Design, Microwave-Assisted Synthesis, Antimicrobial and Anticancer Evaluation, and In Silico Studies of Some 2‑Naphthamide Derivatives as DHFR and VEGFR‑2 Inhibitors

Naphthamide is a common structural framework with diverse pharmacological activities. Ten novel 2-naphthamide derivatives have been designed, synthesized, and evaluated for their in vitro antibacterial, antifungal, and anticancer activities. The title compounds were synthesized from dimethoxybenzaldehyde derivatives through a four-step microwave-assisted synthesis process. The structures were confirmed by ¹H NMR, ¹³C NMR, and MS spectra. Compound 8b showed good antibacterial activity against Escherichia coli, Streptococcus faecalis, Salmonella enterica, MSSA, and MRSA with MIC values of 16, 16, 16, 8, and 16 μg/mL, respectively, compared to ciprofloxacin (MIC = 8–16 μg/mL). Compounds 5b (IC₅₀ = 3.59–8.38 μM) and 8b (IC₅₀ = 2.97–7.12 μM) exhibited good cytotoxic activity against C26, HepG2, and MCF7 cancer cell lines as compared to paclitaxel (IC₅₀ = 2.85–5.75 μM). Moreover, compounds 5b and 8b exhibited better anticancer activity than PTX against the C26 cell line. In particular, compound 8b showed potent in vitro VEGFR-2 inhibitory activity with the IC₅₀ value of 0.384 μM compared with sorafenib (IC₅₀ = 0.069 μM). Therefore, compound 8b is the most potent compound for anticancer activity as indicated by in vitro cell line inhibition, in silico ADMET, molecular docking, and in vitro VEGFR-2 inhibition studies.