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A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, 1 H-, 13 C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC 50 of 0.018 μM for normoxia, and 0.001 μM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC 50 0.25 μM and Abl inhibitory activity with IC 50 0.08 μM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC 50 0.31 μM, VEGFR-2 IC 50 0.68 μM, B-raf IC 50 0.33 μM, ERK IC 50 1.41 μM, CK1 IC 50 0.29 μM and p38-MAPK IC 50 0.38 μM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A new series of tetrasubstituted imidazole carrying sulfonamide as zinc-anchoring group has been designed. The structures of the synthesized derivatives 5 a-l have been confirmed by spectroscopic analysis. These compounds incorporate an ethylenic spacer between the benzenesulfonamide and the rest of the trisubstituted imidazole moiety and were tested as inhibitors of carbonic anhydrases and for in-vitro cytotoxicity. Most of them act as effective inhibitors of the tumor-linked CA isoforms IX and XII, in nanomolar range. Also, different compounds have shown selectivity in comparable with the standard acetazolamide. Our IBS 5 d, 5 g, and 5 l (with Ki: 10.1, 19.4, 19.8 nM against hCA IX and 47, 45, 20 nM against hCA IX) showed the best inhibitory profile. In-vitro screening of all derivatives against a full sixty-cell-lined from NCI at a single dose of 10 μM offered growth inhibition of up to 45 %. Compound 5 b has been identified with the most potent cytotoxic activity and broad spectrum. Docking studies have also been implemented and were also in accordance with the biological outcomes. Our SAR analysis has interestingly proposed efficient tumor-related hCAs IX/XII suppression., (© 2024 Wiley-VCH GmbH.)

This study aimed to isolate and identify three prenylflavonoids (cannflavin A, B, and C) from Cannabis sativa leaves using different chromatographic techniques. The potential of the isolated compounds against SARS-CoV-2 was suggested through several in silico analysis. Structural similarity studies against nine co-crystallized ligands of SARS-CoV-2's proteins indicated the similarities of the isolated cannflavins with the SARS-CoV-2 Papain-Like Protease (PLP) ligand, Y95 . Then, flexible allignment study confirmed this similarity. Docking experiments showed successful binding of all cannflavins within the active pocket of PLP, with energies comparable to Y95 . Among them, cannflavin A demonstrated the most similar binding mode, while cannflavin C exhibited the best energy. Molecular dynamics (MD) simulations and MM-GPSA confirmed the accurate binding of cannflavin A to the PLP. In silico ADMET studies indicated favourable drug-like properties for all three compounds, suggesting their potential as anti-SARS-CoV-2 agents. Further In vitro and In vivo investigations are necessary to validate these findings and establish their efficacy and safety profiles.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B ) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a - j , 8a - j , 9a - c , and 10a - c . The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d , 8g , 8i , and 10c inhibited EGFR with IC 50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC 50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d , 8g , 8i , and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids3a-mof hopeful anticancer activity. According to NCI screening and MTT assay results, compounds3d-3f, 3i,3k,and3ldisplayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these compounds,3eand3fshowed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that3e,3d, and3ihad goodtubulin polymerization inhibition (IC 50  = 5.3, 8.6, and 8.05 µM, respectively) compared to the reference Combretastatin A4 (IC 50  = 2.15 µM). Moreover,3e,3l, and3fexhibited EGFR inhibition (IC 50  = 0.097, 0.154, and 0.334 µM, respectively) compared to Erlotinib (IC 50  = 0.056 µM). Compounds3eand3fwere investigated for their effects on the cell cycle, apoptosis induction, andwnt1/β-cateningene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and β-actin were detected by Western blot. In-silico molecular docking, physicochemical, and pharmacokinetic studies were implemented for the validation of dual mechanisms and other bioavailability standards. Hence, Compounds3eand3fare promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In-vitro screening of these hybrids against a full 60-cell-line panel at a single dose of 10 μM showed significant growth inhibition of up to 95 %. The most active compound showed in-vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF-7 cell line apoptosis together with considerable change in the Bax/Bcl-2 expression ratio. One lead compound led to a significant cell-cycle S-phase arrest, while another blocked the cell cycle at G1/S-phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co-crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Herein, we report the first use of Polymyxin-B antibiotic as a enantio-selector in polymer monolithic capillary. The capillaries were functionalised, characterized and tested for the enantioselective nano-HPLC separation of 50 racemic pharmaceutical drugs. They have been easily prepared by immobilizing Polymyxin-B over the organic polymer for 48 h (P1) or encapsulating Polymyxin-B within the organic polymer (P2) and tested for the enantioselective resolution of racemic drugs. Acceptable resolution was achieved for 21 drugs using RP-HPLC conditions on both (P1) and (P2) capillary columns, while no separation was observed under NP-HPLC conditions. Polymyxin-B is commercially available, easily solubilized and stable in both acidic and neutral media. The developed Polymyxin-B-based polymer monolithic capillaries provide a promising expansion of platform in enantioselective HPLC separations., Competing Interests: Declaration of Competing Interest There's no conflict of interest as what the authors have declared., (Copyright © 2021. Published by Elsevier B.V.)

