Multiple 3D- and 2D-quantitative structure–activity relationship models (QSAR), theoretical study and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against tuberculosis

Author: Thorat, Bapu R. ; Lai, Chin-Hung ; Pandey, Anima ; Mali, Suraj N.

Tuberculosis (TB), an infectious remains a global health burden till date.Considering immense importance of theor. tools in computer aided-drug designing, the current study focuses on common pharmacophore and QSAR anal. of 38 imidazopyridine analogs as anti-TB agents.Our developed atom-based, field-based, and multilinear regression based-QSAR models showed high values for statistical robustness for internal as well as external validations (a correlation coefficient: R2 > 0.9, least standard deviations, higher Fischer coefficient, and cross-validation correlation coefficient: Q2 > 0.5).From our ZINC-Drug-like anal., we were retained with 5 hits (VS1-VS-5), among them VS-4 mol. was found to have high potency (predicted pIC50 (μM) value: 7.96 (against MTB H37Rv ATCC 27,294)) with good theor. properties (high softness, and low hardness values).From our designed analogs (S1-S10), analog S-10 was retained with high potency as well as good pharmacokinetics to act as good anti-mycobacterial agent in future.

01 Aug 2016·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Imidazo[1,2- a ]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo

Q2 · MEDICINE

Article

Author: Miller, Marvin J. ; Cramer, Jeffrey W. ; Schorey, Jeffery ; Cho, Sanghyun ; Godfrey, Alexander ; Masquelin, Thierry ; Cheng, Yong ; Moraski, Garrett C. ; Franzblau, Scott G.

ABSTRACT A panel of six imidazo[1,2- a ]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against Mycobacterium avium strains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse M. avium infection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti- M. avium activity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against M. avium and could potentially serve as an effective addition to a combined treatment regimen.

11 Jul 2013·ACS Medicinal Chemistry Letters

Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and nM Activity vs. Mycobacterium tuberculosis

Article

Author: Parish, Tanya ; Markley, Lowell D. ; Bailey, Mai A. ; Cramer, Jeffrey ; Miller, Marvin J. ; Moraski, Garrett C. ; Alling, Torey ; Hipskind, Philip A. ; Boshoff, Helena ; Ollinger, Juliane

A set of fourteen imidazo[1,2-a]pyridine-3-carboxamides was synthesized and screened against Mycobacterium tuberculosis H₃₇Rv. The minimum inhibitory concentrations of twelve of these agents were ≤ 1 μM against replicating bacteria and five compounds (9, 12, 16, 17 and 18) had MIC values ≤ 0.006 μM. Compounds 13 and 18 were screened against a panel of MDR and XDR drug resistant clinical Mtb strains with the potency of 18 surpassing that of clinical candidate PA-824 by nearly 10 fold. The in vivo pharmacokinetics of compounds 13 and 18 were evaluated in male mice by oral (PO) and intravenous (IV) routes. These results indicate that readily synthesized imidazo[1,2-a]pyridine-3-carboxamides are an exciting new class of potent, selective anti-TB agents that merit additional development opportunities.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	United States	Eli Lilly & Co.	31 Jan 2014

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