Optimization of pyridyl diazepane series compounds for the treatment of malaria

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 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 manifests itself in a disabling way. Metabolic stability is good in rats and moderate in humans. Furthermore, it has good solubility and low toxicity. However, due to the presence of basic heterocycles at both ends of the molecule, the 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 objective 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 the analogues was carried out at the Synthetic Organic Chemistry Laboratory at UNICAMP, based on literature and the expertise developed. On the other hand, activity tests against the parasite were carried out in Prof.’s laboratory. Rafael Guido (USP, Sâo Carlos). Chemical structure-biological activity relationship studies will focus on reducing the risks of hERG and CYP inhibition, introducing electron-withdrawing groups on the pyridine ring and 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.

Project details

Drug Resistance
Drug-based Strategies
Product Development

Oct 2023 — Sep 2024

Brazil