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone ( 5a - e ) and its cyclic analogues hydrazineylidenethiazolidine ( 6a - e ), 2-aminothiadiazole ( 7a - e ), and 2-hydrazineylidenethiazolidin-4-one ( 8a - e ) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c , 7b , and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC 50 , μM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC 50 values of 19.4, 30.7, and 73.7; and compound 8b displayed IC 50 values of 77.5, 53.5, and 121.3 for PI3Kα, β, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b , while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.

Despite the common use of salens and hydroxyquinolines as therapeutic and bioactive agents, their metal complexes are still under development. Here, we report the synthesis of novel mixed-ligand metal complexes (MSQ) comprising salen (S), derived from (2,2'-{1,2-ethanediylbis[nitrilo(E) methylylidene]}diphenol, and 8-hydroxyquinoline (Q) with Co(II), Ni(II), Cd(II), Al(III), and La(III). The structures and properties of these MSQ metal complexes were investigated using molar conductivity, melting point, FTIR, 1 H NMR, 13 C NMR, UV-VIS, mass spectra, and thermal analysis. Quantum calculation, analytical, and experimental measurements seem to suggest the proposed structure of the compounds and its uncommon monobasic tridentate binding mode of salen via phenolic oxygen, azomethine group, and the NH group. The general molecular formula of MSQ metal complexes is [M(S)(Q)(H 2 O)] for M (II) = Co, Ni, and Cd or [M(S)(Q)(Cl)] and [M(S)(Q)(H 2 O)]Cl for M(III) = La and Al, respectively. Importantly, all prepared metal complexes were evaluated for their antimicrobial and anticancer activities. The metal complexes exhibited high cytotoxic potency against human breast cancer (MDA-MB231) and liver cancer (Hep-G2) cell lines. Among all MSQ metal complexes, CoSQ and LaSQ produced IC 50 values (1.49 and 1.95 µM, respectively) that were comparable to that of cisplatin (1.55 µM) against Hep-G2 cells, whereas CdSQ and LaSQ had best potency against MDA-MB231 with IC 50 values of 1.95 and 1.43 µM, respectively. Furthermore, the metal complexes exhibited significant antimicrobial activities against a wide spectrum of both Gram-positive and -negative bacterial and fungal strains. The antibacterial and antifungal efficacies for the MSQ metal complexes, the free S and Q ligands, and the standard drugs gentamycin and ketoconazole decreased in the order AlSQ > LaSQ > CdSQ > gentamycin > NiSQ > CoSQ > Q > S for antibacterial activity, and for antifungal activity followed the trend of LaSQ > AlSQ > CdSQ > ketoconazole > NiSQ > CoSQ > Q > S. Molecular docking studies were performed to investigate the binding of the synthesized compounds with breast cancer oxidoreductase (PDB ID: 3HB5). According to the data obtained, the most probable coordination geometry is octahedral for all the metal complexes. The molecular and electronic structures of the metal complexes were optimized theoretically, and their quantum chemical parameters were calculated. PXRD results for the Cd(II) and La(III) metal complexes indicated that they were crystalline in nature., Competing Interests: The authors declare no conflict of interest.

A novel series of tri-aryl imidazole derivatives 5a - n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3-1.3 μM, and selectivity ratio for hCA IX over hCA XII = 5-12) relative to acetazolamide (Ki = 0.03 μM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI 50 = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI 50 = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK . Molecular modelling simulation showed good agreement with the acquired biological evaluation.

