Prediction of QcrB Inhibition as a Measure of Antitubercular Activity with Machine Learning Protocols.

It has always been a challenge to develop interventional therapies for . Over the years, several attempts at developing such therapies have hit a dead-end owing to rapid mutation rates of the tubercular bacilli and their ability to lay dormant for years. Recently, cytochrome complex (QcrB) has shown some promise as a novel target against the tubercular bacilli, with Q203 being the first molecule acting on this target.

Identification of potential antileishmanial 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-ones, in vitro metabolic stability, cytotoxicity and molecular modeling studies.

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC values range from 55.

Design, synthesis and SAR of antitubercular benzylpiperazine ureas.

N-furfuryl piperazine ureas disclosed by scientists at GSK Tres Cantos were chosen as antimycobacterial hits from a phenotypic whole-cell screen. Bioisosteric replacement of the furan ring in the GSK Tres Cantos molecules with a phenyl ring led to molecule (I) with an MIC of 1 μM against Mtb H37Rv, low cellular toxicity (HepG2 IC ~ 80 μM), good DMPK properties and specificity for Mtb. With the aim of delineating the SAR associated with (I), fifty-five analogs were synthesized and screened against Mtb.

4-Hydroxy-2-pyridone Derivatives and the δ-pyrone Isostere as Novel Agents Against Mycobacterium smegmatis Biofilm Inhibitors.

Background: The treatment of a bacterial infection when the bacterium is growing in a biofilm is a vexed issue. This is because the bacteria in a biofilm behaves differently compared to the individual planktonic free-form. As a result, traditional antibacterial agents lose their activity.

Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity.

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile.

Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-à-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE.

Design and synthesis of triazolopyrimidine acylsulfonamides as novel anti-mycobacterial leads acting through inhibition of acetohydroxyacid synthase.

Novel triazolopyrimidine acylsulfonamides class of antimycobacterial agents, which are mycobacterial acetohydroxyacid synthase (AHAS) inhibitors were designed by hybridization of known AHAS inhibitors such as sulfonyl urea and triazolopyrimidine sulfonamides. This Letter describes the synthesis and SAR studies of this class of molecules by variation of two parts of the molecule, the phenyl and triazolopyrimidine rings. SAR study describes optimisation of enzyme potency, whole cell potency and evidence of mechanism of action.