Investigation of 3-benzoylbenzofurans and their methylated and pyrazole derivatives for potential inhibition of hiv-1 replication

Intro: Approximately 38.4 million people were living with HIV in 2021, with 650 000 AIDS-related deaths reported globally (UNAIDS updates 2022). Antiretrovirals are the combination of drugs against multiple stages of infections and are the most effective HIV treatment currently available (Ma et al., 2021). There were 28.7 million people on antiretrovirals in 2021, and the number of AIDS-related deaths has been reduced by 38% since 2000 (UNAIDS updates 2022). The toxicity of antiretroviral drugs is a drawback, which makes patients less inclined to adhere to therapy, which develops resistance (Ma et al., 2021). Therefore, there is still a need for more antiretrovirals that will target drug- resistant strains. Methods: This study synthesized benzofurans and their methylated and pyrazole derivatives. The compounds were evaluated for their cytotoxicity in TZM-bl cells, and assessed against two HIV pseudoviruses: HIV-1 subtype C (CAP210) and subtype A (Q23). The compounds were docked against various proteins involved in HIV entry (CD4, CCR5 coreceptor, gp41, and gp120) using Maestro 13.1 (Schrödinger 2022-1). Findings: The IC50 values for benzofurans were 5.23 and 14.4 µM for (2,5- dimethoxyphenyl)(5-hydroxynaphtho[1,2-b] furan-3-yl)methanone and 7.07 and 10.5 µM for (5-fluoro-2-methoxyphenyl)(5-hydroxy-1H-cyclopenta[a]naphthalen- 3-yl)methanone . For the methylated benzofurans, the IC50 values were 2.43 and 12.56 µM for (2,5-dimethoxyphenyl)(5-methoxynaphtho[1,2-b]furan-3- yl)methanone and 4.27 and 20.95 µM for (5-fluoro-2-methoxyphenyl) (5- methoxynaphtho[1,2-b]furan-3-yl)methanone. The IC50 values for the pyrazole derivatives were 20.49 and 12.96 µM for 2-[3-(2,5-dimethoxyphenyl)-1H-pyrazol- 4-yl]-4-methoxynaphthalen-1-ol and 29.09 and 15.68 µM for 2-[3-(5-fluoro-2- methoxyphenyl)-1H-pyrazol-4-yl]-4-methoxynaphthalen-1-ol. Pyrazole derivatives were shown to possess minimal cytotoxicity effects on mammalian cells compared to both methylated and non-methylated benzofurans. The CCR5 docking resulted in the best docking scores. Discussion: The compounds demonstrated strong interactions with the amino acids (TYR108, TRP86, and TYR37) that are essential for the gp120-CCR5 interaction, and entry of HIV into the human host cells. Conclusion: Benzofurans, methylated and pyrazole derivatives were successfully synthesized and they demonstrated inhibition activities against HIV- 1 pseudoviruses.