A series of novel piperine-resveratrol hybrids 5a-h was designed, synthesized, and structurally elucidated by IR, and 1 H, 13 C, and 19 F NMR. Antiproliferative activities of 5a-h were evaluated by NCI against sixty cancer cell lines. Compound 5b, possessing resveratrol pharmacophoric phenolic moieties, showed a complete cell death against leukemia HL-60 (TB) and Breast cancer MDA-MB-468 with growth inhibition percentage of -0.49 and -2.83, respectively. In addition, 5b recorded significant activity against the other cancer cell lines with growth inhibition percentage between 80 to 95. New 5a-h hybrids were evaluated for their inhibitory activities against Sirt-1 and Sirt-2 as molecular targets for their antiproliferative action. Results showed that compounds 5a-h were more potent inhibitors of Sirt-2 than Sirt-1 at 5 μm and 50 μm. Compound 5b showed the strongest inhibition of Sirt-2 (78 ± 3% and 26 ± 3% inhibition at 50 μM and 5 μM, respectively). Investigation of intermolecular interaction via Hirschfeld surface analysis indicates that these close contacts are mainly ascribed to the O-H⋯O hydrogen bonding. To get insights into the Sirt-2 inhibitory mechanism, a docking study was performed where 5b was found to fit nicely inside both extended C-pocket and selectivity pocket and could compete with the substrate acyl-Lys. Another possible binding pattern showed that 5b could act by partial occlusion of the NAD + C-pocket. Collectively, these findings would contribute significantly to better understanding the Sirt-2 inhibitory mechanism in order to develop a new generation of refined and selective Sirt-2 inhibitors., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Daptomycin, a macrocyclic antibiotic, is here used as a new chiral selector in preparation of chiral stationary phase (CSP) in a recently prepared polymer monolithic capillary. The latter is prepared using the copolymerization of the monomers glycidyl methacrylate (GMA) and ethylene glycol dimethacrylate (EGDMA) in the presence of daptomycin in water. Under reversed phase conditions (RP), the prepared capillaries were tested for the enantioselective nanoliquid chromatographic separation of fifty of the racemic drugs of different pharmacological groups, such as adrenergic blockers, H1-blockers, NSAIDs, antifungal drugs, and others. Baseline separation was attained for many drugs under RP-HPLC. Daptomycin expands the horizon of chiral selectors in HPLC.

A novel series of thiazolo-pyrazole hybrids has been prepared and assessed for their in vitro COX-1/COX-2 inhibitory activity. Compound 6c exhibited the most selective COX-2 inhibition profile (SI of 264) not far of Celecoxib (294). In-vivo anti-inflammatory activity revealed that compound 6d exhibited the highest activity (97.30% inhibition of edema) exceeding reference standard Indomethacin (84.62% inhibition of edema). The ulcerogenic liability tested, using gross, microscopic, biochemical analysis and apoptotic genes expression, showed that compound 6b matched the optimal candidate activity (ulcer index = 120, selectivity index of ~ 162 and 77% in-vivo inhibition of edema). Meanwhile, compound 6 m (ulcer index = 0) showcased the highest safety profile. Molecular modeling analysis and drug likeness studies presented appreciated agreement with the biological evaluation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using 1 H NMR, 13 C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1 - 21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa . As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2 - 6 , oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus , but did have poor activity against Candida albicans , ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC 50 of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC 50 = 170 nM). Compounds 4, 5, and 6 showed IC 50 values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC 50 = 11 µM).

The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.

Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC 50 0.041-0.081 μM, SI 139.74-321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3-48.3, 1 h; 58.4-60.5, 2 h; 70.8-83.2, 3 h; 78.9-89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE 2 and NO. A novel series of aryl carboximidamides 4a-g and their cyclized 3-aryl-1,2,4-oxadiazoles 5a-g counterparts derived from indomethacin 1 were synthesized. Most of the target compounds displayed lower LPS-induced NO production IC 50 in RAW 264.7 cells and potent in vitro iNOS and PGE2 inhibitory activity than indomethacin. Moreover, in carrageenan-induced rat paw oedema method, most of them exhibited higher in vivo anti-inflammatory activity than the reference drug indomethacin. Notably, 4 hrs after carrageenan injection, compound 4a proved to be the most potent anti-inflammatory agent in this study, with almost two- and eight-fold more active than the reference drugs indomethacin (1) and celecoxib, respectively. Compound 4a proved to be inhibitor to LPS-induced NO production, iNOS activity and PGE2 with IC 50 of 10.70 μM, 2.31 μM, and 29 nM; respectively. Compounds 4a and 5b possessed the lowest ulcerogenic liabilities (35% and 38%, respectively) compared to 1. Histopathological analysis revealed that compounds 4a and 5b demonstrated reduced degeneration and healing of ulcers. Molecular docking studies into the catalytic binding pocket of the iNOS protein receptor (PDB ID: 1r35) showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and ADMET analysis were calculated where compound 4a had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed anti-inflammatory therapy and entitled to be used as future template for further investigations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A novel series of thiazolopyrimidines and fused thiazolopyrimidines was designed and synthesized as topoisomerase II alpha inhibitors. All synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compound 3a was found to be the most potent inhibitor on renal cell line (A-498) causing 83.03% inhibition (IC 50  = 1.89 μM). DNA-flow cytometric analysis showed that compound 3a induce cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Moreover, fused thiazolopyrimidines 3a showed potent topoisomerase II inhibitory activity (IC 50 = 3.19 μM) when compared with reference compound doxorubicin (IC 50 = 2.67 μM). Docking study of all the synthesized compounds showed that compound 3a interacts in a similar pattern to etoposide and stabilizing the topoisomerase cleavage complex (Top2-cc) that accounts for its high potency., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI 50 ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI 50 level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC 50 values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC 50  = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of -9.80 to -11.25 kcal/mol compared to -12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

