Desenho racional de fármacos auxiliado por computador de novos derivados 2-amino-tiofeno como agente anti-Leishmania e antifúngico

Abstract

Drug development is a challenging, expensive, and time-consuming process, although this process has been accelerated due to the development of computational tools and methodologies. Medicinal chemistry plays a central role in several processes aimed at identifying bioactive substances and developing lead compounds with optimized pharmacodynamic and pharmacokinetic properties. Therefore, this study aims to perform computer-aided drug design (CADD) studies and synthesize promising molecules with biological activity for leishmaniasis and fungal diseases. In the first chapter, a series of 2-amino-thiophene (2-AT) derivatives were virtually screened using QSAR tools, ADMET filters and prediction models, allowing the direct synthesis of compounds, which were evaluated in vitro against promastigotes and axenic amastigotes of Leishmania amazonensis. All compounds were properly synthesized and 8 of them proved to be active against at least one of the evolutionary forms of the parasite with IC50 values lower than 10 μM. Compounds 8CN and DCN-83, respectively, are the most active against promastigote and amastigote forms, with IC50 values of 1.20 and 0.71 μM. As a result, these findings demonstrate that the ligand-based virtual screening (LBDD) technique proved to be quite effective and saved time, effort, and money in the selection of potential anti-Leishmania agents. In the second chapter, 17 new 2-AT derivatives were designed and synthesized using molecular simplification through green chemistry procedures to improve the lipophilicity of these molecules for use against dermatophyte fungi diseases. Using microwave assisted synthesis compounds were obtained in good yields (35-85 %). Compounds 4a-q presented good druglikeness and pharmacokinetic profiles and no cytotoxicity up to 100 μM. The compounds presenting the best antifungal profiles were 4e, 4f, 4g, 4k, 4l, 4m, 4o and 4p with MIC values between 16 - 64 μg.mL-1, against more than one fungi specie, being in some cases better than the reference drug fluconazole. As a result, the planning strategy based on the structure of the ligand, the structure-activity relationships (SAR) and cytotoxic evaluation of the most active compounds was a success, improving the pharmacokinetic profile and solubility in water, developing from the 2-AT derivatives new promising antifungal drugs.