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The expanded structure- and ligand-based drug design strategy was utilized to obtain a multitargeting SARS-CoV-2 inhibitor, compound 9a, with an IC50 value of 8.86 μM.

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.

Addressing the global need for the development of safe and potent NSAIDs, new series of oxadiazolo and thiadiazolo fused pyrmidinones were synthesized and initially tested for their analgesic activity. All tested compounds showed promising analgesic activity compared with the reference standard indomethacin. Moreover, anti-inflammatory activity evaluation, ulcerogenic liability, and in vitro COX-1, COX-2 enzyme inhibition assays were also performed for the most active derivatives. The methoxyphenyl piperazinyl derivative 3d showed analgesic activity surpassing indomethacin with protection of 100%, and 83%; respectively. Also 3d showed good anti-inflammatory activity with relatively lower ulcer index compared with other tested compounds, and potent COX-1 and COX-2 inhibitory activity with IC50 = 0.140, 0.007 μm, respectively, and with a selectivity index of 20.00 which was better than the reference standards and the other tested congeners. Additionally, compounds 3b, 3g and 3h revealed moderate selectivity (SI = 3.53, 3.70 and 5.87, respectively). Moreover, in silico physicochemical parameters revealed that the new fused pyrimidinones demonstrated promising pharmacokinetic properties. Furthermore, computational studies in form of 2D-quantitative structure-activity relationship (2D-QSAR) and 3D-pharmacophore confirmed the potential analgesic properties of the new target compounds.

Aim: Using cytotoxic agents with apoptosis induction may represent one of new strategies for cancer treatment to overcome the increased resistance of the disease. Methodology: Two series of benzo[f][1,4]oxazepine-3,5(2H,4H)-diones (compounds 5, 6a–f) and 3-phenylbenzo[f][1,4]oxazepin-5(4H)-ones (compounds 10, 11a-f) were synthesized and screened for their cytotoxicity against leukemia K-562 and breast T-47D cancer cell lines as well as normal fibroblasts WI-38. Results: The tested compounds revealed good cytotoxicity and selectivity toward cancer cell lines relative to the normal cells, especially compounds 6f, 10 and 11e, f. These compounds were screened for cell cycle disturbance and apoptosis induction. They were found to cause PreG1 apoptosis and complete cell growth arrest at G2/M. They induce apoptosis via caspase-3 and Bax activation and downregulation of Bcl2. Conclusion: benzo[f][1,4]oxazepine represents a scaffold for further optimization to obtain promising anticancer agents.

Responding to the great demand of developing potent NSAIDs with an enhanced safety profile and reasonable selectivity, in the present study novel 4-fluorobenzamide derivatives were synthesized and screened for their anti-inflammatory and analgesic activities using carrageenan-induced rat paw edema method and acetic acid-induced abdominal writhing in mice, respectively. All the new target compounds except the carbamothioylhydrazine series (5a-d), and the 4-fluorophenyl thiadiazolo derivative 6b showed promising anti-inflammatory activity ranged between 53.43 and 92.36% inhibition of edema (at 3 h) compared to the reference standard indomethacin (65.64%). All the newly synthesized compounds showed potent analgesic activity ranged between 71 and 100 % writhing protection compared to indomethacin (74.06%). Moreover, the most active compounds; the ester hybrids 2a,b, the thioureido quinazolinones 4b,c, and the thiadiazole congener 6a, showed promising gastric tolerability with ulcer index ranged between 0 and 6.60 compared to indomethacin (12.13). The thioureido quinazolinone derivatives 4b,c showed the most potent anti-inflammatory and analgesic activities with a remarkable gastric tolerability compared to the other derivatives. The 4-chlorophenyl derivative 4b is considered the most promising analogue showing 92.36% inhibition of edema, 100% writhing protection in analgesia testing, and a COX-2 selectivity index of 5.75 which was better than that of indomethacin and celecoxib standards (selectivity index = 0.27 and 4.55; respectively). Moreover, it showed an ulcer index equals zero with gastric acidity and mucin levels comparable to that of the control group indicating its minor effect on gastric cell physiology and its high tolerability. Molecular docking studies predicted the binding pattern of the newly synthesized compounds in COX-1 and COX-2 enzymes confirming the ability of the most active candidates to satisfy the structural features required for binding and rationalized their selectivity based on their docking binding patterns and scores. Furthermore, the newly synthesized 4-fluorobenzamide derivatives possess promising predicted pharmacokinetic properties indicated by calculating their key physicochemical parameters and absorption percentages.

Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC50 = 1.29 and 0.93 μM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC50 = 1.57 and 1.33 μM, respectively) compared to doxorubicin (IC50 = 1.88 and 7.30 μM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4–6(a–f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13–15(a–f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 μM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 μM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 μM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 μM) relative to VCH-759 (EC50 = 5.29 μM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 μM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 μM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.

