Unveiling new thiazole-clubbed piperazine derivatives as multitarget anti-AD: Design, synthesis, and in silico studies.

New thiazole-clubbed piperazine derivatives were designed, synthesized, evaluated for their inhibitory capabilities against human acetylcholinesterase and butyrylcholinesterase (hAChE and/or hBuChE) and ß-amyloid (Aß) aggregation, and investigated for their metal chelating potential as multitarget agents for the treatment of Alzheimer's disease. Compounds 10, 19-21, and 24 showed the highest hAChE inhibitory activity at submicromolar concentrations, of which compound 10 was the most potent with a half-maximal inhibitory concentration (IC50) value of 0.151 µM. Compounds 10 and 20 showed the best hBuChE inhibitory activities (IC50 values of 0.135 and 0.103 µM, respectively), in addition to remarkable Aß1-42 aggregation inhibitory activities and metal chelating capabilities. Both compounds were further evaluated against human neuroblastoma SH-SY5Y and PC12 neuronal cells, where they proved noncytotoxic at their active concentrations against hAChE or hBuChE. They also offered a significant neuroprotective effect against Aß25-35-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Compound 10 displayed acceptable physicochemical properties and could pass the blood-brain barrier. The molecular docking study revealed the good binding interactions of compound 10 with the key amino acids of both the catalytic active site and the peripheral anionic site of hAChE, explaining its significant potency.

Design, synthesis, and docking study of new quinoline derivatives as antitumor agents.

New quinolines substituted with various heterocycles and chalcone moieties were synthesized and evaluated as antitumor agents. All the synthesized compounds were in vitro screened against 60 human cancer cell lines. Compound 13 showed the highest cytotoxicity toward 58 cell lines, exhibiting distinct growth inhibition values (GI50 ) against the majority of them, including SR, HL-60 (TB) strains (leukemia), and MDA-MB-435 strains (melanoma), with GI50 values of 0.232, 0.260, and 0.300 µM, respectively. It exhibited great selectivity toward cancer cell lines, with less toxic effect against normal cells represented by skin fibroblast (BJ) and breast epithelial cell lines (MCF-10F). The enzyme inhibitory activity of compound 13 was evaluated against topoisomerase 1 (Topo 1), epidermal growth factor receptor and vascular endothelial growth factor receptor 2, where it displayed worthy Topo 1 inhibition activity with an IC50 value of 0.278 µM compared with camptothecin as a reference drug (IC50 0.224 µM). Docking studies were performed to investigate the recognition profile of compound 13 with the Topo 1 enzyme binding site.

Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study.

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds 5c and 5d exhibited the most desirable multiple functions for AD; they were strong hAChE inhibitors with IC50 values of 0.44 and 0.25 µM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC50 = 0.08 and 0.14 µM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aß aggregation and decreasing Aß-related neurodegeneration, especially compound 5d, which was 8 times more effective than curcumin with IC50 = 0.74 µM and 76% inhibition at 10 µM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC50 = 0.38 and 0.44 µM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC50 = 5.15 and 2.42 µM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe+2, Zn+2, and Cu+2, inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD.

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.

Benzimidazole-based protein kinase inhibitors: Current perspectives in targeted cancer therapy.

Targeted therapy has emerged to be the cornerstone of advanced cancer treatment, allowing for more selectivity and avoiding the common drug toxicity and resistance. Identification of potential targets having vital role in growth and survival of cancer cells got much easier with the aid of the recent advances in high throughput screening approaches. Various protein kinases came into focus as valuable targets in cancer therapy. Meanwhile, benzimidazole-based scaffolds have gained significant attention as promising protein kinase inhibitors with high potency and varied selectivity. Great diversity of these scaffolds has inspired the medicinal chemists to inspect the effect of structural changes upon inhibitory activity on the molecular level through modeling studies. The present review gathers all the considerable attempts to develop benzimidazole-based compounds; designed as protein kinase inhibitors with anticancer activity since 2015; that target aurora kinase, CDK, CK2, EGFR, FGFR, and VEGFR-2; to allow further development and progression regarding benzimidazoles.