Ligand‐Based Virtual Screening, Parallel Solution‐Phase and Microwave‐Assisted Synthesis as Tools to Identify and Synthesize New Inhibitors of Mycobacterium tuberculosis

Abstract

In an attempt to identify new inhibitors of the growth of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, a procedure for the generation, design, and screening of a ligand-based virtual library was applied. This used both an in silico protocol centered on a recursive partitioning (RP) model described herein, and a pharmacophoric model for antitubercular agents previously generated by our research group. Two candidates emerged from databases of commercially available compounds, both characterized by a minimum inhibitory concentration (MIC) of 25 microg mL(-1). Based on these compounds, two series of derivatives were synthesized by both parallel solution-phase and microwave-assisted synthesis, leading to enhanced antimycobacterial activity. During both the design and synthesis, attention was focused on the efficient allocation of available resources with the aim of reducing the overall costs associated with calculation and synthesis.

Synthesis, biological evaluation and SAR study of novel pyrazole analogues as inhibitors of Mycobacterium tuberculosis

“…4 The major suggestion derived from biological results was that the p-chlorobenzoyl moiety at C4 of pyrazole ring with general structure A was fundamental for the activity. However, no investigations were carried out on the effects that the introduction of different substituents at N1, N2 and C3 of the pyrazole ring might produce on antimycobacterial activity.…”

Synthesis, characterization and in vitro biological evaluation of some new 1,3,5-triazine-chalcone hybrid molecules as Mycobacterium tuberculosis H37Rv inhibitors

“…Although this disease can be cured with the current therapy, the treatments require six to nine months of time period that is too long, and accompanied by significant toxicity [3]. These factors make patient compliance to therapy very difficult, and this noncompliance frequently selects for drug-resistant TB bacteria [4]. An increasing occurrence of deaths due to tuberculosis and the known drawbacks of the current existing drugs including the emergence of multi drug-resistant strains have led to a renewed interest in the discovery of new antitubercular agents with novel modes of actions [5].…”

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N′-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria

“…Moreover, aldehydes 8a-b were reacted with benzylhydroxylamine to afford oximes 10a-b 18 which, after treatment with NaCNBH 3 , led to the corresponding hydroxylamines 11a-b in excellent yields.…”

“…General procedure. 18 The appropriate aldehyde 8a-b (1 mmol) was dissolved in 5mL of THF in a round bottom flask.…”