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

Abstract

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 IC50 = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.

• Authors: S Kapil, P K Singh, A Kashyap, O Silakari
• Journal: SAR and QSAR in environmental research (SAR QSAR Environ Res) Vol. 30 Issue 12 Pg. 919-933 (Dec 2019) ISSN: 1029-046X [Electronic] England
• PMID: 31702401 (Publication Type: Journal Article)

Chemical References

• Antiprotozoal Agents
• Benzimidazoles
• Benzoxazoles
• Multienzyme Complexes
• Protozoan Proteins
• thymidylate synthase-dihydrofolate reductase
• Phosphorylcholine
• miltefosine
• Oxidoreductases
• pteridine reductase
• Tetrahydrofolate Dehydrogenase
• Thymidylate Synthase

Topics

• Antiprotozoal Agents (chemical synthesis, chemistry, pharmacology)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Benzoxazoles (chemical synthesis, chemistry, pharmacology)
• Drug Discovery
• Inhibitory Concentration 50
• Leishmania donovani (drug effects, metabolism)
• Models, Molecular
• Multienzyme Complexes (chemistry)
• Oxidoreductases (chemistry)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protozoan Proteins (chemistry)
• Structure-Activity Relationship
• Tetrahydrofolate Dehydrogenase (chemistry)
• Thymidylate Synthase (chemistry)