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 Oacetylserine
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, 1H NMR, 13C-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.
Microscopic Examination Of Postcapillary Cerebral Venues In Hemorrhagic Stroke
