Design, Synthesis, Biological Evaluation and Molecular Docking Studies of New Thiazolidinone Derivatives as NNRTIs and SARS-CoV-2 Main Protease Inhibitors

Abstract

HIV-1 remains a major health problem worldwide since the virus has developed drug-resistant strains, so, the need for novel agents is urgent. The protein reverse transcriptase plays fundamental role in the viruses' replication cycle. FDA approved Delavirdine bearing a sulfonamide moiety, while thiazolidinone has demonstrated significant anti-HIV activity as a core heterocycle or derivative of substituted heterocycles. In this study, thirty new thiazolidinone derivatives (series A, B and C) bearing sulfonamide group were designed, synthesized and evaluated for their HIV-1 RT inhibition activity predicted by computer program PASS taking into account the best features of available NNRTIs as well as against SARS-COV-2 main protease. Seven compounds showed good anti-HIV inhibitory activity, with two of them, C1 and C2 being better (IC₅₀ 0.18 μΜ & 0.12 μΜ respectively) than the reference drug nevirapine (IC₅₀ 0.31 μΜ). The evaluation of molecules to inhibit the main protease revealed that 6 of the synthesized compounds exhibited excellent to moderate activity with two of them (B4 and B10) having better IC₅₀ values (0.15 & 0.19 μΜ respectively) than the reference inhibitor GC376 (IC₅₀ 0.439 μΜ). The docking studies is coincides with experimental results, showing good binding mode to both enzymes.

Keywords: AIDS; COVID; HIV-1 reverse transcriptase; Molecular docking; SARS-CoV-2; Sulfonamides; Synthesis design; Thiazolidinone.

Figure 1

Docking at the allosteric site of HIV‐1 RT and 2D interaction of A) Group A, B) Group B, C) Group C and D) Pharmacophore features’ depictions in Ligandscout.

Scheme 1

General synthesis. Reagents and conditions: (a) Conventional method: dry toluene, reflux for 30–108 h, (b) microwave‐assisted technic: 100 °C, power 100 W, pressure 250 psi, 31 min.

Figure 2

Docking of compound C1 at the allosteric site of HIV‐1 RT and 2D interaction diagram.

Figure 3

Docking of compound C2 at the allosteric site of HIV‐1 RT and 2D interaction diagram.

Figure 4

Docking pose of compound B4 in SARS‐CoV‐2 main protease structure 6 M2 N and 2D interaction diagram.

Figure 5

Docking pose of compound B10 in SARS‐CoV‐2 main protease structure 6 M2 N and 2D interaction diagram.

Figure 6

A) Docking of the initial ligand 5,6,7‐trihydroxy‐2‐phenyl‐4H‐chromen‐4‐one to the SARS‐CoV‐2 main protease structure 6 M2 N. The docked ligand is in green and the initial ligand in yellow. B) Docking of the initial ligand TMC 125 (green) as Compared to the Docked Conformation of TMC 125 (yellow).