In vitro cytotoxicity and docking study of novel symmetric and asymmetric dihydropyridines and pyridines as EGFR tyrosine kinase inhibitors.

Quinolines have a weighty effect as anticancer agents and 1,4-DHPs have demonstrated efficacy as anticancer agents in several studies, as well. New hybrid models of symmetric and asymmetric 1,4-DHPs and pyridines linked at C3 of 2-chloroquinoline as a new anticancer scaffold, were designed and synthesized. Hantszch 1,4-DHPs method was adopted for chemical synthesis. MTT assay was performed for the evaluation of cytotoxicity, and EGFR tyrosine kinase assay was performed to investigate binding to our selected compounds, measured by ELISA. The IC50 expressed in µM values revealed that compounds 4a,b, and 5i,k showed the best results against the tested four cell lines than the reference drug 5-Flurouuracil. Compound 5k displayed the most potent cytotoxic activity with IC50  values in the low µM range (12.03 ± 1.51: 20.09 ± 2.16 µM), compared with 5-Fu IC50 range (40.74 ± 2.46: 63.81 ± 2.69 µM). The incorporation of 2-chloroquinoline at C3 to C4 of 1,4-DHP could be proposed as an anticancer scaffold rather than its analogous pyridines. Ester fragments connected to 1,4-DHPs ring as a lipophilic part are essential for anticancer activity. The chirality at C4 improved the anticancer activity. The hydrogen and halogen bond facilitated protein-ligand binding mode and affinity.

Synthesis, biological evaluation and in silico molecular docking of novel 1-hydroxy-naphthyl substituted heterocycles.

The versatile precursor 2-acetyl-4-allyl-1-hydroxy naphthalene was synthesized efficiently via Claisen rearrangement 2-acetyl-1-allyloxynaphthalene. The Claisen-Schmidt condensation of latter precursor afforded the corresponding chalcones which were exploited to synthesize a series of potential heterocycles such as pyrazoline, isoxazoline, benzocoumarin and benzoflavone. The synthesized products showed potent antioxidant and antimicrobial activities. Chalcone 3c, naphthyl pyrazoline 6b and hydroxycoumarin 13 exhibited the highest activity as antioxidants. Their binding mode showed specialized recognition of hydroxycoumarin 13 with the triad key amino acids at the active site of the oxidoreductase enzyme (PDB code 1DXO). 1-Hydroxynaphth-2-yl pyrazoline (6b) revealed the highest efficacy against both Gram positive and negative bacterial species. In silico molecular docking of pyrazoline 6b endorsed its proper binding at the active site of the 2EX6 enzyme which explains its potent antibacterial activity in comparison with standard ampicillin.

Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs.

In order to produce potent new leads for anticancer drugs, a new series of quinazoline analogs was designed to resemble methotrexate (MTX, 1) structure features and fitted with functional groups believed to enhance inhibition of mammalian DHFR activity. Molecular modeling studies were used to assess the fit of these compounds within the active site of human DHFR. The synthesized compounds were evaluated for their ability to inhibit mammalian DHFR in vitro and for their antitumor activity in a standard in vitro tissue culture assay panel. Compounds 28, 30, and 31 were the most active DHFR inhibitors with IC(50) values of 0.5, 0.4, and 0.4microM, respectively. The most active antitumor agents in this study were compounds 19, 31, 41, and 47 with median growth inhibitory concentrations (GI(50)) of 20.1, 23.5, 26.7, and 9.1microM, respectively. Of this series of compounds, only compound 31 combined antitumor potency with potent DHFR inhibition; the other active antitumor compounds (19, 41, and 47) all had DHFR IC(50) values above 15microM, suggesting that they might exert their antitumor potency through some other mode of action. Alternatively, the compounds could differ significantly in uptake or concentration within mammalian cells.