Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

PLOS One, 2009

Background: Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over onethird of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration.

PLOS One, 2009

Background: Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over onethird of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration.

Journal of Chemical Information and Modeling, 2009

Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5′-thiourea-substituted R-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r 2 ) 0.90, q 2 ) 0.83 entire set, r 2 ) 0.86, q 2 ) 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5′-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptordependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.

Medicinal Chemistry …, 2011

The emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis and the continuing pandemic of tuberculosis emphasizes the urgent need for the development of new and potent anti-tubercular agents. In an effort to develop new and more effective agents to treat tuberculosis emphasis was focused on quantification of structureeactivity relationship of oxazolyl thiosemicarbazone derivatives. The de novo analysis gave insight to some important structural features i.e. nitro group on phenyl ring at R 1 position is optimal for the activity and might be responsible for electronic interaction, while phenyl ring at R position interact with the hydrophobic pocket more effectively as compared to unsubstituted or methyl substituted analogs. Hansch approach offered the understanding and parameterization of interactions of the inhibitor with receptor. Similarly QSAR analysis gave some important physicochemical properties, i.e. empirical aromatic index (ARR) and 3D-MoRSE code value of scattering angle at 8Å À1 . These two physicochemical properties shall be helpful in the development of more potent analogs.

Microbiology (Reading, England), 2002

Analogues of the antibiotic thiolactomycin (TLM) have been synthesized and have been shown to have enhanced activity against whole cells of Mycobacterium tuberculosis H37Rv and against mycolic acid biosynthesis in cell extracts of Mycobacterium smegmatis. TLM has a methyl-branched butadienyl side chain attached at position 5 on a 'thiolactone' ring, namely 4-hydroxy-3,5-dimethyl-5H-thiophen-2-one. Various combinations of strong bases were explored to create a reactive anion at position 5 on the thiolactone ring which could react with halides to produce 5-substituted derivatives; the best reagent was two equivalents of lithium-bis-(trimethylsilyl)amide in tetrahydrofuran. The analogue with a 5-tetrahydrogeranyl substituent showed the best biological activity with an MIC(90) for M. tuberculosis of 29 micro M and 92% mycolate inhibition in extracts of M. smegmatis, as compared to 125 micro M and 54%, respectively, for TLM; other related C(10) and C(15) isoprenoid derivatives ha...

Antibiotics, 2020

In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl) -4H-1,2,4-triazole-3-thiol (1) and its Schiff bases 2, 3, and 4 were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by resazurin microtiter assay (REMA) plate method. Test compound 1 exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound 1 was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and N-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound 1 via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound 1 compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound 1 involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5-α6 helix movement. Test compound 1-specific structural changes at the ALA274-ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound 1 when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.

Structure, 2009

Mycobacteria have a unique cell wall consisting of mycolic acids, very long chain lipids that provide protection and allow the bacteria to persist within human macrophages. Inhibition of cell wall biosynthesis is fatal for the organism and a starting point for the discovery and development of novel antibiotics. We determined the first crystal-structures of KasA, a key enzyme involved in the biosynthesis of long-chain fatty acids, in its apo-form and bound to the natural product inhibitor thiolactomycin (TLM). Detailed insights into the interaction of the inhibitor with KasA and the identification of a polyethylene glycol molecule which mimics a fatty acid substrate of approximately 40 carbon atoms length, represent the first atomic view of a mycobacterial enzyme involved in the synthesis of long chain fatty acids and provide a robust platform for the development of novel TLM analogs with high affinity for KasA. † This work was supported in part by NIH grants AI44639, AI70383 and through the Deutsche Forschungsgemeinschaft (SFB630 and Forschungszentrum FZ82).

ACS medicinal chemistry letters, 2016

Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High-throughput screening yielded two lead scaffolds of inhibitors of Mycobacterium tuberculosis (Mtb) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistant Mtb strain. Model structures of Eis-inhibitor complexes explain the structure-activity relationship.

Bioorganic & Medicinal Chemistry Letters, 2005

Structurally modified analogues of naturally occurring antibiotic thiolactomycin, substituted at 4-position of the thiolactone ring have been prepared and evaluated for their antitubercular activity. Some of the compounds have exhibited potential activity against Mycobacterium tuberculosis.

European journal of medicinal chemistry, 2020

Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors