Abstract
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 μM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents.
Highlights
Human immunodeficiency virus type 1 (HIV-1) is the main causative agent of acquired immunodeficiency syndrome (AIDS), which remains a serious public health problem throughout the world [1]
The current studies have been focused on the identification of new chemical classes that are able to retain the intrinsic potency and structural elements of the bidentate metal-binding pharmacophore which is essential for strand transfer inhibition and the halo-substituted phenyl rings which interact with
In has the shown that the nature and pattern of halogen phenyl substitution can significantly affect the potency discovery of compound 5, we found that a 4’-fluorophenyl moiety, which is present in 1 and 3, of
Summary
Human immunodeficiency virus type 1 (HIV-1) is the main causative agent of acquired immunodeficiency syndrome (AIDS), which remains a serious public health problem throughout the world [1]. HIV-1 integrase (IN) is a virally encoded enzyme essential for virus replication, which mediates insertion of the double-stranded DNA provirus into the host genome [2]. Integration is the final step before irreversible and productive HIV-1 infection of the target cell [3]. It was identified as an attractive target nearly 20 years ago [4], the first generation drugs targeting. Continuous mutation of the viral genome leads to multi-drug resistant viral strains that are no longer susceptible to the current therapy [7,8]. The current studies have been focused on the identification of new chemical classes that are able to retain the intrinsic potency and structural elements of the bidentate metal-binding pharmacophore (red color) which is essential for strand transfer inhibition and the halo-substituted phenyl rings (blue color) which interact with
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