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Ibrahim A Darwish,1 Nasr Y Khalil,1 Nawaf A Alsaif,1 Rashed N Herqash,2 Ahmed YA Sayed,1 Hamdy M Abdel-Rahman3,4 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 2Medicinal Aromatic and Poisonous Plant Research Centre, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 3Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt; 4Department of Medicinal Chemistry, College of Pharmacy, Nahda University, Banisuef, EgyptCorrespondence: Ibrahim A DarwishDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi ArabiaTel +966 114677348Fax +966 114676220Email idarwish@ksu.edu.saBackground: Linifanib (LFB) is a multi‐targeted receptor tyrosine kinase inhibitor used in the treatment of hepatocellular carcinoma and other types of cancer. The charge-transfer (CT) interaction of LFB is important in studying its receptor binding mechanisms and useful in the development of a reliable CT-based spectrophotometric assay for LFB in its pharmaceutical formulation to assure its therapeutic benefits.Purpose: The aim of this study was to investigate the CT reaction of LFB with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ) and its application in the development of a novel 96-microwell spectrophotometric assay for LFB.Methods: The reaction was investigated, its conditions were optimized, the physicochemical and constants of the CT complex and stoichiometric ratio of the complex were determined. The solid-state LFB-DDQ complex was synthesized and its structure was analyzed by UV-visible, FT-IR, and 1H-NMR spectroscopic techniques, and also by the computational molecular modeling. The reaction was employed in the development of a novel 96-microwell spectrophotometric assay for LFB.Results: The reaction resulted in the formation of a red-colored product, and the spectrophotometric investigations confirmed that the reaction had a CT nature. The molar absorptivity of the complex was linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9526 and 0.9459, respectively. The stoichiometric ratio of LFB:DDQ was 1:2. The spectroscopic and computational data confirmed the sites of interaction on the LFB molecule, and accordingly, the reaction mechanism was postulated. The reaction was utilized in the development of the first 96-microwell spectrophotometric assay for LFB. The assay limits of detection and quantitation were 1.31 and 3.96 μg/well, respectively. The assay was successfully applied to the analysis of LFB in its bulk and tablets with high accuracy and precision.Conclusion: The assay is simple, rapid, accurate, eco-friendly as it consumes low volumes of organic solvent, and has high analysis throughput.Keywords: linifanib, 2,3-dichloro-3,5-dicyano-1,4-benzoquinone, charge-transfer reaction, spectroscopic techniques, 96-microwell spectrophotometric assay, high-throughput pharmaceutical analysis

Traditional uses for the plant Medicago sativa ( M. sativa ) (Alfalfa) (Family: Fabaceae) include liver protection, antioxidant activity, and the treatment of bleeding and digestive issues. This study aims to assess the effect of ethanol extract of M. sativa (EEMS) on experimental-induced ulcers in diabetic rats. By pylorus ligation and ethanol administration, gastric ulcers were induced in diabetic rats. Five groups each consisting of six rats in each model were used. All other groups except Group I were made diabetic by giving rats alloxan (140 mg/kg i.p.). Vehicles were given to Group I (normal control) and Group II (diabetes control) rats. Group III (positive control) received ranitidine 50 mg/kg, and Group IV and V received EEMS at doses of 100 and 400 mg/kg, respectively. In the pylorus ligation and ethanol-induced stomach ulcer model of rats, the findings demonstrated that EEMS (100 mg/kg) showed a decreased ulcer index of 2.01 ± 0.41 and was found statistically significant against the diabetes control group (p < 0.001) as well as, an ulcer index of 0.68 ± 0.22 by EEMS (400 mg/kg) with a significant reduction in the ulcer index (p < 0.001). EEMS (100 and 400 mg/kg) reduce free acidity by 13.16 ± 0.65 mEq/L and 9.83 ± 0.30 mEq/L, respectively. EEMS also showed a protective impact on the liver and kidneys of diabetic rats. Antihyperglycemic action was also discovered in diabetic animals. The findings of the current investigation demonstrated that ethanolic extract of M. sativa possesses anti-ulcer activity in diabetic rats. Ethanolic extract of M. sativa may be a treatment option for stomach ulcers that also have diabetes., Competing Interests: 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., (© 2023 The Author(s).)

