Nonacidic thiophene-based derivatives as potential analgesic and design, synthesis, biological evaluation, and metabolic stability study.

Nonsteroidal anti-inflammatory drugs represent one of the most popularly used classes of drugs. However, their long-term administration is associated with various side effects including gastrointestinal ulceration. One of the major reasons of NSAIDs ulcerogenicity is direct damage of the epithelial lining cells by the acidic moieties present in many drugs. Another drawback for this acidic group is its rapid metabolism and clearance through Phase II conjugation. Three series of thiophene and thienopyrimidine derivatives were designed and synthesized as nonacidic anti-inflammatory agents. In vivo testing of their analgesic activity indicated that compounds 2b and 7a-d showed higher PI values than that of the positive control drugs, indomethacin and celecoxib. The latter compounds 2b and 7a-d were subjected to further anti-inflammatory activity testing where they showed comparable percentage edema inhibition to that of indomethacin and celecoxib. Compounds 2b, 7a, 7c, and 7d inhibited PGE2 synthesis by 61.10%-74.54% (71.47% for indomethacin, and 80.11% for celecoxib). The same compounds inhibited the expression of rat mPGES-1 and cPGES3 by 74%-83% (77% for indomethacin, and 82% for celecoxib) and 48%-70% (62% for indomethacin, and 70% for celecoxib), respectively. The stability of the most active compound 2b in Nonenzymatic gastrointestinal fluids and in human plasma was tested. Additionally, studying the metabolic stability of compound 2b in S9 rat liver fraction showed that it displayed a slow in vitro clearance with half-life time 1.5-fold longer than indomethacin. The metabolites of 2b were predicted via UPLC-MS/MS. In silico ADMET profiling study was also included.

Synthesis and biological evaluation of new coumarin derivatives as cytotoxic agents.

New coumarin derivatives 9a-f, 10a-e, and 11a-f were synthesized and evaluated for their cytotoxic activity against a human breast cancer cell line (MCF-7). All compounds exhibited good activity in the nanomolar range, using doxorubicin and erlotinib as positive controls. The most active compound 9d with IC50 of 21 nM was tested against the HCT-116, HepG-2, A549, and SGC-7901 cell lines, with IC50 values of 0.021, 0.170, 0.028, and 0.11 µM, respectively. Compound 9d was further investigated for its ability to suppress the expression of epidermal growth factor receptor (EGFR). Compound 9d decreased the concentration of EGFR by 87%, using erlotinib as a positive control. A docking study revealed similar or higher scores than for erlotinib and similar binding poses providing interactions with the hinge region of the tyrosine kinase (TK). Besides the effect on expression, this in silico investigation predicts the possibility of direct binding between the new coumarin derivatives and the EGFR TK. Moreover, computational calculation for ADME properties for the most active compounds 9d, 9e, 10c, and 11c revealed the expected high gastrointestinal tract absorption, moderate water solubility with no central nervous system toxicity, and druglikeness.

Probing benzenesulfonamide-thiazolidinone hybrids as multitarget directed ligands for efficient control of type 2 diabetes mellitus through targeting the enzymes: α-glucosidase and carbonic anhydrase II.

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.

Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors.

Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 µM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 µM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 µM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.

Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: Potency and side effects.

Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections. Although being potent, susceptibility to CNS side effects limits their use. It was observed that improvements in absorption, activity and side effects were achieved via modifications at the N atom of the C7 of the side chain. To meet the increasing demand for development of new antibacterial agents, nineteen novel ciprofloxacin-sulfonamide hybrid molecules were designed, synthesized and characterized by IR, 1H NMR and 13C NMR as potential antibacterial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. Most of the synthesized compounds showed significant antibacterial activity that was revealed by testing their inhibitory activity against DNA gyrase, DNA topoisomerase IV as well as their minimum inhibitory concentration against Staphylococcus aureus. Six ciprofloxacin-sulfonamide hybrids (3f, 5d, 7a, 7d, 7e and 9b) showed potent inhibitory activity against DNA topoisomerase IV, compared to ciprofloxacin (IC50: 0.55 µM), with IC50 range: 0.23-0.44 µM. DNA gyrase was also efficiently inhibited by five ciprofloxacin-sulfonamide hybrids (3f, 5d, 5e, 7a and 7d) with IC50 range: 0.43-1.1 µM (IC50 of ciprofloxacin: 0.83 µM). Compounds 3a and 3b showed a marked improvement in the antibacterial activity over ciprofloxacin against both Gram-positive and Gram-negative pathogens, namely, Staphylococcus aureus Newman and Escherichia coli ATCC8739, with MIC = 0.324 and 0.422 µM, respectively, that is 4.2-fold and 3.2-fold lower than ciprofloxacin (MIC = 1.359 µM) against the Gram-positive Staphylococcus aureus, and MIC = 0.025 and 0.013 µM, respectively, that is 10.2-fold and 19.6-fold lower than ciprofloxacin (MIC = 0.255 µM) against the Gram-negative Escherichia coli ATCC8739. Also, the most active compounds showed lower CNS and convulsive side effects compared to ciprofloxacin with a concomitant decrease in GABA expression.