New imidazolidindiones and tetra-substituted imidazole derivatives were designed, synthesized, and evaluated for the anticonvulsant activity through pentylenetetrazole (PTZ)-induced seizures and maximal electroshock (MES) tests using valproate sodium and phenytoin sodium as reference drugs, respectively. Most of the target compounds showed excellent activity against pentylenetetrazole (PTZ)-induced seizures with fair to no-activity against MES. Compounds 3d, 4e, 11b, and 11e showed higher activity (120%) than that of valproate sodium in PTZ model. Almost all compounds showed no neurotoxicity, as indicated by the rotarod test. Estimation of physicochemical properties and pharmacokinetic profiles of the target compounds were studied. The chemical structures of the target compounds were characterized by different spectrometric methods and elemental analysis., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two series of novel 1,2,4-triazol-3-yl-thioacetamide 3a-b and 4a-b and 5-pyrazin-2-yl-3H-[1,3,4]oxadiazole-2-thiones 9a-h were designed and synthesized. The compounds prepared have been identified using 1 H NMR, 13 C NMR and elemental analyses. The synthesized compounds 3a, 3b, 4a, 4b, 9a, 9b, 9d-e and 9f have been evaluated with α-difluoromethylornithine (DFMO) as a control drug for their in vitro antitrypanosomal activity against Trypanosoma brucei. Results showed that 3b was the most active compound in general and also more potent than control DFMO. 3b was 8 folds more potent than the reference with IC 50 of 0.79 μM and IC 90 of 1.35 μM, respectively compared to DFMO (IC 50  = 6.10 μM and IC 90 of 8.66 μM). The tested compounds showed moderate cytotoxicity with selectivity indices ranging from 12 (9d) to 102 (3b) against L6 cells. Docking study was performed into ten of T. brucei enzymes which have been identified as potential/valid targets for most of the antitrypanosomal agents. The results of the docking study revealed high binding scores toward many of the selected enzymes. A good correlation was observed only between log (IC 50 ) of antitrypanosomal activity of the new compounds and their calculated Ki values against TryR enzyme (R 2  = 0.726). Compound 3b, the most active as antitrypanosomal agents exhibited similar binding orientation and interaction to those of WP6 against TryR enzyme. However, in a next round of work, a complementary studies will be carried out to clarify the mechanism of action of these compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Designing new metal-based molecular antibiotics is an efficient approach to overcome the growing threat of antimicrobial resistance. In this paper, novel Cr(III), Fe(III) and Cu(II) complexes comprising substituted aryl imidazole ligand (MSEB), namely (2-(1-(2-hydroxyethyl)-4,5-diphenyl-1H-imidazole-2-yl)(4-bromophenol)) have been synthesized and characterized using infra-red (IR), ultraviolet-visible (UV-Vis) and 1 H, 13 C NMR spectroscopic techniques, together with elemental (CHN) and thermogravimetric analyses, molar conductance, and magnetic susceptibility measurements. The combined results along with the DFT calculations revealed a 1:1 (M: L) stoichiometric ratio and the complexes adopted distorted-octahedral geometries to afford [Cr(MSEB)Cl 2 (H 2 O) 2 ], [Fe(MSEB)(NO 3 ) 2 (H 2 O) 2 ] and [Cu(MSEB)Cl(H 2 O) 3 ] respectively. Biological studies showed that all complexes exhibited powerful antimicrobial activity against various strains of bacteria and fungi, S. aureus (+ve), E. coli (-ve) and P. aeruginosa (-ve) bacteria and T. Rubrum, C. albicans, and A. flavus fungi. Moreover, the three metal-complexes showed high in vitro cytotoxicity against Colon (HCT-116), Breast (MCF-7), and hepatic cellular (HepG-2) carcinoma cell lines, with MSEBCu complex being the most cytotoxic one. Finally the binding interactions of the complexes with CT-DNA were explored using UV-Vis spectroscopy, viscosity and gel electrophoreses measurements., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A rapid and specific spectrofluorimetric method with higher sensitivity was developed for determination of ledipasvir (LDS) in tablets and human plasma. The proposed method relies on hydrogen bonding formations between the hydroxyl groups of polyoxyethylene 50 stearate and LDS, causing significant enhancement of its native fluorescence. The fluorescence intensity was measured at 430 nm after excitation at 340 nm. The fluorescence-concentration plot was rectilinear over the range 1-400 ng mL -1 with detection and quantification limits of 0.25 and 1.10 ng mL -1 , respectively. The high sensitivity of the proposed method permits its application for ledipasvir determinations in real human plasma even in the presence of co-administered drugs sofosbuvir and ribavirin. Moreover, the proposed method was further extended to stability studies of ledipasvir after exposure to different forced degradation conditions according to ICH guidelines, along with the structural elucidation of its degradation products utilizing IR and Mass spectra. A proposal for the degradation pathways was presented., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Novel and sensitive electrochemical sensor was fabricated for the assay of anti-HCV ledipasvir (LEDV) in different matrices. The designed sensor was based on 3D spinel ferromagnetic NiFe 2 O 4 nanospheres and reduced graphene oxide (RGO) supported by morpholinium acid sulphate (MHS), as an ionic liquid (RGO/NSNiFe 2 O 4 /MHS). This sensor design was assigned to synergistically tailor the unique properties of nanostructured ferrites, RGO, and ionic liquid to maximize the sensor response. Electrode modification prevented aggregation of NiFe 2 O 4, increasing electroactive surface area and allowed remarkable electro-catalytic oxidation of LEDV with an enhanced oxidation response. Differential pulse voltammetry was used for detection LEDV in complex matrices whereas; cyclic voltammetry and other techniques were employed to characterize the developed sensor properties. All experimental factors regarding sensor fabrication and chemical sensing properties were carefully studied and optimized. Under the optimum conditions, the designated sensor displayed a wide linear range (0.4-350 ng mL -1 ) with LOD of 0.133 ng mL -1 . Additionally, the proposed sensor demonstrated good selectivity, stability and reproducibility, enabling the quantitative detection of LEDV in Harvoni ® tablets, human plasma and in a pharmacokinetic study. Our findings suggest that the developed sensor is a potential prototype material for fabrication of high-performance electrochemical sensors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An innovative spectrofluorometric method was developed for the analysis of a recently FDA approved anti-hepatitis C velpatasvir (VELP). The developed method was relied on dispersive solid phase extraction (dSPE) using synergistic effect of reduced graphene oxide (RGO) and cobalt hydroxide nanoparticles (CHNPs) in addition to cloud point extraction (CPE) using polyethylene glycol 6000 (PEG 6000) as non-ionic surfactant. This method combines the merits of preconcentration and interferences elimination achieved by dSPE and CPE, respectively. All relevant parameters such as surfactant concentration, ionic strength, pH, incubation time and others were thoroughly investigated and optimized. Fluorometric detection of VELP was carried out at excitation wavelength of 350 nm and emission wavelength of 415 nm. Under the optimum conditions, a linear calibration curve was achieved in the range of 0.5-45 ng mL -1 . Limits of detection (LOD) and quantification (LOQ) based on three and ten times the standard deviation of the blank were 0.040 and 0.112 ng mL -1 , respectively. This method was successfully applied for determination of VELP in real samples such as tablets, human plasma and urine samples with good recoveries., Competing Interests: Authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Here we report the first encapsulation of three carbamylated amylose namely R-, S- and R/S-amylose 2,3(3,5-dimethylphenylcarbamate)-6-ethylphenylcarbamate in organic polymer monolith in situ capillary columns. The columns were investigated for the enantioselective nano-liquid chromatographic separation of a set of racemic pharmaceuticals, namely, α- and β-blockers, anti-inflammatory drugs, antifungal drugs, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, antihistaminics, anticancer drugs, and antiarrhythmic drugs. Baseline separation was achieved for several drugs under reversed phase chromatographic conditions and only few drugs were separated under normal phase conditions. The developed columns provide more economical analysis under environmentally benign conditions., (Copyright © 2017. Published by Elsevier B.V.)

