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

Surface overlay of compounds 40 (cyancolor) and 53 (yellow color) with Trypanothione reductase. [Display omitted] 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 treatme...

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Published in:Bioorganic & medicinal chemistry letters 2017-05, Vol.27 (9), p.1886-1891
Main Authors: Masood, Mir Mohammad, Hasan, Phool, Tabrez, Shams, Ahmad, Md. Bilal, Yadava, Umesh, Daniliuc, Constantin G., Sonawane, Yogesh A., Azam, Amir, Rub, Abdur, Abid, Mohammad
Format: Article
Language:English
Subjects:
1,2,3-Triazole
Amino acid tail
Amino Acids - chemistry
Amino Acids - pharmacology
Anti-leishmanial
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Click Chemistry
Docking studies
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
Trypanothione reductase
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Summary:Surface overlay of compounds 40 (cyancolor) and 53 (yellow color) with Trypanothione reductase. [Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.03.049