and 44. These synthetic intermediates could lead to the total synthesis of new lanosterol-based inhibitors. [ABSTRACT FROM AUTHOR]