Design, synthesis, in vitro and in silico studies of novel 4-oxoquinoline ribonucleoside derivatives as HIV-1 reverse transcriptase inhibitors
Autor: | Luana da S. M. Forezi, Andressa Marttorelli, Maria Cecília B. V. de Souza, Fernanda da C. S. Boechat, Carlos Rangel Rodrigues, Juliana L. Abrantes, Helena Carla Castro, Thiago Moreno L. Souza, Mariana M. J. Ribeiro, Alessandra Mendonça Teles de Souza |
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Rok vydání: | 2020 |
Předmět: |
Models
Molecular Drug Anti-HIV Agents In silico media_common.quotation_subject Allosteric regulation Microbial Sensitivity Tests 01 natural sciences Structure-Activity Relationship 03 medical and health sciences Pharmacokinetics Drug Discovery Humans 030304 developmental biology media_common Pharmacology chemistry.chemical_classification 0303 health sciences 4-Quinolones Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry General Medicine Ribonucleoside Virology HIV Reverse Transcriptase In vitro Reverse transcriptase 0104 chemical sciences Enzyme Drug Design HIV-1 Reverse Transcriptase Inhibitors Ribonucleosides |
Zdroj: | European Journal of Medicinal Chemistry. 194:112255 |
ISSN: | 0223-5234 |
Popis: | Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 μM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 μM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design. |
Databáze: | OpenAIRE |
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