18479-80-6Relevant academic research and scientific papers
Synthesis of new cyclic imides derived from safrole, structure-and ligand-based approaches to evaluate potential new multitarget agents against species of leishmania
Athayde-Filho, Petr?nio F.,Costa, Normando A. da Silva,Lima, Tatjana K. de Souza,Lira, Bruno F.,Luis, Cristiane C. S.,Luis, José A. de Sousa,Rocha, Juliana da Camara,Scotti, Luciana,Scotti, Marcus T.
, p. 39 - 51 (2020)
Background: Leishmaniasis is a neglected disease that does not have adequate treatment. It affects around 12 million people around the world and is classified as a neglected disease by the World Health Organization. In this context, strategies to obtain new, more active and less toxic drugs should be stimulated. Sources of natural products combined with synthetic and chemoinformatic methodologies are strategies used to obtain molecules that are most likely to be effective against a specific disease. Computer-Aided Drug Design has become an indispensable tool in the pharmaceutical industry and academia in recent years and has been employed during various stages of the drug design process. Objectives: Perform structure-and ligand-based approaches, synthesize and characterize some compounds with materials available in our laboratories to verify the method’s efficiency. Methods: We created a database with 33 cyclic imides and evaluated their potential anti-Leishmanial activity (L. amazonensis and L. donovani) through ligand-and structure-based virtual screening. A diverse set selected from ChEMBL databanks of 818 structures (L. donovani) and 722 structures (L. amazonensis), with tested anti-Leishmanial activity against promastigotes forms, were classified according to pIC50 values to generate and validate a Random Forest model that shows higher statistical indices values. The structures of four different L. donovani enzymes were downloaded from the Protein Data Bank and the imides’ structures were submitted to molecular docking. So, with available materials and technical feasibility of our laboratories, we have synthesized and characterized seven compounds through cyclization reactions between isosafrole and maleic anhydride followed by treatment with different amines to obtain new cyclic imides to evaluate their anti-Leishmanial activity. Results: In silico study allowed us to suggest that the cyclic imides 516, 25, 31, 24, 32, 2, 3, 22 can be tested as potential multitarget molecules for leishmanial treatment, presenting activity probability against four strategic enzymes (Topoisomerase I, N-myristoyltransferase, cyclophilin and O-acetylserine sulfhydrylase). The compounds synthesized and tested presented pIC50 values less than 4.7 for Leishmania amazonensis. Conclusion: After combined approach evaluation, we have synthesized and characterized seven cyclic imides by IR,1 H NMR,13 C-APT NMR, COSY, HETCOR and HMBC. The compounds tested against promastigote forms of L. amazonensis presented pIC50 values less than 4.7, showing that our method was efficient in predicting true negative molecules.
Synthesis, in silico study, theoretical stereochemistry elucidation and antifungal activity of new imides derived from safrole
Barbosa-Filho, José M.,Cordeiro, Laísa V.,Costa, Normando A. S.,Cruz, Luiz E. G.,Lima, Edeltrudes O.,Lira, Bruno F.,Rocha, Gerd B.,Souza, Helivaldo D. S.,Vilela, Raquel F.,de Assis, Kelyonara M. S.,de Athayde-Filho, Petronio F.
, p. 2091 - 2103 (2020/10/12)
Ten imides derived from safrole, 4a-4j, were synthesized and their structures were fully characterized by infrared (IR) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry (HRMS) analysis. Among the ten imides studied, eight are new. The compounds were evaluated in an in silico study and showed strong to moderate antifungal activity against various strains of Candida and Cryptococcus. In particular, compounds 4b, 4c and 4h exhibited strong antifungal activity, with minimum inhibitory concentration (MICs) between 0.17-0.73 μmol mL-1. The compound 4j exhibited antifungal activity with MIC 1.28 μmol mL-1 for all strains tested. In silico studies of the parameters of Lipinski's rule of five indicated that these compounds are potential new drug candidates. The predict oral bioavailability can be evaluated through these parameters. In addition, a computational study helped assigning the stereochemistry of compound 4j, where the synthesized mixture is composed by two stereoisomers, 4j(1) (SRR) and 4j(2) (RSS).
