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Physico-chemical, in vitro potency, pharmaco-kinetic and dynamic properties of anti-TB drugs

Lakshminarayana, Suresh Bangalore, Tan, Bee Huat, Paul C, Ho, Manjunatha, Ujjini Havaldar, Veronique, Dartois, Thomas , Dick and Rao, Srinivasa P.S. (2014) Physico-chemical, in vitro potency, pharmaco-kinetic and dynamic properties of anti-TB drugs. Journal of Antimicrobial Chemotherapy.


Physico-chemical properties, in vitro potency, and in vitro and in vivo pharmacokinetic (PK) properties of new leads are critical determinants of in vivo efficacy. Hence, understanding how these parameters correlate is important for early drug discovery and preclinical development. In the current study we have characterized 36 first-line, second-line and other anti-TB drugs as well as clinical candidates. Although these data for most compounds have been reported, comparability of the existing data is limited as different methods and readouts were employed. Here we have generated a compendium of anti-TB drug characteristics using standardized methodology as a reference for the TB drug discovery community. Although the physico-chemical properties of anti-mycobacterials were diverse, they were proximal to gram negative anti-bacterials. Most of the compounds were bactericidal and had activity in a macrophage infection model. Majority of the anti-TB compounds showed good solubility, permeability and metabolic stability in standard in vitro PK assays. Improved solubility and Caco-2 permeability was noticed when compounds had molecular weight and cLog P < 500 and 5, respectively. Comprehensive data analysis using human PK parameters and their correlation with in silico and in vitro compounds properties showed that volume of distribution, clearance, plasma protein binding and oral bioavailability had significant relationship with cLogP. Not surprisingly, most compounds having moderate to high oral bioavailability complied with Lipinski’s rule of 5, and also had good solubility and high permeability.

Item Type: Article
Keywords: Mycobacterium, Tuberculosis, Drug Discovery, Invitro potency, In vitro and in vivo pharmacokinetics
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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