Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties

Mir Mohammad Masood; Phool Hasan; Shams Tabrez; Md Bilal Ahmad; Umesh Yadava; Constantin G Daniliuc; Yogesh A Sonawane; Amir Azam; Abdur Rub; Mohammad Abid

doi:10.1016/j.bmcl.2017.03.049

Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties

Bioorg Med Chem Lett. 2017 May 1;27(9):1886-1891. doi: 10.1016/j.bmcl.2017.03.049. Epub 2017 Mar 22.

Authors

Affiliations

¹ 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.
² 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.
³ Infection and Immunity Lab, Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁴ Department of Chemistry, TNB College, TM Bhagalpur University, Bhagalpur 812007, Bihar, India.
⁵ Department of Physics, Deen Dayal Upadhyay Gorakhpur University, Gorakhpur, UP 273009, India.
⁶ Organisch-Chemisches Institut, Westfälische Wilhelm-Universität Münster, 48149, Germany.
⁷ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA.
⁸ Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁹ 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.

PMID: 28359789
DOI: 10.1016/j.bmcl.2017.03.049

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.

Keywords: 1,2,3-Triazole; Amino acid tail; Anti-leishmanial; Click chemistry; Docking studies; Trypanothione reductase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / chemistry*
Amino Acids / pharmacology*
Antiprotozoal Agents / chemistry*
Antiprotozoal Agents / pharmacology*
Click Chemistry
Humans
Leishmania donovani / drug effects*
Leishmania donovani / enzymology
Leishmaniasis / drug therapy
Molecular Docking Simulation
NADH, NADPH Oxidoreductases / antagonists & inhibitors
NADH, NADPH Oxidoreductases / metabolism
Triazoles / chemistry*
Triazoles / pharmacology*

Substances

Amino Acids
Antiprotozoal Agents
Triazoles
NADH, NADPH Oxidoreductases
trypanothione reductase