Avaliação pré-clínica de novos compostos de pirimidopirimidina para combate à leishmaniose

The most severe form of Leishmaniasis, VL, may be fatal if left untreated in over 95% of cases. Leishmaniasis mainly strikes the most economically vulnerable populations in developing countries with limited access to health facilities, where the detection and control of the infection are scarce(Leishmaniasis, 2023). However, the disease is spreading to new areas due to population migration and climate change(Alves et al., 2018) and in the near future, it may become a global threat if there is no general use of effective drugs. The only approach to treat leishmaniasis is chemotherapy once there is no efficacious vaccine. All available drugs present considerable toxicity and high cost and have to be administered by the parenteral route, except for miltefosine, demanding hospitalization and leading to low compliance of the patients. Furthermore, different Leishmania species affect different populations, treatment failures occur, and resistance to the drugs emerged. Additionally, a considerable number of patients are excluded from the available treatments because of HIV co-infection, pregnancy, renal failure, or disease severity(Leishmaniasis, 2023). Following the appeals of WHO, the research community has been deeply involved in the search for new anti-Leishmania drugs; however, no new medicine has reached the clinic in the last 15 years(Visceral Leishmaniasis | DNDi, 2020), which highlights how challenging the discovery of new antileishmanials is. According to Drugs for Neglected Diseases Initiative, a not-for-profit worldwide research organization developing new treatments for Leishmaniasis, the new drugs should be highly effective against different species of Leishmania, present low toxicity, have oral administration (OA), low cost, and chemical stability so they can be used where they are needed. The main objective of this project is to identify a lead compound for development as a new anti-leishmanial agent. The lead will present high in vivo efficacy, oral route of administration (OA), and no observable toxicity. This will be achieved through the specific aims: 1-Optimization of the Hit compound by rational design and synthesis of new derivatives, and its salts, to get highly potent, non-toxic and, compounds with PK properties compatible with OA. 2-Development of a nanoformulation for OA and simultaneously improve pharmacological properties of the drug. 3-Determination in vitro of potency and toxicity of the new synthesized compounds, respectively against L. infantum promastigotes and intracellular amastigote forms and THP1 cell line. 4-Determination of in vivo PK properties using the SNAP-PK approach of the 12 most promising derivatives (12 compounds and their nanoformulations, best selectivity index and best early in vitro ADMET properties) for identification of the most favorable compound for OA. 5-Determinations of in vivo efficacy of the six compounds that showed the best PK properties. The team is aware of how our main objective is ambitious, as in the drug discovery and development of drugs the attrition is enormous mainly due to new compounds may show low potency and lack of safety. However, previous results of the team showed that our compounds are highly potent and have good safety profile so the team is confident that in this project the new derivatives will be still more potent and continue to have good safety profile.