Design, In Silico Screening, Synthesis, and In Vitro Assessment of 1,4-Naphthoquinone-Tethered Hybrid Molecules to...

In silico docking and ADMET-based screening were applied to an in-house library of 52 virtual hybrids of 1,4-naphthoquinone substituted with natural moieties. Promising multidisease targeting hybrids with suitable druggability were synthesized and evaluated in vitro for their antibacterial, antifungal, and anticancer activities. The hybrid of 1,4-naphthoquinone with menthol (9), thymol (10), and uracil (17) exhibited a promising minimum inhibitory effect (MIC = 4-12 μg/mL) against the Gram-positive bacteria Bacillus cereus and B. subtilis, as well as the Gram-negative bacteria Serratia marcescens and Escherichia coli, along with antifungal activity against the strains Alternaria alternata and Aspergillus niger. The derivative 10 exhibited the highest anticancer activity (IC₅₀ = 4.59 μg/mL), while the rest showed IC₅₀ values in the 12.28- 62.98 μg/mL range against the human breast carcinoma cell line MCF-7. The 1,4-naphthoquinone-isoniazid hybrid (16) showed IC₅₀ values of 35.0, 3.0, and 0.3 μg/mL, respectively, against A549, MDA-MB-231, and SK-BR-3 cancer cell lines, while derivatives 9, 10, and 17 showed IC₅₀ in the range of 4-60 μg/mL. Meanwhile, the derivatives did not show toxicity to normal HEK-293 cells. The interaction of derivatives 10 and 16 with 4,5-diaryl isoxazole Hsp90 chaperone (PDB: 2VCJ) was further verified through 100 ns molecular dynamics simulation studies. The findings support the possible use of 1,4-naphthoquinone hybrid scaffolds for addressing cancer and concurrent microbial infections.