Aim: In spite of the availability of different chemotherapies for cancer treatment, there is still a need for new candidates with higher efficacy and lower toxicity. Methodology: Aurones 7a–f, 8a–f and furoaurones 13a–f, 16a–c were synthesized. Some compounds were selected by the National Cancer Institute, USA, for cytotoxicity screening. Results & discussion: The furoaurone derivative, 13a was the most active one exhibiting promising growth inhibition against leukemia, K562 and melanoma, MDA-MB-435 cells at concentration of 10 μM. It induced apoptosis in both cell lines by activation of CASP3 and inhibition of CDK2. Additionally, 13a showed good selectivity over normal kidney and liver cells. Simulation docking study was undertaken to gain insight into the possible binding mode of 13a in the CDK2 enzyme. Conclusion: The furoaurone 13a can be considered as a scaffold for further optimization to obtain more active hits. Graphical abstract [Formula: see text]

Aim: The discovery of new bronchodilators with higher efficacy than theophylline is an important issue for asthmatic patients. Materials & methods: Theophylline 2, 8-bromotheophylline 4 and theobromine 6 were reacted with different 2/3-chloro-N-phenylacetamides 1a-d or their propanamide analogs 1e-g to obtain 3a-g, 5a-g and 7a-g, respectively. The target compounds were screened for their in vitro bronchodilator activity using isolated guinea pig tracheal rings precontracted with histamine and compared with their precursors. Results: Many compounds exhibited promising activity especially 3d, 3f, 5d, 7d and 7e. 2D-QSAR study resulted in a significant model (N = 24, n = 5, R 2 = 0.848, R 2cvOO = 0.748, R 2cvMO = 0.745, F = 21.215, s 2 = 0.0002) using CODESSA-Pro software. Conclusion: These compounds can be considered as promising hits for potent bronchodilators that may be useful for further investigations. [Formula: see text]

Aim: The discovery of new generation of selective COX-2 inhibitors with potential analgesic and anti-inflammatory activity and minimal side effects is a major interest. Materials & methods: Novel imidazole and imidazo[1,5-a]quinazoline derivatives were prepared and evaluated for their analgesic and anti-inflammatory activities. COX-1/COX-2 isozyme selectivity testing and molecular docking were performed. Key physicochemical parameters were calculated. Results: All tested compounds exhibited significant activities compared with indomethacin as reference drug. Pharmacological evaluation showed that compounds 3c and 14c possess promising analgesic activity, pronouncing anti-inflammatory effect and reasonable COX-2 selectivity. Molecular docking attributed their good activity to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355 and Ser530. Most compounds obeyed ‘Lipinski's rule of five’ and possess promising pharmacokinetic properties.

Some novel 1,3,4-trisubstituted pyrazoles were synthesized and screened for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability. They showed anti-inflammatory and analgesic activities with better GIT tolerance than the standard drug phenylbutazone. In addition, IC50 values for 5e and 8e were recorded. Compound 5e was found to be the most active one as anti-inflammatory and analgesic agent. On the other hand, COX-1/COX-2 isozyme selectivity was also done which showed equal inhibition to both isoforms.

Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated using the carrageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs. The most active derivatives as anti-inflammatory agents were accordingly tested for their analgesic activity using the p-benzoquinone-induced writhing method in mice and results revealed that these compounds had also good analgesic activity. The ulcerogenic liability of the selected compounds was also evaluated. Results showed that the selected derivatives had anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching about 82% inhibition with a considerable gastric safety profile.

The synthesis of some new heterodiazole and their annulated imidazo[2,1-b]1,3,4-oxa/thiadiazolone 6a-d, 7a-d; 1,3,4-oxa or thiadiazole[3,2-a]pyrimidine diamine 8a-d and 1,3,4-oxa or thiadiazole-3-piperidino-1-propamide 11a,b derivatives have been described. The obtained compounds were evaluated for their in-vitro antitumor activity. A single dose (10 μM) of the test compounds were used in the full National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 6c and 6d displayed appreciable anticancer activity against leukemia, non-small cell lung, CNS and showed moderate activity against colon, melanoma, and breast cancer cells lines. Compound 6c possessed remarkable broad-spectrum antitumor activity which almost 4 fold more active than the known drug 5-FU with GI(50), TGI, and LC(50) values of 6.0, 17.4, and 55.1 μM, respectively.

Certain imidazoquinazolin-5(4H)-one derivatives have been synthesized by replacement of the 4-amino group compound I with different moieties of expected biological activity. Representative example of the synthesized compounds were tested for their anti-inflammatory, analgesic, antipyretic and anticonvulsant activities. Certain derivatives showed activities higher than that of the reference drugs.

The synthesis of new 1,2,4-trisubstituted imidazolinone derivatives was described. The new compounds were designed as dual p38αMAPK and ERK1/2 inhibitors through hybridization of pharmacophoric elements associated with inhibition of these kinases. The kinase inhibition assay revealed excellent activity in the nanomolar range; especially compounds 6d and 7h which seemed promising candidates for such dual activity with IC50 values of 4.5 and 4.7 nM against p38αMAP, 25.0 and 24.0 nM against ERK1, and 3.2 and 3.5 nM against ERK2, respectively. These compounds were further tested for their antiproliferative activity against nine cancer cell lines, where they elicited high activity in the sub-micromolar range against breast, prostate and melanoma cells.

The synthesis of some new 3-substituted quinazolin-4(3H)-ones and 3,4-dihydro-quinazolin-2(1H)-one derivatives and their biological evaluation as antitumor agents using the National Cancer Institute (NCI), disease oriented antitumor screening protocol are investigated. Compounds 2-[2-(4-chlorophenyl)-2-oxo-ethylthio]-3-(4-methoxyphenyl)quinazolin-4(3H)-one (3b), and 3-(4-chlorophenyl)-2-[2-(4-methoxyphenyl)-2-oxo-ethylthio]quinazolin-4(3H)-one (3d), are broad-spectrum antitumors showing effectiveness toward numerous cell lines that belong to different tumor subpanels, Compounds 3b, 3d are the most active members in this study. Those two quinazoline analogues could be considered as useful templates for future development to obtain more potent antitumor agent(s).