Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids

Author(s)

Fernandes, Fabio S. ^[1] ; Santos, Hugo ^[1] ; Lima, Samia R. ^[1] ; Conti, Caroline ^[1] ; Rodrigues Jr, Manoel T. ; Zeoly, Lucas A. ^[2] ; Ferreira, Leonardo L. G. ^[3] ; Krogh, Renata ^[3] ; Andricopulo, Adriano D. ^[3] ; Coelho, Fernando ^[2]

Affiliation

^[1] Univ Estadual Campinas, Inst Chem, Lab Synth Nat Prod & Drugs, POB 6154, BR-13083970 Campinas, SP - Brazil

^[2] Rodrigues Jr, Jr., Manoel T., Univ Estadual Campinas, Inst Chem, Lab Synth Nat Prod & Drugs, POB 6154, BR-13083970 Campinas, SP - Brazil

^[3] Univ Sao Paulo, Inst Phys Sao Carlos, Lab Med & Computat Chem, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 201, SEP 1 2020.
• Web of Science Citations: 0

Abstract

A series of highly active hybrids were discovered as novel antiparasitic agents. Two heterocyclic scaffolds (1,2,4-oxadiazole and 3-hydroxy-2-oxindole) were linked, and the resulting compounds showed in vitro activities against intracellular amastigotes of two protozoan parasites, Tiypanosoma cruzi and Leishmania infantum. Their cytotoxicity was assessed using HFF-1 fibroblasts and HepG2 hepatocytes. Compounds 5b, 5d, 8h and 8o showed selectivity against L. infantum (IC50 values of 3.89, 2.38, 2.50 and 2.85 mu M, respectively). Compounds 4c, 4q, 8a and 8k were the most potent against T. cruzi, exhibiting IC50 values of 6.20, 2.20, 2.30 and 2.20 mu M, respectively. Additionally, the most potent anti-T. cruzi compounds showed in vitro efficacies comparable or superior to that of benznidazole. These easy-to-synthesize molecules represent novel chemotypes for the design of potent and selective lead compounds for Chagas disease and leishmaniasis drug discovery. (C) 2020 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 18/02611-0 - Post-Functionalization of Small Ply-functionalized Molecules: A Robust Approach to the Synthesis of New Structural Patterns with POtential Biological Activity
• Grantee: Fernando Antonio Santos Coelho
• Support type: Regular Research Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 16/23005-6 - Synthesis of new heterocycles exhibiting potential biological activities by exploring the Morita-Baylis-Hillman adducts as building blocks
• Grantee: Fábio de Souza Fernandes
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/09205-0 - New frontiers of the Morita-Baylis-Hillman reaction: 1) New applications of a bifunctional catalyst derived from imidazole. 2) Studies on the asymmetric synthesis of a natural high-potency sweetener
• Grantee: Hugo dos Santos
• Support type: Scholarships in Brazil - Doctorate (Direct)