In vitro ADME characterization of the lead compound 1 identified for visceral leishmaniasis was undertaken and further structural analogs were synthesized for antileishmanial screening. Compound 1 was highly permeable in intestinal PAMPA model (31 × 10−6 cm/s) and was moderately bound to mouse and human plasma proteins (% bound 85–95%), its blood to plasma concentration ratio was less than 1, but the compound was unstable in blood. Compound 1 was found to have no CYP450 liability with CYP2C9, 2C19, 2D6 and 3A4. It showed inhibition with CYP1A2 with an IC50 value of 0.50 μM. Analogs of 1 were synthesized and subsequently characterized for in vitro activity against the intracellular form of Leishmania donovani. Resulting quinolines were found to have similar efficacy as 1 against the parasite. Compounds 8b and 8f were found to be the most active with IC50 values of 0.84 μM and 0.17 μM, respectively compared to 0.22 μM for compound 1. Of all the analogs tested, 8d was stable in hamster, mouse and human liver microsomes but lost the efficacy with an IC50 of 6.42 μM. Based on the in vitro efficacy and DMPK profile, compounds 8b and 8f seem the best candidates to be screened in further assays.
Gopinath, V.S.; Rao, M.; Shivahare, R.; Vishwakarma, P.; Ghose, W.; Pradhan, A.; Hundupur, R.; Das Sarma, K.; Gupta, S.; Puri, S.K.; Launay, D.; Martin, D. Design, synthesis, ADME characterization and antileishmanial evaluation of novel substituted quinoline analogs. Bioorganic and Medicinal Chemistry Letters (2014) 24 (9) 2046-2052. [DOI: 10.1016/j.bmcl.2014.03.065]