The endocannabinoid system Our current understanding of the endocannabinoid system (ECS) defines two types of endogenous agonist: esters and amides of fatty acids. The esters and amides are synthesised by two independent enzyme systems; separate hydrolases also terminate their action. The functions of these endocannabinoids are primarily mediated through two G protein-coupled receptors, although there is evidence for activation of TRPV1 vanilloid receptors and PPAR nuclear hormone receptors, as well as through allosteric regulation of other receptors, channels and enzymes (Alexander and Kendall, 2007).

: In the drug discovery setting, undesirable ADMET properties of a pharmacophore with good predictive power obtained after a tedious drug discovery and development process may lead to late-stage attrition. The early-stage ADMET profiling has introduced a new dimension to leading development. Although several high-throughput in vitro models are available for ADMET profiling, however, the in silico methods are gaining more importance because of their economic and faster prediction ability without the requirements of tedious and expensive laboratory resources. Nonetheless, in silico ADMET tools alone are not accurate and, therefore, ideally adopted along with in vitro and or in vivo methods in order to enhance predictability power. This review summarizes the significance and challenges associated with the application of in silico tools as well as the possible scope of in vitro models for integration to improve the ADMET predictability power of these tools.

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A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 mg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC ¼ 16-64 mg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.