Hosam Elshihawy

Design, synthesis, and enzyme kinetics of novel benzimidazole and quinoxaline derivatives as methionine synthase inhibitors.

Methionine synthase catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate. Benzimidazole and deazatetrahydrofolates derivatives have been shown to inhibit methionine synthase by competing with the substrate 5-methyltetrahydrofolate. In this study, a novel series of substituted benzimidazoles and quinoxalines were designed and assessed for inhibitory activity against purified rat liver methionine synthase using a radiometric enzyme assay. Compounds 3g, 3j, and 5c showed the highest activity against methionine synthase (IC₅₀: 20 μM, 18 μM, 9 μM, respectively). Kinetic analysis of these compounds using Lineweaver-Burk plots revealed characteristics of mixed inhibition for 3g and 5c; and uncompetitive inhibition for 3j. Docking study into a homology model of the rat methionine synthase gave insights into the molecular determinants of the activity of this class of compounds. The identification of these drug-like inhibitors could lead the design of the next generation modulators of methionine synthase.

Novel pyrazoles and pyrazolo[1,2- a ]pyridazines as selective COX-2 inhibitors; Ultrasound-assisted synthesis, biological evaluation, and DFT calculations

COX-2 is an inducible enzyme mediating inflammatory responses. Selective targeting of COX-2 is useful for developing anti-inflammatory agents devoid of ulcerogenic activity. Herein, we report the design and synthesis of a series of pyrazoles and pyrazolo[1,2-a]pyridazines with selective COX-2 inhibitory activity and in vivo anti-inflammatory effect. Both series were accessed through acid-catalyzed ultrasound-assisted reactions. The most active compounds in this study are two novel molecules, 11 and 16, showing promising selectivity and decent IC50 of 16.2 and 20.1nM, respectively. These compounds were also docked into the crystal structure of COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding. Finally, Mulliken charges and electrostatic surface potential were calculated for both compound 11 and celecoxib using DFT method to get insights into the molecular determinants of activity of this compound. These results could lead to the development of novel COX-2 inhibitors with improved selectivity.

Novel 4-substituted-2(1H)-phthalazinone derivatives: synthesis, molecular modeling study and their effects on α-receptors

Novel 4-(4-bromophenyl)phthalazine derivatives connected via an alkyl spacer to amine or N-substituted piperazine were designed and synthesized as promising α-adrenoceptor antagonists. The structures of the phthalazine derivatives were established using elemental and spectral analyses. Twelve of the tested compounds displayed significant α-blocking activity. Molecular modeling studies were performed to rationalize the biological results. Among the tested compounds, 7j displayed the best-fitting score and the highest in vitro activity.

Synthesis of Some Novel 2,6-Disubstituted Pyridazin-3(2H)-one Derivatives as Analgesic, Anti-Inflammatory, and Non-Ulcerogenic Agents

Some novel 2,6‐disubstituted pyridazine‐3(2H)‐one derivatives were synthesized and evaluated for in vitro cyclooxygenase‐2 (COX‐2) inhibitory efficacy. Compounds 2‐{[3‐(2‐methylphenoxy)‐6‐oxopyridazin‐1(6H)‐yl]methyl}‐1H‐isoindole‐1,3(2H)‐dione (5a), 2‐propyl‐6‐(o‐tolyloxy)pyridazin‐3(2H)‐one (6a), and 2‐benzyl‐6‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)pyridazin‐3(2H)‐one (16a) showed the most potent COX‐2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 μM, respectively. The synthesized compounds with the highest COX‐2 selectivity indices were evaluated for their anti‐inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti‐inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening.