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.
Highlights
The retroviral protease (PR) of human immunodeficiency virus type 1 (HIV-1) is one of the key enzymes for virus replication
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
Substituted aromatic aldehydes are used for synthesis of arylmethylene-β-ketoesters via Knoevenagel reaction with ethyl acetoacetate in the presence of piperidine as a basic agent and glacial acetic acid
Summary
The retroviral protease (PR) of human immunodeficiency virus type 1 (HIV-1) is one of the key enzymes for virus replication. It cleaves protein and glycoprotein precursors to yield active viral enzymes and structural proteins. The inactive HIV-1 PR leads to noninfectious virions. This fact stimulated search of potent substances with antiprotease activity inhibiting HIV-1 replication. During the past 12 years, a number of peptidomimetic analogs—inhibitors of HIV-1 PR (PIs)— have been clinically introduced, but the largest part of them show poor pharmacological characteristics such as bad oral bioavailability, rapid clearance, and tolerability problems— often associated with lypodystrophy and dyslipidemia [1]. Because of being peptidomimetics, viral isolates quickly demonstrate a high degree of resistance and cross-resistance even when using the members of the group before PIs were put on the market [2]
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