Synthesis, molecular modeling, selective aldose reductase inhibition and hypoglycemic activity of novel meglitinides.

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.

Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line.

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

Pharmacophore modeling, 3D-QSAR, synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR.

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure-activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.

Synthesis and molecular modeling of novel non-sulfonylureas as hypoglycemic agents and selective ALR2 inhibitors.

Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilities to discriminate in vitro between aldehyde reductase (ALR1) and aldose reductase (ALR2) were determined. The molecular docking and the in silico prediction studies were performed to rationalize the obtained biological results and to predict the physicochemical properties and drug-likeness scores of the new compounds. N-(2,4-Dichlorophenyl)-2-(2',4'-dioxospiro[fluorene-9,5'-imidazolidine]-3'-yl)acetamide (3e) displayed an 84% reduction in blood glucose level superior to that of repaglinide 66% and showed an IC50 value of 0.37 µM against ALR2 that is superior to that of sorbinil 3.14 µM. Compound (3e) was selective 96 fold towards ALR2 which is closely related to serious diabetic complications. Based on the identification of this hit candidate, a new generation of safe and effective antidiabetic agents could be designed.

Molecular modelling and synthesis of spiroimidazolidine-2,4-diones with dual activities as hypoglycemic agents and selective inhibitors of aldose reductase.

Novel derivatives of spiroimidazolidinedione were synthesized and evaluated as hypoglycemic agents through binding to sulfonylurea receptor 1 (SUR1) in pancreatic beta-cells. Their selectivity index was calculated against both aldehyde reductase (ALR1) and aldose reductase (ALR2). Aldehyde reductase is a key enzyme in the polyol pathway that is involved in the etiology of the secondary diabetic complications. All structures were confirmed by microanalysis and by IR, 1H NMR, 13C NMR and EI-MS spectroscopy. The investigated compounds were subjected to molecular docking and an in silico prediction study to determine their free energy of binding (ΔG) values and predict their physicochemical properties and drug-likeness scores. Compound 1'-(5-chlorothiophene-2-ylsulfonyl)spiro[cyclohexane-1,5'-imidazolidine]-2',4'-dione showed IC50 0.47 µM and 79% reduction in blood glucose level with a selectivity index 127 for ALR2.

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.

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.