Background: Morus alba Linn, referred to as white mulberry, is a potential traditional medicine for diabetes and neuroprotection., Aim: Isolation, characterization, development and evaluation of phytoconstituent based formulation for diabetic neuropathy., Material and Methods: The stem Bark of M. alba was peeled and subjected to extraction. A phytoconstituent was then isolated by column chromatography and characterized using Mass spectroscopy, FTIR, and NMR. The isolated phytoconstituent was used to formulate a nanoemulsion. Nanoemulsion was also characterized for viscosity, surface tension, refractive index, pH, and particle size. Selected nanoemulsion formulations were then tested for acute oral toxicity and diabetic neuropathy, including behavioral, hematological, histopathological, and biomarker examinations., Results: The spectral analysis affirmed that the isolated compound was found to be chrysin. A nanoemulsion formulation was made using the chrysin and was characterized and found to be stable during the stability testing and fulfilled all other testing parameters. Then acute oral toxicity study of the formulations was found to be safe. Formulations were found to possess significant results against diabetic neuropathy in rats. Biomarkers were analyzed for their mechanistic involvement in reducing neuropathy in rats, and it was found that the oxidative pathway was considerably restored, suggesting that chrysin causes these effects via this pathway., Conclusions: Results suggests that isolated phytoconstituent (chrysin) from the bark of Morus alba derived nanoemulsion has protective and beneficial effects by diminishing the oxidative damage against alloxan-induced diabetic neuropathy in rats., Competing Interests: 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., (© 2023 The Author(s).)

Alzheimer's disease (AD) is a progressive neurological illness that is distinguished clinically by cognitive and memory decline and adversely affects the people of old age. The treatments for this disease gained much attention and have prompted increased interest among researchers in this field. As a springboard to explore new anti-Alzheimer's chemical prototypes, the present study was carried out for the synthesis of benzoxazole-oxadiazole analogues as effective Alzheimer's inhibitors. In this research work, we have focused our efforts to synthesize a series of benzoxazole-oxadiazole ( 1 - 19 ) and evaluating their anti-Alzheimer properties. In addition, the precise structures of synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1 H-NMR, 13 C-NMR and HREI-MS. To find the anti-Alzheimer potentials of the synthesized compounds ( 1 - 19 ), in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), inhibitory activities were performed using Donepezil as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were due to different substitution patterns of substituent(s) at the variable position of both acetophenone aryl and oxadiazole aryl rings. The results of the anti-Alzheimer assay were very encouraging and showed moderate to good inhibitory potentials with IC 50 values ranging from 5.80 ± 2.18 to 40.80 ± 5.90 µM (against AChE) and 7.20 ± 2.30 to 42.60 ± 6.10 µM (against BuChE) as compared to standard Donepezil drug (IC 50 = 33.65 ± 3.50 µM (for AChE) and 35.80 ± 4.60 µM (for BuChE), respectively. Specifically, analogues 2 , 15 and 16 were identified to be significantly active, even found to be more potent than standard inhibitors with IC 50 values of 6.40 ± 1.10, 5.80 ± 2.18 and 6.90 ± 1.20 (against AChE) and 7.50 ± 1.20, 7.20 ± 2.30 and 7.60 ± 2.10 (against BuChE). The results obtained were compared to standard drugs. These findings reveal that benzoxazole-oxadiazole analogues act as AChE and BuChE inhibitors to develop novel therapeutics for treating Alzheimer's disease and can act as lead molecules in drug discovery as potential anti-Alzheimer agents.

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis., Competing Interests: 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., (© 2023 The Author(s).)

The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.

A series of 12 compounds was designed and synthesized, based on 2-mercaptobenzoxazole derivatives containing either the substituted benzenes 4a - d , substituted isatins 5a - f , or heterocycles 6a - b . The in vitro antiproliferative activity of the compounds was evaluated against hepatocellular carcinoma (HepG2), mammary gland cancer (MCF-7), breast cancer (MDA-MB-231), and the epithelioid cervix carcinoma (HeLa) cancer cell lines. Compounds 4b , 4d , 5d , and 6b had the most potent antiproliferative activity, with IC 50 values ranging from 2.14 to 19.34 µM, compared to the reference drugs, doxorubicin and sunitinib. Compound 6b revealed a remarkably broad antitumor activity pattern against HepG2 (IC 50 6.83 µM), MCF-7 (IC 50 3.64 µM), MDA-MB-231 (IC 50 2.14 µM), and HeLa (IC 50 5.18 µM). In addition, compound 6b showed potent inhibitory activities against EGFR, HER2, VEGFR2, and the CDK2 protein kinase enzymes, with IC 50 values of 0.279, 0.224, 0.565, and 0.886 µM, respectively. Moreover, compound 6b induced caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Finally, a molecular docking simulation was performed for compound 6b to predict the potential ligand-protein interactions with the active sites of the EGFR, HER2, and VEGFR2 proteins.

