Planejamento, síntese e estudo da relação entre a estrutura química e a atividade biológica de uma série de 1,3,4-oxadiazóis

Abstract

This work involved the planning, synthesis, and characterization of a series of 1,3,4-oxadiazole derivatives with varying substitution patterns, aimed at potential cytotoxic activity. Two synthetic methodologies were employed: the first based on hydrazone formation followed by I₂-mediated cyclization, yielding 32 hydrazones and 29 2,5-disubstituted oxadiazoles; the second involved cyclization with CS₂ followed by a Mannich reaction, which produced 15 novel 1,3,5-trisubstituted oxadiazoles. Cytotoxicity assays IC50 were performed on the synthetic intermediates (hydrazones and alkyl/aryl-1,3,4-oxadiazole-2-thiols) and the final di- and trisubstituted oxadiazoles against tumor cell lines 4T1, CT26.WT, and B16.F10, as well as non-tumor lines BHK-21 and J774A.1. Four hydrazones (19, 26, 30, and 31) exhibited activity against the 4T1 tumor line, with compound 31 demonstrating selectivity superior to cisplatin. It was observed that lipophilicity and halogen substitution, particularly bromine, enhanced the cytotoxic profile. The 2,5-disubstituted oxadiazoles were generally less active than their corresponding hydrazones, with the exception of compounds 66 and 67. In contrast, the trisubstituted oxadiazoles showed increased cytotoxicity as the lipophilic chain length increased, though with low selectivity, favored by the presence of alkylated piperazines. Furthermore, compounds 31, 66, and 83 inhibited cell migration in tumor lines, suggesting potential for anti-metastatic studies. In antimicrobial evaluations, 12 hydrazones and 12 oxadiazoles showed no activity against Lactobacillus fermentum, Leuconostoc mesenteroides, and Saccharomyces cerevisiae. However, ongoing studies with derivatives 83–97 revealed that fluorinated 1,3,4-oxadiazole-2,3-trisubstituted derivatives exhibited promising performance against L. mesenteroides comparable to ampicillin, particularly the 12-carbon fluorinated analog (97).