Synthesis and Inhibiting Activity of Some 4-Hydroxycoumarin Derivatives on HIV-1 Protease

Abstract

Six novel 4-hydroxycoumarin derivatives were rationally synthesized, verified, and characterized by molecular docking using crystal HIV-1 protease. Molecular docking studies predicted antiprotease activity of (7) and (10). The most significant functional groups, responsible for the interaction with HIV-1 protease by hydrogen bonds formation are pyran oxygen, atom, lactone carbonyl oxygen and one of the hydroxyl groups. The newly synthesized compounds were biologically tested in MT-4 cells for inhibiting HIV-1 replication, exploring the protection of cells from the cytopathic effect of HIV measured by cell survival in MTT test. One derivative −7 showed 76–78% inhibition of virus infectivity with IC50 = 0.01 nM, much less than the maximal nontoxic concentration (1 mM). Antiprotease activity of 7 in two different concentrations was detected to be 25%. Nevertheless, the results of study of (7) encourage using it as a pharmacophore for further synthesis and evaluation of anti-HIV activity.

Therapeutic potential of coumarins as antiviral agents

“…The highest inhibition of HIV-1 PR (25%) and highest MT4 cell survival (78%) were demonstrated by compound containing m-nitrophenyl derivative (44) ( Fig. 10) [40].…”

Diastereoselective One‐Pot Synthesis of Coumarin‐4‐carboxamido‐3‐esters via a Four‐Component Isocyanide‐Based Reaction and Molecular Docking Study

“…A number of comparative studies have shown scavenging effect of coumarins against reactive oxygen species (ROS) and their potential anti‐inflammatory activity, particularly in the treatment of inflammatory bowel disease (IBD) . Compounds containing coumarin moiety have also been reported to have an inhibition effect towards lipidic peroxidation, prostaglandin biosynthesis, and HIV‐1 PR …”

“…[13] Compounds containing coumarin moiety have also been reported to have an inhibition effect towards lipidic peroxidation, prostaglandin biosynthesis, [13] and HIV-1 PR. [14] In many studies, the substitutions at C-3 and C-4 of the coumarin nucleus resulted in improved biological activity, such as the cytotoxic and anti-inflammatory potency, [9,15,16] compared to the simple coumarin molecule. For example, in recent works [17,18] synthesis of some substituted coumarin derivatives bearing a thiazole or pyrazole unit have been reported to possess antimicrobial, analgesic and anti-inflammatory activities (Scheme 1).…”

Antioxidant activity of 3-substituted-4-hydoxycoumarin derivatives

“…Otherwise, 4-hydroxycoumarin and its derivatives have drawn much attention due to their wide range of pharmacological effects. Many of them exhibit other important pharmacological properties, including antipyretic and antinociceptive 12 , anti-inflammatory [13][14] , antibacterial 15 , anti-viral 16 , anti-HIV 17 , antioxidant 18 and anti-cancer 19 effects. Thus, the goal of this work was to evaluate the relationship between the structure and the radical scavenging activity of synthetic 3-substituted-4-hydroxycoumarins, namely 3-acetyl-4-hydroxycoumarin, 3-ethoxycarbonyl-4-hydroxycoumarin and 3-acetylphenylhydrazone-4-hydroxycoumarin, in comparison to 4-hydroxycoumarin and BHT used as references (table 1).…”