Exploring New Scaffolds for the Dual Inhibition of HIV-1 RT Polymerase and Ribonuclease Associated Functions

• Main Authors: Rita Meleddu, Angela Corona, Simona Distinto, Filippo Cottiglia, Serenella Deplano, Lisa Sequeira, Daniela Secci, Alessia Onali, Erica Sanna, Francesca Esposito, Italo Cirone, Francesco Ortuso, Stefano Alcaro, Enzo Tramontano, Péter Mátyus, Elias Maccioni
• Format: Article
• Language: English
• Published: MDPI AG 2021-06-01
• Series: Molecules
• Subjects: HIV-RT; ribonuclease H; dual inhibitors; docking; putative binding
• Online Access: https://www.mdpi.com/1420-3049/26/13/3821

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. Pursuing on our investigation on potential anti HIV multi-target agents we have designed and synthesized a small library of biphenylhydrazo 4-arylthiazoles derivatives and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity. In particular, compound 2-{3-[(2-{4-[4-(hydroxynitroso)phenyl]-1,3-thiazol-2-yl} hydrazin-1-ylidene) methyl]-4-methoxyphenyl} benzamide bromide (<b>EMAC2063</b>) was the most potent towards RNaseH (IC₅₀ = 4.5 mM)- and RDDP (IC₅₀ = 8.0 mM) HIV RT-associated functions.