Síntese e avaliação biológica de compostos duais frente às enzimas NS2B-NS3 dos vírus Dengue e Zika e nsP2 do vírus Chikungunya

Abstract

Dengue (DENV) and Zika (ZIKV) viruses are flaviviruses that belong to the Flaviviridae family, which are transmitted by the bite of the infected vector, in this case, mosquitoes from the Aedes spp. genus. Viral replication of both is a function of non-structural protein 3 (NS3pro), which acts in association with NS2B, increasing the efficiency of the enzymatic activity. Thus, this protein complex represents an attractive target for the design of novel antiviral drugs. Chikungunya virus (CHIKV) is considered to be an Old World pathogen belonging to the Togaviridae family. This is an arbovirus from the Alphavirus genus that is also transmitted by Aedes spp. In this, non-structural protein 2 (nsP2) is related to the cleavage of non-structural polyproteins, fundamental to the CHIKV replication process. In sense, this thesis aimed to develop four series of bioactive compounds, rationally designed using computational techniques. In total, 82 benzothiazoles coupled to different acids were synthesized and evaluated toward NS2B-NS3 protease. Among these, 7 compounds showed significant activity, and the (E)-3-(4-(tert-butyl)phenyl)-N-(6-methoxybenzo[d]thiazol-2-yl)acrylamide (75) exhibited the best activity, with IC50 values of 7.6 and 11 μM upon ZIKV and DENV proteases, respectively. Also, it was verified that the active derivatives exert activity by a non-competitive mechanism. All results were used to construct the structure-activity relationship of each series of analogs, as well as, used during the discussion of molecular docking results. In parallel, a new virtual protocol for application in the study of anti-CHIKV compounds was developed with satisfactory results, with r2 values of 0.7 (ChemScore) and 0.84 (GoldScore). Finally, it has been observed that the synthesized derivatives cannot act as Michael acceptor-type mechanism and that these have more promising chemical characteristics than the compounds found in the literature.