Síntese, caracterização e avaliação antimalárica de 1H-1,2,3- triazóis-1,4-dissubstituídos derivados da melatonina e triptamina

Abstract

Present in more than 90 countries, malaria is considered one of the most lethal infectious diseases in the world. Caused by parasites of the Plasmodium genus, it is transmitted by female Anopheles mosquitoes. The most recent data on the epidemiology of the disease released by the World Health Organization (WHO) estimate that in 2023 there were approximately 263 million cases of malaria worldwide, with more than 597,000 deaths. The search for new compounds with antimalarial activity is urgent, since resistance to the classic drugs used for treatment has already been described in countries where the disease is endemic. Melatonin is a hormone with an indole structure and plays a central role in controlling the replication of the parasite that causes malaria and stabilizing parasitemia. Blocking the pathway of this hormone may contribute to the discovery of new antimalarial drugs. The aim of this work was to prepare triazoles derived from the indole nucleus that may exhibit antimalarial activity on the parasite cell cycle, inhibiting the growth or causing the death of Plasmodium falciparum. Several novel molecules containing in their structure, heterocyclic 1H-1,2,3-triazole rings and benzene ring with different substituents were designed and synthesized in this work by means of the CuAAC “click chemistry” reaction catalyzed by copper (I). In the synthesis step, the melatonin precursor was subjected to the alkylation reaction to form the respective terminal alkyne intermediate (3). Subsequently, this intermediate was treated with different prepared aromatic azidocompounds (1a-e) to form the respective triazole products of the series (4a-e) derived from melatonin with yields ranging from 68 to 91%. Tryptamine, a congener of melatonin, was also used as a precursor in the formation of triazole sulfonamide compounds of the series (8a-e) and (11a-e) with yields ranging from 59.4 to 91%. The structural elucidation of the intermediates and products obtained was successfully performed using IR and NMR spectroscopic techniques of 13C and 1H isotopes. Compounds (10), (4d) and (4e) exhibited measurable antimalarial activity with IC50 values of 33.38 ± 1.487 µM, 31.92 ± 6.370 µM and 11.57 ± 1.863 µM, respectively, showing low cytotoxicity in mammalian cells. Among these, (4e) emerged as the most potent and least cytotoxic with SI (>4.32). These results highlight the potential of these three compounds as promising candidates for further investigation, providing a solid basis for future studies aiming at their optimization and development as antimalarial agents.