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4H-Chromene derivatives are promising anticancer compounds known to bind within the colchicine binding site of the tubulin protein. Among these, the 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile-based 4H-chromenes scaffold is known to produce a significant impact on tubulin proteins. Other molecules with similar pharmacophores are also known for their colchicine binding site targeting abilities. However, tubulin is not a single protein; multiple isoforms have been reported, and some are comparatively more important under malignant conditions. Therefore, the research findings presented herein include a detailed understanding of the interaction pattern of the 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile series for their colchicine binding ability against various tubulin isoforms proteins. We have established the current series anticancer potential and structural activity relationship. The series revealed promising anticancer potential, and MNC-1 was the best among all. However, a serious side effect of this scaffold is a major problem, as these derivatives indiscriminately bind to the tubulin of malignant and normal cells. However, the expression profile of tubulin isoforms was found to be different in normal and malignant cell types. Therefore, selective killing of the malignant cell seems possible by designing a 4H-chromenes derivative selective against particular tubulin isoforms. The insights provided herein clearly indicate the differences in the binding pattern of different 4H-chromenes derivatives against different tubulin isoforms. Therefore, with precise structural modification, these molecules' selective targeting against cancer cells seems quite possible. [ABSTRACT FROM AUTHOR]

Twenty-five (Ia–Iu, IIa–IIb, IIIa, and IVa) diarylidene-N-methyl-4-piperidones (DANMPs) were synthesized and characterized via UV, FT-IR, NMR, and MS while Id was characterized also by single crystal XRD. Twenty-one compounds shortlisted after initial in vitro anti-plasmodial activity successive screenings at 100 μM and 10 μM were evaluated for their IC50s against chloroquine-sensitive Pf3D7, chloroquine-resistant PfINDO, and artemisinin-resistant PfMRA-1240 strains. The four most promising compounds were Ie (IC50s μM 0.35MRA, 1.39INDO, 1.923D7), If (IC50s μM 1.07MRA, 1.36INDO, 3.393D7), Ir (IC50s μM 0.74MRA, 2.45INDO, 1.443D7), and In (IC50s μM 1.27MRA, 1.8INDO, 1.73D7). Resistance indices as low as 0.2 to 0.5 for these potent compounds and <1 for most other compounds suggest their greater potency against drug resistant strains than the drug sensitive strain. The parasiticidal action of Ir was seen within 4 h against the trophozoite stage of the parasite, which is known to express the highest levels of PLP synthase. In silico docking scores of −7.0 to −8.0 kcal mol−1 between potent DANMPs and PfPLP synthase, the direct binding of Ir studied by SPR to recombinantly expressed and purified PfPdx-1 and inhibition of Pdx1 enzymatic activity by Ir suggest this vital enzyme to be a probable target for the DANMPs. The non-hemolytic nature of Ir and conformity of most DANMPs to Lipinski's parameters indicate their potential as new anti-plasmodial leads with PfPLP synthase as one of their targets. [ABSTRACT FROM AUTHOR]