The title compound, C 24 H 21 N 3 O 3 , crystallizes with two unique but closely r.m.s. overlay fit = 0.215 Å) comparable mol-ecules (1 and 2) in the asymmetric unit of the triclinic unit cell. In molecule 1, the dihedral angles between the central imidazlole ring and the benzene-ring substituents are 42.51 (9), 45.41 (9) and 56.92 (8)°, respectively. Comparable data for molecule 2 are 39.36 (10), 34.45 (11) and 60.34 (8)°, respectively. The rings at the 2-positions carry p -nitro substituents that subtend dihedral angles of 12.9 (4)° in mol-ecule 1 and 11.7 (4)° in mol-ecule 2 to their respective benzene ring planes. The imidazole rings also have propan-2-ol substituents on the 1-N atoms, which adopt extended conformations for the N-C-C-C chains. In the crystal, classical O-H⋯N hydrogen bonds combine with C-H⋯O, C-H⋯N and C-H⋯π(ring) hydrogen bonds and stack the molecules along the a -axis direction.

The title compound, C 24 H 21 ClN 2 O, crystallizes with two unique mol-ecules in the asymmetric unit. In each mol-ecule, the central imidazole ring is substituted at the 2-, 4- and 5-positions by benzene rings. The 2-substituted ring carries a Cl atom at the 4-position. One of the imidazole N atoms in each mol-ecule has a propan-2-ol substituent. In the crystal, a series of O-H⋯N, C-H⋯O and C-H⋯Cl hydrogen bonds, augmented by several C-H⋯π(ring) inter-actions, generate a three-dimensional network of mol-ecules stacked along the a -axis direction.

