New series of indole derivatives analogous to donepezil, a well known anti-Alzheimer and acetylcholinesterase inhibitor drug, was synthesized. A full chemical characterization of the new compounds is provided. Biological evaluation of the new compounds as acetylcholinesterase inhibitors was performed. Most of the compounds were found to have potent acetylcholinesterase inhibitor activity compared to donepezil as standard. The compound 1-(2-(4-(2-fluorobenzyl) piperazin-1-yl)acetyl)indoline-2,3-dione (IIId) was found to be the most potent.

A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman’s method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl)piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.

New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5‐lipoxygenase (5‐LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX‐2 selectivity index. Moreover, they showed potent 5‐LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti‐inflammatory activity using the carrageenan‐induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX‐2 and 5‐LOX active sites was performed to rationalize their anti‐inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual‐acting COX‐2/5‐LOX inhibitors to be used as potent and safe anti‐inflammatory agents.

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising antiinflammatory activity. Compound 3j was found to be the most promising derivative, with IC 50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC 50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC 50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC 50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC 50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC 50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

New cytotoxic agents based on benzothienopyrimidine scaffold were designed, synthesized, and evaluated against the MCF‐7 breast cancer line in comparison to erlotinib and letrozole as reference drugs. Eight compounds demonstrated up to 20‐fold higher anticancer activity than erlotinib, and five of these compounds were up to 11‐fold more potent than letrozole in MTT assay. The most promising compounds were evaluated for their inhibitory activity against EGFR and ARO enzymes. Compound 12, which demonstrated potent dual EGFR and ARO inhibitory activity with IC50 of 0.045 and 0.146 µM, respectively, was further evaluated for caspase‐9 activation, cell cycle analysis, and apoptosis. The results revealed that the tested compound 12 remarkably induced caspase‐9 activation (IC50 = 16.29 ng/ml) caused cell cycle arrest at the pre‐G1/G1 phase and significantly increased the concentration of cells at both early and late stage of apoptosis. In addition, it showed a higher safety profile on normal MCF‐10A cells, and higher antiproliferative activity on cancer cells (IC50 = 8.15 µM) in comparison to normal cells (IC50 = 41.20 µM). It also revealed a fivefold higher selectivity index than erlotinib towards MCF‐7 cancer cells. Docking studies were performed to rationalize the dual inhibitory activity of compound 12.