Synthesis, biological and molecular dynamics investigations with a series of triazolopyrimidine/triazole-based benzenesulfonamides as novel carbonic anhydrase inhibitors.

In the presented work, we report the design and synthesis of different new sets of triazolopyrimidine-based (9a-d) and triazole-based (11a-h, 13a-c, 15a,b, 17a,b and 21a-g) benzenesulfonamides. The newly synthesized sulfonamides were assessed for their inhibitory activities toward four human (h) metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms; hCA I, II, IX and XII. The four examined isoforms were inhibited by the prepared sulfonamides (9a-d, 11a-h, 13a-c, 15a,b, 17a,b and 21a-g) in variable degrees with KIs ranges: 94.4-4953.5 nM for hCA I, 6.9-837.6 nM for hCA II, 3.3-85.0 nM for hCA XI, and 4.4-105.0 nM for hCA XII. In particular, sulfonamides 11e, 21a and 21e emerged as single-digit nanomolar hCA IX and hCA XII inhibitors. Interestingly, triazolopyrimidine-based sulfonamide 9d and triazole-based sulfonamide 21e were found to be the most selective hCA IX inhibitors over hCA I (SI = 100.85 and 210.58, respectively) and hCA II (SI = 18.54 and 38.36, respectively). Thereafter, sulfonamides 9d and 21e were docked into the active site of CAs II, IX and XII, then poses showing the best scoring values and favorable binding interactions were subjected to a MM-GBSA based refinement and, limited to CA IX and XII, to a cycle of 100 ns molecular dynamics.

Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation.

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with KIs ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC50 = 6.4, 8.0 and 11.6 µM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.

New ibuprofen derivatives as H2S and NO donors as safer anti-inflammatory agents.

Aim: Nonsteroidal anti-inflammatory drugs are expansively used worldwide. However, their prolonged administration is associated with serious side effects, especially gastrointestinal ulceration. Materials & methods: New ibuprofen derivatives hybridized with H2S- or NO-donating moieties were synthesized and evaluated for their anti-inflammatory activity and ulcerogenic effect. COX-1/COX-2 isozymes selectivity test for the most promising derivatives was performed. Molecular docking studies were performed. Results: Most of the compounds showed promising anti-inflammatory activity comparable to that of ibuprofen (% edema inhibition = 76.6 and ulcer index = 21.26) with much better gastrointestinal tract tolerance (ulcer indices ranging from 0 to 14.67), especially compound 2 -H2S donor- (% edema inhibition = 75.5 and ulcer index = 11.75) and compound 16 -NO donor- (% edema inhibition = 65.4 and ulcer index = 8.66).

Application of hydrazino and hydrazido linkers to connect benzenesulfonamides with hydrophilic/phobic tails for targeting the middle region of human carbonic anhydrases active site: Selective inhibitors of hCA IX.

Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following KI ranges: 76.8-357.4 nM for hCA I, 8.2-94.6 nM for hCA II, 2.0-46.3 nM for hCA XI, and 8.3-88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC50 values equal 3.32 ±â€¯0.06 and 8.53 ±â€¯0.32 µM, respectively, which are comparable to the reference drug doxorubicin (IC50 = 2.36 ±â€¯0.04 and 8.39 ±â€¯0.25 µM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results.