Between the functionalized chromones, 3-formylchromone is a highly reactive synthon used in many reactions due to the presence of electron-deficient centers at C-2, C-4 and the C-3 formyl group. Reaction of the -CHO group with nitrogen nucleophiles such as hydrazine and aminopyrazole derivatives has led to the formation of a variety of molecules that have been studied in detail for being of interest to drug discovery. Chromone-3-carboxaldehydes react with aromatic primary hydrazines mainly at the formyl group by a straightforward 1,2-addition to form the corresponding hydrazone, but when the reaction is submitted to prolonged heating, a pyrazole-type structure is produced by a 1,4-addition reaction accompanied by pyrone ring-opening followed by recyclization and proton transfer. On the other hand, reaction of 3-formylchromone with equimolar quantities of aminopyrazole derivatives was shown to afford mainly pyrazolo[1,5-a]-pyrimidines, formed by the above-mentioned cyclization process of an imine intermediate.
Led by the biological and pharmacological relevance of the 3-formylchromone derivatives and its interesting chemistry, in this work we present the synthesis of a series of pyrazoles (4a-c), hydrazones (5a-c), pyrazolo[1,5-a]-pyrimidines (6a, 6b) and one pyrazolo[3,4-b]-pyridine (7) and the report on their in vitro anti-leishmanial and anti-trypanosomal activity. Chemical results showed that the formation of regioisomer 7 may arise from an imine intermediary that undergoes 1,4-addition at C-2 by attack of C-4' from the pyrazole instead of the nitrogen atom N-2'. To the best of our knowledge, this is the first report regarding formation of pyrazolo[3,4-b]-pyridines by intramolecular attack of an sp2 carbon atom.
The in vitro studies were performed against strains of Leishmania mexicana (bel 21) and Tripanosoma cruzi (DM28). Compounds 5a and 5b showed activity at micromolar level and good selectivity index (SI) with IC50 values of 6.3 (SI = 3.4) and 15 (SI = 1.9) mM for L. Mexicana and 4.1 (SI = 5.2) and 10 (SI = 3) mM for T. cruzi respectively. From the above-mentioned results, compounds 5a and 5b may be considered for further chemical modifications in order to increase their activity as potential antiparasitic agents.
