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Design, synthesis and antitrypanosomal activity of heteroaryl-based 1,2,4-triazole and 1,3,4-oxadiazole derivatives
- Source :
- Bioorganic chemistry. 100
- Publication Year :
- 2020
-
Abstract
- Two series of novel 1,2,4-triazol-3-yl-thioacetamide 3a-b and 4a-b and 5-pyrazin-2-yl-3H-[1,3,4]oxadiazole-2-thiones 9a-h were designed and synthesized. The compounds prepared have been identified using 1H NMR, 13C NMR and elemental analyses. The synthesized compounds 3a, 3b, 4a, 4b, 9a, 9b, 9d-e and 9f have been evaluated with α-difluoromethylornithine (DFMO) as a control drug for their in vitro antitrypanosomal activity against Trypanosoma brucei. Results showed that 3b was the most active compound in general and also more potent than control DFMO. 3b was 8 folds more potent than the reference with IC50 of 0.79 μM and IC90 of 1.35 μM, respectively compared to DFMO (IC50 = 6.10 μM and IC90 of 8.66 μM). The tested compounds showed moderate cytotoxicity with selectivity indices ranging from 12 (9d) to 102 (3b) against L6 cells. Docking study was performed into ten of T. brucei enzymes which have been identified as potential/valid targets for most of the antitrypanosomal agents. The results of the docking study revealed high binding scores toward many of the selected enzymes. A good correlation was observed only between log (IC50) of antitrypanosomal activity of the new compounds and their calculated Ki values against TryR enzyme (R2 = 0.726). Compound 3b, the most active as antitrypanosomal agents exhibited similar binding orientation and interaction to those of WP6 against TryR enzyme. However, in a next round of work, a complementary studies will be carried out to clarify the mechanism of action of these compounds.
- Subjects :
- Stereochemistry
Trypanosoma brucei brucei
Antiprotozoal Agents
Protozoan Proteins
Trypanosoma brucei
01 natural sciences
Biochemistry
chemistry.chemical_compound
Sterol 14-Demethylase
Structure-Activity Relationship
Drug Discovery
medicine
Molecular Biology
IC50
chemistry.chemical_classification
Oxadiazoles
Binding Sites
biology
010405 organic chemistry
Chemistry
Organic Chemistry
1,2,4-Triazole
Triazoles
biology.organism_classification
In vitro
0104 chemical sciences
Molecular Docking Simulation
010404 medicinal & biomolecular chemistry
Enzyme
Mechanism of action
Docking (molecular)
Drug Design
Proton NMR
medicine.symptom
Subjects
Details
- ISSN :
- 10902120
- Volume :
- 100
- Database :
- OpenAIRE
- Journal :
- Bioorganic chemistry
- Accession number :
- edsair.doi.dedup.....e5ccaa27da4a6d9b91c507c1f8958229