Síntese e avaliação do potencial biológico de derivados de N-acil-2-aminobenzotiazol contra o vírus Zika

Abstract

The Zika virus (ZIKV) is a flavivirus belonging to the flaviridae family, which is transmitted by the bite of the infected vector, in this case, the mosquito of the Aedes aegypti genus. One of the strategies for the development of new antivirals is the inhibition of the NS2B-NS3 protease, which is essential for viral replication. The work addresses the synthesis of 19 novel N-acyl-2-aminobenzothiazole derivatives, with potential biological activity against ZIKV. The compounds were evaluated for their ability to inhibit ZIKV replication and the ability to inhibit ZIKV’s NS2B-NS3 protease. Compound 33 was the most promising of the series of modifications made to the p-amino-benzamide core, demonstrating significant efficacy against ZIKV, with an EC50 value of 5.1 µM. In addition, the compound showed a selectivity index of 25.1, suggesting that it is 25.1 times morem effective in inhibiting ZIKV than in causing toxic effects in host cells. Other in vitro antivir results showed that compounds 40 and 60 from the series of modifications to the sulfonamide core and the benzothiazole core, respectively, also showed efficacy against ZIKV, about twice as high as compound 2 selected as the initial hit, both presenting EC50 close to 5 µM, presenting selectivity indices of 9.2 and 7.7, respectively, considered as promising candidates. Thus, compounds 33, 40 and 60 were selected and tested at 10 µM against the inhibition of replication of the BHK-21-RepZIKV_IRES-Neo replicon, expressing a reduction in luminescent activity of Renilla luciferase by 63.4%, 60.4% and 75.5%, respectively. Based on the antiviral activity assays with ZIKV virus and replicon, the most promising compounds were identified as potential candidates to inhibit the NS2B-NS3 protease, and therefore, were subjected to a secondary screening to confirm their ability to inhibit the NS2B-NS3 enzyme of ZIKV, with the aim of verifying the potential biochemical target. The initial screening assays with NS2B-NS3 confirmed that the tested compounds showed promiscuous activity, not confirming the NS2B-NS3 enzyme as a biochemical target for the mechanism of action of this synthesized chemical class. The compounds that stood out the most in the initial enzymatic screening and in the ZIKV replication assays, were compounds 2, 32, 40, 41, 48, 59, 60 and 65 submitted to evaluation through computational methods in relation to their ADME-tox profile (absorption, distribution, metabolism, excretion, toxicity), presenting favorable properties for drug candidates.