BIOLOGICAL EVALUATION OF QUINOXALINE COMPOUNDS AS ANTI-HIV AGENTS TARGETING REVERSE TRANSCRIPTASE ENZYME.

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

Mar del Plata

Congreso; REUNIÓN ANUAL DE SOCIEDADES DE BIOCIENCIA 2019 LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC) LI Reunión Anual de la Asociación Argentina de Farmacología Experimental (SAFE) XXI Reunión Anual de la Sociedad Argentina de B; 2019

Abstract/Resumen: Infections by human immunodeficiencyvirus (HIV) still represent a serious concern and a global threatto human health. Due to appearance of multi-resistant virusstrains, the poor compliance of treatments and the adverse sideeffects of the antiretroviral therapy, the development of newtreatment agents, more active, less toxic and with increasedtolerability to mutations is still required. Quinoxaline derivativesare an emergent class of heterocyclic compounds with a widespectrum of biological activities and therapeutic applications.These types of compounds have also shown high potency in theinhibition of HIV reverse transcriptase (RT) and HIV replication incell culture. In this context, the aim of this work was thediscovery of novel RT inhibitors containing a quinoxaline scaffold.For this purpose, a chemical library of these type of compoundswith potential RT inhibitory activity was previously constructedand then screened, using docking and a 3D-QSAR model. Thisscreening led to the synthesis of twenty-five quinoxalinecompounds. Here we present the results of the biological activityevaluation of these derivatives formerly synthesized. First, all ofthe compounds were assayed as inhibitors of the recombinantwild-type RT enzyme. From this evaluation, six compoundsshowed interesting inhibitory capabilities. The most promising,compound 3, showed an IC50 of 0.33 ± 0.12 μM, slightly higherthan nevirapine?s (IC50= 0.10 ± 0.02 μM). Then, the anti-HIVactivities on MT4 infected cells and the cytotoxicity of thequinoxaline derivatives with the highest RT inhibitory capabilitieswere evaluated. Compound 3 showed excellent anti-HIVproperties with an EC50 of 0.030 ± 0.001 μM, smaller thannevirapine?s (EC50= 0.060 ± 0.001 μM). Also, another compound showed interesting anti-HIV capabilities with an EC50of 1.6 ± 0.4 μM. In conclusion, two quinoxaline derivatives, 12and 3, showed promising inhibitory activity profiles and could bedefined as hit and lead compounds, respectively. The furtherdevelopment of these will likely provide novel and more potentRT inhibitors for HIV treatment.