title: Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties.
abstract: According to WHO, leishmaniasis is a major tropical disease, ranking second after malaria. Significant efforts have been therefore invested into finding potent inhibitors for the treatment. In this work, eighteen novel 1,2,3-triazoles appended with l-amino acid (Phe/Pro/Trp) tail were synthesized via azide-alkyne click chemistry with moderate to good yield, and evaluated for their anti-leishmanial activity against promastigote form of Leishmania donovani (Dd8 strain). Among all, compounds 40, 43, and 53 were identified with promising anti-leishmanial activity with IC50=88.83±2.93, 96.88±12.88 and 94.45±6.51μM respectively and displayed no cytotoxicity towards macrophage cells. Moreover, compound 43 showed highest selectivity index (SI=8.05) among all the tested compounds. Supported by docking studies, the lead inhibitors (40, 43 and 53) showed interactions with key residues in the catalytic site of trypanothione reductase. The results of pharmacokinetic parameters suggest that these selected inhibitors can be carried forward for further structural optimization and pharmacological investigation.
authors.affiliation: Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
authors.forename: Mir Mohammad
authors.initials: MM
authors.lastname: Masood
authors.affiliation: Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Department of Chemistry, TNB College, TM Bhagalpur University, Bhagalpur 812007, Bihar, India.
authors.forename: Phool
authors.initials: P
authors.lastname: Hasan
authors.affiliation: Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
authors.forename: Shams
authors.initials: S
authors.lastname: Tabrez
authors.affiliation: Department of Chemistry, TNB College, TM Bhagalpur University, Bhagalpur 812007, Bihar, India.
authors.forename: Md Bilal
authors.initials: MB
authors.lastname: Ahmad
authors.affiliation: Department of Physics, Deen Dayal Upadhyay Gorakhpur University, Gorakhpur, UP 273009, India.
authors.forename: Umesh
authors.initials: U
authors.lastname: Yadava
authors.affiliation: Organisch-Chemisches Institut, Westfälische Wilhelm-Universität Münster, 48149, Germany.
authors.forename: Constantin G
authors.initials: CG
authors.lastname: Daniliuc
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
authors.forename: Yogesh A
authors.initials: YA
authors.lastname: Sonawane
authors.affiliation: Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
authors.forename: Amir
authors.initials: A
authors.lastname: Azam
authors.affiliation: Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
authors.forename: Abdur
authors.initials: A
authors.lastname: Rub
authors.affiliation: Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA. Electronic address: mabid@jmi.ac.in.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abid
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D057930:Click Chemistry; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology; D007896:Leishmaniasis / Q000188:drug therapy; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000981:Antiprotozoal Agents; D014230:Triazoles; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
keywords: 1,2,3-Triazole; Amino acid tail; Anti-leishmanial; Click chemistry; Docking studies; Trypanothione reductase