The central imidazole ring of the title compound, C24H20Cl2N2O, is twisted with respect to with the planes of the 2,6-di-chloro-benzene and two phenyl rings, making dihedral angles of 74.06 (18), 28.52 (17) and 67.65 (18)°, respectively. The phenyl ring not adjacent to the N-bonded 2-hy-droxy-propyl group shows the greatest twist, presumably to minimize steric inter-actions. In the crystal, mol-ecules are linked by O-H⋯N and C-H⋯O hydrogen-bond contacts into chains along the a-axis direction. The series of parallel chains form a two-dimensional sheet approximately parallel to the bc diagonal. In addition, C-H⋯π inter-actions are observed between the sheets. The atoms of the 2-hy-droxy-propyl group and the N atom of the 1H-imidazole ring to which it is bonded are disordered over two sets of sites, with an occupancy ratio of 0.722 (5):0.278 (5). The structure was refined as an inversion twin.

The central imidazole ring in the title compound, C28H30N2O2, makes dihedral angles of 28.42 (13), 71.22 (15) and 29.50 (14)°, respectively, with the phenyl rings in the 4- and 5-positions and the 3,4-di-meth-oxy-phenyl group. In the crystal, mol-ecules are linked by C-H⋯O and C-H⋯N hydrogen bonds, weak π-π stacking inter-actions [centroid-centroid distance = 3.760 (2) Å] and C-H⋯π contacts, forming a three-dimensional network.

The title compound, C26H25BrN2, is isomorphous with the chloro derivative [2-(4-chloro-phen-yl)-1-pentyl-4,5-diphenyl-1H-imidazole; Mohamed et al. (2013 ▶). Acta Cryst. E69, o846-o847]. The two phenyl rings and the 4-bromo-phenyl ring are oriented at dihedral angles of 30.1 (2), 64.3 (3) and 42.0 (2)°, respectively, with respect to the imidazole ring. In the crystal, mol-ecules stack in columns along the b-axis direction, however, there are no significant inter-molecular inter-actions present.

In the title compound, C26H25ClN2, the phenyl rings and the 2-(4-chloro-phen-yl) group make dihedral angles of 30.03 (11), 67.49 (12) and 41.56 (11)°, respectively, with the imidazole ring. In the crystal, the mol-ecules inter-act with each other via very weak C-H⋯π contacts, forming layers parallel to (110).

The title compound, C25H20N2O2, crystallized with two mol-ecules in the asymmetric unit, in one of which the atoms of the terminal propenyl group are disordered over two sets of sites, with a refined occupancy ratio of 0.870 (4):0.130 (4). The central imidazole ring makes dihedral angles of 25.51 (11), 40.73 (11) and 27.36 (11)° with the three pendant rings in one molecule and 22.56 (10), 60.72 (10) and 5.85 (10)° in the other. In the crystal, mol-ecules are linked by N-H⋯N and C-H⋯O hydrogen bonds, forming a three-dimensional network. The crystal structure also features C-H⋯π inter-actions and π-π stacking [centroid-centroid distances = 3.8834 (18) and 3.9621 (17) Å] inter-actions.

In the title compound, C26H24N2O2, the two phenyl and the 2,5-di-meth-oxy-phen-yl rings are inclined to the imidazole ring at dihedral angles of 30.38 (8), 56.59 (9) and 73.11 (9)°, respectively. In the crystal, mol-ecules are linked by pairs of C-H⋯O inter-actions into centrosymmetric dimers with graph-set notation R 2 (2)(8). C-H⋯π inter-actions are also observed.

In the title compound, C24H20N2, one of the ring C atoms and one of the ring N atoms are disordered over two sets of sites in a 0.615 (3):0.385 (3) ratio. The two parts of the disordered imidazole ring adopt an envelope conformation, with the undisordered ring N atom as the flap, displaced by -0.118 (6) and 0.226 (7) Å, respectively, in the two disorder components from the plane through the other ring atoms. The crystal structure features C-H⋯N hydrogen bonds and C-H⋯π inter-actions, which lead to the formation of infinite chains along [010].

In the title compound, C20H18ClN5S, the toluene and triazole rings are oriented almost perpendicular to each other, making a dihedral angle of 89.97 (9)°, whereas the dihedral angle between cholorophenyl and pyrazole rings is 54.57 (11)°. In the crystal, pairs of N-H⋯N hydrogen bonds link the mol-ecules into inversion dimers. Weaker C-H⋯S and C-H⋯Cl inter-actions are also present.

The title compound, C24H19ClN2, crystallizes with two independent mol-ecules in the asymmetric unit. The prop-2-enyl substituents on the imidazole rings adopt similar conformations in the two mol-ecules. The 4-and 5-substituted phenyl rings and the benzene ring make dihedral angles of 67.06 (8), 5.61 (8) and 41.09 (8)°, respectively, with the imadazole ring in one mol-ecule and 71.53 (8), 28.85 (8) and 41.87 (8)°, respectively, in the other. The crystal structure features C-H⋯π inter-actions and weak π-π stacking inter-actions [centroid-centroid distances = 3.6937 (10) and 4.0232 (10) Å] between the chloro-phenyl rings, which form a three-dimensional supramolecular structure.

