Biological evaluation of quinoxaline compounds as Anti-HIV agents targeting reverse transcriptase enzyme

SALVATORI, MELINA; MARTINI, FLORENCIA; BARRIONUEVO, EMILIANO; TURK, GABRIELA; TAVERNA PORRO, MARISA; FABIAN, LUCAS; MOGLIONI, ALBERTINA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2019

SAIC/SAFE/SAB/SAP/AACyTAL/NANOMED-AR/HCS

Infections by human immunodeficiency virus (HIV) still represent a serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains, the poor compliance of treatments and the adverse side effects of the antiretroviral therapy, the development of new treatment agents, more active, less toxic and with increased tolerability to mutations is still required. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase (RT) and HIV replication in cell culture. In this context, the aim of this work was the discovery of novel RT inhibitors containing a quinoxaline scaffold. For this purpose, a chemical library of these type of compounds with potential RT inhibitory activity was previously constructed and then screened, using docking and a 3D-QSAR model. This screening led to the synthesis of twenty-five quinoxaline compounds. Here we present the results of the biological activity evaluation of these derivatives formerly synthesized. First, all of the compounds were assayed as inhibitors of the recombinant wild-type RT enzyme. From this evaluation, six compounds showed interesting inhibitory capabilities. The most promising, compound 3, showed an IC50 of 0.33 µM ± 0.12 µM, slightly higher than nevirapine?s (IC50 = 0.10 µM ± 0.02 µM). Then, the anti-HIV activities on MT4 infected cells and the cytotoxicity of the quinoxaline derivatives with the highest RT inhibitory capabilities were evaluated. Compound 3 showed excellent anti-HIV properties with an EC50 of 0.030 µM ± 0.001 µM, smaller than nevirapine?s (EC50=0.060 µM ± 0.001 µM). Also, another compound showed interesting anti-HIV capabilities with an EC50 of 1.6 µM ± 0.4 µM. In conclusion, two quinoxaline derivatives, 12 and 3, showed promising inhibitory activity profiles and could be defined as hit and lead compounds, respectively. The further development of these will likely provide novel and more potent RT inhibitors for HIV treatment.