The compounds were also screened for their activity against two solid cancer cell lines, Cal27 and HepG2. Many compounds exhibited remarkable activity against both cell lines in MTT cell viability assays, with the type A inhibitors 9b and 9d, along with the type B inhibitor 13f, emerging as the most potent compounds. Interestingly, the type C compounds exhibited very low cytotoxicity. The hit compounds from the in vitro anticancer screening were further evaluated in a caspase 3/7 activation assay in Cal27 cells. Additionally, the antiplasmodial hit compound 18b was included to corroborate its low cytotoxicity in an orthogonal assay. Compound 9d showed the strongest caspase activation when Cal27 cells were treated with a threefold IC50 from the MTT assays. Furthermore, treatment of Cal27 cells with 9b, 9d, 13f, and 18b resulted in hyperacetylation of histone H3 and α-tubulin, indicating effective cellular target engagement. An extended HDAC inhibition profile for the most cytotoxic compounds 9b, 9d, and 13f confirmed their HDAC1-3 preferential inhibition. In conclusion, 9b, 9d, and 13f were identified as potent antitumor compounds in vitro. Compound 9d has emerged as the most promising, potentially serving as a starting point for developing anti-tumor HDAC inhibitors with significantly reduced cytotoxicity against non-tumor cells compared to quisinostat.