The title compound, C26H24Cl2N2, crystallizes with two independent mol-ecules (1 and 2) in the asymmetric unit. In mol-ecule 1, the two phenyl and 2,6-di-chloro-phenyl rings are inclined to the imidazole ring at angles of 74.12 (14), 26.13 (14) and 67.30 (14)°, respectively. In mol-ecule 2, due to the different mol-ecular environment in the crystal, the corresponding angles are different, viz. 71.72 (15), 16.14 (15) and 80.41 (15)°, respectively. In the crystal, mol-ecules 1 and 2 are linked by C-H⋯Cl inter-actions, and inversion-related 2 mol-ecules are linked by C-H⋯π inter-actions. There are no other significant inter-molecular inter-actions present.

In the title compound, C19H16BrClO4, both the fused xanthene rings and one of the cyclo-hexane rings adopt envelope conformations, while the other cyclo-hexane ring is in a chair conformation. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, forming infinite chains running along [10-1] incorporating R 2 (2)(16) ring motifs. In addition, C-H⋯π inter-actions and weak π-π stacking inter-actions [centroid-centroid distance = 3.768 (3) Å] help to consolidate the packing.

The title compound, C26H25N3, crystallizes with four independent mol-ecules, 1-4, in the asymmetric unit of the triclinic unit cell. The allyl substituents on the imidazole rings adopt similar conformations in all four mol-ecules. The imadazole and the 4-and 5-substituted phenyl rings of two pairs of molecules in the asymmetric unit stack parallel to (110). In contrast, the dimethyl-aniline systems in these pairs of mol-ecules are almost normal to one another, with dihedral angles of 85.84 (10) and 85.65 (10)° between the benzene rings of the two dimethyl-aniline fragments of mol-ecules 1 and 2, and 3 and 4, respectively. The crystal structure features an extensive series of C-H⋯π inter-actions that link the mol-ecules into undulating rows along the c axis. The crystal studied was a pseudo-merohedral twin with twin law [-100, 0-10, 111] and the BASF parameter refined to 0.513 (3).

In the title compound, C24H22N2O2, the central imidazole ring makes dihedral angles of 49.45 (8), 88.94 (9) and 19.43 (8)° with the benzene ring and the two phenyl rings, respectively. The dihedral angle between the phenyl rings is 77.86 (9)°, and they form dihedral angles of 49.06 (9) and 67.31 (8)° with the benzene ring. In the crystal, mol-ecules are linked by O-H⋯N hydrogen bonds, forming chains along the b axis. These chains are connected by C-H⋯O hydrogen bonds, forming a two-dimensional network parallel to (100). In addition, C-H⋯π inter-actions are also observed. The terminal C and O atoms of the ethanol group are disordered over two sets of sites with an occupancy ratio of 0.801 (5):0.199 (5).

In the title compound, C(16)H(14)ClN(3)O(2)S, the dihedral angle between the benzene and pyrazole rings is 52.75 (2)°, while that between the pyrazole and 4-chloro-phenyl rings is 54.0 (3)°. The terminal sulfonamide group adopts an approximately tetra-hedral geometry about the S atom with a C-S-N angle of 108.33 (10)°. In the crystal, pairs of N-H⋯N hydrogen bonds lead to the formation of inversion dimers. These dimers are linked via a second pair of N-H⋯N hydrogen bonds and C-H⋯O interactions, forming a two-dimensional network lying parallel to the bc plane. The two-dimensional networks are linked via C-H⋯Cl interactions, forming a three-dimensional structure.

The title compound, C27H28N2O, is a lophine (2,4,5-triphenyl-1H-imidazole) derivative with an n-pentyl chain on the amine N atom and a 4-meth-oxy substituent on the benzene ring. The two phenyl and meth-oxy-benzene rings are inclined to the imidazole ring at angles of 25.32 (7), 76.79 (5) and 35.42 (7)°, respectively, while the meth-oxy substituent lies close to the plane of its benzene ring, with a maximum deviation of 0.126 (3) Å for the meth-oxy C atom. In the crystal, inversion dimers linked by pairs of C-H⋯O hydrogen bonds generate R2(2)(22) loops. These dimers are stacked along the a-axis direction.

The mol-ecular conformation of the title compound, C13H8BrFN2O3, is essentially planar, with maximum deviations of 0.076 (1) and -0.080 (2) Å for the O atoms of the NO2 group. The mol-ecular conformation is stabilized by an intra-molecular O-H⋯N hydrogen bond, forming an S(6) ring motif. In the crystal, pairs of mol-ecules are linked via two pairs of C-H⋯O hydrogen bonds, forming inversion dimers that enclose R(2)2(7)R(2)2(10)R(2)2(7) ring motifs.

