title: Design, synthesis, ADME characterization and antileishmanial evaluation of novel substituted quinoline analogs.
abstract: 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.
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Vadiraj S
authors.initials: VS
authors.lastname: Gopinath
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Mukkavilli
authors.initials: M
authors.lastname: Rao
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Shivahare
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Vishwakarma
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Ghose
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Pradhan
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Ramamohan
authors.initials: R
authors.lastname: Hindupur
authors.affiliation: Advinus Therapeutics Ltd, Bangalore 560 058, India.
authors.forename: Koushik Das
authors.initials: KD
authors.lastname: Sarma
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India. Electronic address: gupta_suman@yahoo.com.
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Launay
authors.affiliation: Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.
authors.forename: Denis
authors.initials: D
authors.lastname: Martin
mesh_terms: D000818:Animals; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D011804:Quinolines; D014344:Trypanocidal Agents; D003577:Cytochrome P-450 Enzyme System
keywords: ADME assays; In vitro activity; Leishmania donovani; Substituted quinoline-chalcones