Design, synthesis and biological evaluation of new antiparasitic agents having 1,2,4-oxadiazole motif in their structures

• Grant number: 21/13544-5
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2022
• End date: September 30, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Fernando Antonio Santos Coelho
• Grantee: Thaynan Aparecida Bueno Chagas
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Chagas Disease and Leishmaniasis are two fatal neglected tropical diseases, with a high worldwide incidence and endemic in Brazil. The therapeutic arsenal currently available for the treatment of these pathologies is limited, expensive and highly toxic. Thus, the development of new drugs for the treatment of these diseases is crucial. In this sense, five hybrid oxadiazole derivatives (hits), recently synthesized by our research group to which, showed promising trypanocidal and leishmanicidal activity, but with a toxicological profile that requires attention. Thus, given progress for this work, this direct doctoral research project has as main aims to optimize these hits in order to obtain a more metabolically stable substance, with less toxicity and greater parasitic activity. In the first part of this project, a study of the structure-activity relationship through structural changes based on pharmacokinetic aspects will be carried out. In the second part, other structural modifications are proposed, such as the addition of pharmacophoric groups. At this time of the work, molecular docking assays will be carried out using the enzymes CYP51 and TryR, which are essential for the survival of the parasites, as therapeutic targets. Substances with better target inhibition potential will be synthesized and pharmacologically evaluated. The success of the proposed approaches will make it possible to acquire a library of novel bioactive substances likely to be new prototypes of trypanocidal and leishmanicidal drugs. (AU)