2. Academic Validation
  3. Design, synthesis and antitrypanosomal activity of heteroaryl-based 1,2,4-triazole and 1,3,4-oxadiazole derivatives

Design, synthesis and antitrypanosomal activity of heteroaryl-based 1,2,4-triazole and 1,3,4-oxadiazole derivatives

  • Bioorg Chem. 2020 Jul;100:103933. doi: 10.1016/j.bioorg.2020.103933.
Montaser Sh Shaykoon 1,  Adel A Marzouk 1,  Osama M Soltan 1,  Amira S Wanas 2,  Mohamed M Radwan 3,  Ahmed M Gouda 4,  Bahaa G M Youssif 5,  Mohamed Abdel-Aziz 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
  • 2 National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Pharmacognosy Department, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
  • 3 National Center for Natural Products Research, University of Mississippi, MS 38677, USA.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address: [email protected].
PMID: 32446119 DOI: 10.1016/j.bioorg.2020.103933
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.

Keywords

1,2,4-triazole; 1,3,4-oxadiazole; Antitrypanosomal; Docking; Pyrazine.

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