Evaluation of the structure-property relationship of benzoxazinone derivatives against Chagas Disease

F. D. AGUIAR; M. A. DESSOY; M. C. MOLLO; E. LEE; S. M. DUARTE; R. KROGH; L. L. G. FERREIRA; R. C. CHELUCCI; A. D. ANDRICOPULO; CRUZ, LUIZA R.; KRATZ, JADEL M.; DIAS, LUIZ C.

Congreso; BrazMedChem 2023; 2023

Chagas Disease (CD) affects about 6 million people¹, and current chemotherapy has contraindications that compromise the safety and efficacy of the treatment. The Lead Optimization Latin America (LOLA) consortium is part of an international cooperation aimed at developing effective and safe treatments for CD. Based on a phenotypic screening against T. cruzi, the benzoxazinone series stood out for its potency and selectivity but showed low metabolic stability in in vivo pharmacokinetic studies (Figure 1). In this sense, this work aims to optimize the ADME properties of this series. Investigation of the structure-property relationship (SPR) of the benzoxazinone series is ongoing. Electron-withdrawing substituents (EWG) were introduced on the left side of the core (Figure 2, in green) to reduce the tendency for cytochrome P450-mediated oxidative metabolism². On the right side of the core (in blue), N-ethyl-morpholine was replaced due to its susceptibility to undergo biotransformation reactions. In previous studies conducted by our research group, heterocycles such as piperidine and piperazine were poorly tolerated in terms of potency and permeability. Therefore, we chose to add carbon bridges³, fluorine atoms, and change the size of the rings4. These are classic strategies for improving metabolic stability, measured through the level of metabolic clearance in the mouse liver microsome (MLM) assay. The suggested modifications slightly reduced lipophilicity, but the lipophilic ligand efficiency (LLE) value remained close to 3 in most cases, due to loss of potency.Preliminary in vitro results showed an increase in metabolic stability due to the introduction of EWG and N-ethyl-morpholine replacement but accompanied by a reduction in the inhibitory potential against T. cruzi. The next steps are to expand the envisaged synthesis scope, exploring bioisosteric and linker modifications.