Optimization of compounds from the pyridyl diazepane series for the treatment of malaria

• Grant number: 23/10388-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2023
• End date: June 30, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Luiz Carlos Dias
• Grantee: Stephany Vieira Carmello
• 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

The objective of the scientific initiation project is to continue the search for pharmacological innovations for the treatment of malaria, through the synthesis of new analogues of target molecules sent by MMV, as starting points. It is expected that the synthesized compounds will be able to progress in the drug development chain, reaching an adequate profile for a clinical candidate, and that in the future they will be able to promote the treatment of malaria, controlling this prevalent disease with disastrous consequences in patients where the lack of effective and safe therapies is disabling.In this project, the student will initially be involved in the validation program of the Piridyl diazepane series. The Hit compound in this series (compound MMV1812065) has an IC50 of 0.53 µM against P. falciparum and is active against resistant strains of the parasite. Metabolic stability is good in rats and moderate in humans. In addition, it has good solubility and low toxicity. However, due to the presence of basic heterocycles at both ends of the molecule, compound MMV1812065 is a cytochrome P (CYP) inhibitor. Another disadvantage of this series is the moderate affinity for the hERG channel.In addition to improving potency against the target parasite, the aim in this series is to reduce the risks of CYP and hERG inhibition. In this regard, 15 (fifteen) analogues were synthesized and tested against the target parasite. The synthesis of analogues was carried out at UNICAMP's Laboratory of Synthetic Organic Chemistry, based on works in the literature and on the expertise developed. On the other hand, activity tests against the parasite were carried out in the laboratory of Prof. Rafael Guido (USP, São Carlos).Chemical structure-biological activity relationship studies will focus on reducing the risks of hERG and CYP inhibition by introducing electron-withdrawing groups on the pyridine ring and on the imidazole group to reduce basicity. Finally, the introduction of bulky substituents on the left side of the molecule (LHS) aims to further reduce the risk of CYP inhibition.