Structure based designing of benzimidazole/benzoxazole derivatives as anti-leishmanial agents

• Published in: SAR and QSAR in environmental research Vol. 30; no. 12; pp. 919 - 933
• Main Authors: Kapil, S., Singh, P.K., Kashyap, A., Silakari, O.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.12.2019; Taylor & Francis Ltd
• Subjects: Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Benzimidazoles; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Biomolecules; Biosynthesis; Chemotherapy; Computer applications; Dihydrofolate reductase; dihydrofolate reductase-thymidylate synthase; Drug Discovery; Folic acid; Homology; homology modelling; Imidazole; Inhibitory Concentration 50; Leishmania donovani - drug effects; Leishmania donovani - metabolism; Leishmaniasis; Miltefosine; Models, Molecular; Molecular dynamics; MTT assay; Multienzyme Complexes - chemistry; Oxidoreductases - chemistry; pharmacophore; Phosphorylcholine - analogs & derivatives; Phosphorylcholine - pharmacology; Protozoan Proteins - chemistry; Pteridine reductase 1; Reductases; Software; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - chemistry; Thymidylate synthase; Thymidylate Synthase - chemistry; Vector-borne diseases; homology modelling; Leishmaniasis; dihydrofolate reductase-thymidylate synthase; pharmacophore; MTT assay; pteridine reductase 1
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2019.1684357

Folates are essential biomolecules required to carry out many crucial processes in leishmania parasite. Dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) involved in folate biosynthesis in leishmania have been established as suitable targets for development of chemotherapy against leishmaniasis. In the present study, various computational tools such as homology modelling, pharmacophore modelling, docking, molecular dynamics and molecular mechanics have been employed to design dual DHFR-TS and PTR1 inhibitors. Two designed molecules, i.e. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were synthesized. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to evaluate in vitro activity of molecules against promastigote form of Leishmania donovani using Miltefosine as standard. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were found to be moderately active with showed IC 50  = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.