In the title compound, C19H17NO2, the dihedral angle between the benzene ring and the naphthalene ring system is 9.72 (5)°, while the torsion angle of the C-N-C-C bridging group is 179.24 (17)°. The methyl group of the 1-phenyl-ethanol moiety is disordered over two positions with a refined occupancy ratio of 0.775 (5):0.225 (5). The mol-ecular conformation is stabil-ized by an intra-molecular N-H⋯O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, forming zigzag chains propagating along the c-axis direction. Neighbouring chains are linked via C-H⋯O inter-actions, forming a two-dimensional slab-like network parallel to the bc plane.

The asymmetric unit of the title compound, C34H16O5, contains two independent mol-ecules (A and B) with similar conformations. The two benzene rings attached to the nine-membered ring are inclined to one another at 63.62 (14)° in mol-ecule A and 68.23 (12)° in mol-ecule B. One intra-moleculer C-H⋯O hydrogen bond occurs in mol-ecule A and two are observed in mol-ecule B. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming a three-dimensional network structure with R(2)2(10) and R(2)2(24) ring motifs. Aromatic π-π stacking interactions [centroid-centroid distances = 3.7572 (19), 3.6996 (19) and 3.7043 (19) Å] are also observed. The unit cell contains a pair of voids of 37 (2) Å(3) about an inversion centre but the residual electron density (highest peak = 0.19 e Å(-3) and deepest hole = -0.20 e Å(-3)) in the difference Fourier map suggests that no solvent mol-ecule occupies this void.

The asymmetric unit of the title compound, C(25)H(22)N(2)O, contains two independent mol-ecules (A and B), with significantly different conformations. In mol-ecule A, the central imidazole ring makes dihedral angles of 88.26 (10) and 12.74 (11)° with the two phenyl rings, and 22.06 (9)° with the benzene ring. In mol-ecule B, one of the phenyl rings is disordered over two sites, each having an occupancy of 0.5. Here the central imidazole ring forms dihedral angles of 79.24 (10)° with the ordered phenyl ring, and 3.5 (5) and 22.6 (5)° with the two parts of the disordered phenyl ring. The dihedral angle involving the benzene ring is 67.49 (10)°. The -N-C(H(2))-C(H)-C(H(2)) torsion angles of the prop-1-ene group in the two mol-ecules are very similar, 0.5 (3) and 1.3 (4)° for mol-ecules A and B, respectively. The crystal structure is stabilized by C-H⋯π inter-actions.

In the title compound, C(26)H(24)N(2)O(2), the planar 1H-imidazole ring makes dihedral angles of 35.78 (4), 26.35 (5) and 69.75 (5)°, respectively, with the dimeth-oxy-phenyl ring and the phenyl rings in the 4- and 5-positions. In the crystal, C-H⋯O hydrogen bonds connect neighbouring mol-ecules, forming infinite chains running along the b axis. Furthermore, the crystal structure exhibits a C-H-⋯π inter-action between a methyl H atom and a phenyl ring from an adjacent mol-ecule.

The incidence of insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM) in Benghazi, Libya in the < 35-year age group during the period 1981-1990 are reported. Incidence data for IDDM were based on prospective registration of patients while incidence data for NIDDM were based on analysis of files. Case ascertainment of IDDM cases was estimated to be > 95%. Incidence of total diabetes (IDDM and NIDDM) (per 100000 population) was significantly higher in females (43.8; 95% confidence Interval (CI) 40.6-47.2) than in males (28.9, 26.6-31.3) (P < 0.001). The overall incidence rates of IDDM and NIDDM were 9.0 (CI, 8.1-10.0) and 27.3 (CI, 25.4-28.2), respectively. Rates of IDDM were 9.4 (CI, 8.1-10.9) among males and 8.5 (CI, 7.3-10.0) among females. Rates of NIDDM were 19.6 (CI, 18.1-22.2) among males and 35.3 (CI, 32.4-37.8) among females. IDDM patients showed a female predominance in the 0- to 14-year age range (P > 0.05) and a male predominance in the 15- to 34-year age range (P > 0.05). NIDDM showed equal incidence in males and females in the 0- to 14-year age range and twofold higher incidence in females than in males in the 15- to 34-year age group (P < 0.001). Yearly variation and seasonality of onset were not significant in IDDM cases (P > 0.05). Fifty-six percent of NIDDM cases were obese compared to only 6% of IDDM cases. The study revealed that diabetes mellitus is a common chronic disease in children and young Libyan Arabs. It has shown that NIDDM in Benghazi is twofold higher in females than in males in the 15- to 34-year age group. It has also shown that age per se is not a reliable criterion for the classification of diabetes into IDDM and NIDDM.