A New Class of Antituberculosis Agents

Abstract

Long-chain lipid envelopes are characteristic of mycobacteria such as those that cause tuberculosis and leprosy. Inhibition of fatty acid synthesis or elongation is a strategy demonstrated to be clinically effective against M. tuberculosis. A new class of compounds designed to inhibit the beta-ketoacyl synthase reaction of fatty acid synthesis has been developed. Of >30 compounds described, the most active were acetamides containing alkylsulfonyl substituents. Inhibitory activities were acutely sensitive to net charge, chain length, and degree of unsaturation. The most active compound 5 (alkyl = C(10)) contained a single methylene spacer between the sulfone and carboxamide and exhibited an MIC of 0.75-1.5 microg/mL, comparable to first-line antituberculosis drugs. These compounds are species-specific, exhibiting no significant activity against bacterial species other than M. tuberculosis and closely related strains. The synthesis, biological activity, and specificity of these compounds are described.

Study of Schiff-Base-Derived with Dioxygenated Rings and Nitrogen Heterocycle as Potential β-Ketoacyl-acyl Carrier Protein Synthase III (FabH) Inhibitors

“…Docking Study Molecular docking of compound 2E into the 3D Xray structure of E. coli FabH (PDB: 1HNJ) 8) was carried out using Discovery Studio (v3.1) as implemented through the graphical user interface DS-CDOCKER protocol. 21) The 3D structures of the aforementioned compounds were constructed using Chem 3D ultra 12.0 (Chemical Structure Drawing Standard; Cambridge Soft Corporation, U.S.A.) and energy minimized by using MMFF94 with 5000 iterations and minimum RMS gradient of 0.10. The crystal structures of E. coli FabH (PDB: 1HNJ) 8) complex were retrieved from the RCSB Protein Data Bank (http://www.rcsb.org/pdb/).…”

“…FabH has been identified is the key target enzyme in the fatty acid synthesis of bacteria, and can be chosen as the new target for developing broad-spectrum antibiotics. [16][17][18] Many research groups including our group devoted to investigating antibacterial with FabH as target, and some potential FabH inhibitors with high antibacterial activities have been exploited [19][20][21][22][23][24] (Fig. 1).…”

Role of quinolones and quinoxaline derivatives in the advancement of treatment of tuberculosis

“…NFQs lack a 6-fluorine in their quinolone nucleus differentiating them from fluorinated quinolones such as gatifloxacin and moxifloxacin. NFQs target a broad spectrum of bacteria and they seem to act preferentially through inhibition of DNA gyrase [94]. NFQs are currently being tested against Mtb.…”

New drugs and vaccines for drug-resistantMycobacterium tuberculosisinfections

“…β-sulphonylcarboxamide compounds were designed as mimics of the reactive acetyl enolate intermediate in the condensation reaction these enzymes catalyze [86]. The most potent antimycobacterial compounds discovered through this strategy were amide derivatives of 3-sulphonyl fatty acids bearing alkyl chains of between eight and ten carbons in length; MICs as low as 0.75 µg/ml are comparable to frontline anti-TB agents.…”

“…The most potent antimycobacterial compounds discovered through this strategy were amide derivatives of 3-sulphonyl fatty acids bearing alkyl chains of between eight and ten carbons in length; MICs as low as 0.75 µg/ml are comparable to frontline anti-TB agents. Surprisingly, the activity profile of these compounds was particularly species dependent, they exhibit no significant activity against bacteria other than M. tuberculosis and closely related strains, including nonpathogenic mycobacteria [86]. One of these, N-octanesulphonylacetamide (OSA), was tested further against several pathogenic and drug-resistant mycobacteria, including MDR-TB, strains [87].…”