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4 - 27 . The hCA I isoform was efficiently inhibited by Schiff's bases 4 - 6 , 10 - 19 , 22 - 27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2 , 3 , 4 , 10 , 11 , 16 , 18 , 24 , 26 , and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2 - 27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3 , 10 , 11 , 13 , 15 - 19 , and 24 possessed potent hCA XII inhibitory activities with K I values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7 , 8 , 9 , and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with K I rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5 , 7 , 8 , 9 , 14 , 18 , 19 , and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12 , 14 , and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2 , 5 , 7 - 14 , 19 - 23 , and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5 , 7 , 8 , 13 , 14 , 15 , 17 , 20 , 21 , and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one ( 1 ), 4-acetyl aniline ( 2 ) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1 H-NMR, and single crystal analysis proved the structure of synthesized compound ( 4 ), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⋯ S and C-H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R 2 2 (8) and R 2 2 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC 50 = 1.97 μM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC 50 values of 6.2 and 4.9 μM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC 50  = 3.53 and 2.18 μM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC 50 value of 3.9 nM, which is very close to that of sorafenib (IC 50  = 3.13 nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC 50 values ranging from 11.7 to 15.3 μM. Also, these compounds showed promising VEGFR-2 inhibition with IC 50 values of 4.2, 5.7, and 4.7 nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Pemigatinib (PMB) is a small molecule inhibitor of fibroblast growth factor receptor 1 (FGFR1), FGFR2 and FGFR3. On April 17, 2020, the US Food and Drug Administration granted accelerated approval for PMB for the treatment of adults with previously treated, unresectable metastatic or locally advanced cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement. PMB is considered the first targeted treatment for cholangiocarcinoma approved in the US. In this study, in silico prediction of PMB metabolic stability was done using the WhichP450 module of the StarDrop software package. Further, an LC-MS/MS analytical method was developed for PMB quantification in human liver microsomes (HLM) to experimentally assess metabolic stability. PMB and flavopiridol (FVL), used as an internal standard IS, were resolved using an isocratic mobile phase and a C18 stationary phase. The LC-MS/MS method showed linearity in the range of 5 to 500 ng mL -1 in an HLM matrix ( R 2 = 0.9995). The lower limit of quantification (LLOQ) was 5 ng mL -1 , indicating sensitivity. The inter- and intra-day accuracy and precision were within a variability of 10, confirming the reproducibility of the method. The measured in vitro half-life and intrinsic clearance of PMB were 27.29 min and 25.40 μL min -1 mg -1 , respectively. PMB showed a moderate extraction ratio suggesting good bioavailability. The developed analytical method is the first LC-MS/MS method specific for PMB quantification with application to metabolic stability assessment., Competing Interests: The authors report no conflicts of interest for this work., (This journal is © The Royal Society of Chemistry.)

The antitumor activity of newly synthesized 4-anilino-2-vinylquinazolines 8a-r was measured comparable to sorafenib as a standard drug. The 2-vinylquinazolines 8a-r were evaluated for their in vitro antitumor activity. The most active antitumor agents were subjected to in vitro VEGFR-2 inhibition and apoptotic inducing assay. Compounds 8 h, 8 l, and 8r showed potential antitumor activities with IC 50 values of 4.92-14.37 μM relative to the reference drug, sorafenib (IC 50 values of 5.47-9.18 μM). Compound 8 h possessed potential VEGFR-2 inhibitory activity (IC 50  = 60.27 nM) compared to standard drug sorafenib (IC 50  = 55.43 nM), whereas compound 8 l showed moderate inhibitory activity (IC 50  = 93.50 nM). The most active compound, 8 h, exhibited total apoptosis with 36.24% on MCF-7 cells, more than the apoptotic effect provoked by sorafenib (32.46%) and the cell cycle arrested at a G1/S phase. Compound 8 h, a potent VEGFR-2 inhibitor, was docked into the VEGFR-2 binding pocket, where this compound showed binding interaction similar to co-crystallized inhibitor sorafenib., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Quetiapine (QTP) is a short-acting atypical antipsychotic drug that treats schizophrenia or manic episodes of bipolar disorder. Human serum albumin (HSA) is an essential transport protein that transports hormones and various other ligands to their intended site of action. The interactions of QTP with HSA and their binding mechanism in the HSA-QTP system was studied using spectroscopic and molecular docking techniques. The UV-Vis absorption study shows hyperchromicity in the spectra of HSA on the addition of QTP, suggesting the complex formation and interactions between QTP and HSA. The results of intrinsic fluorescence indicate that QTP quenched the fluorescence of HSA and confirmed the complex formation between HSA and QTP, and this quenching mechanism was a static one. Thermodynamic analysis of the HSA-QTP system confirms the involvement of hydrophobic forces, and this complex formation is spontaneous. The competitive displacement and molecular docking experiments demonstrated that QTP is preferentially bound to HSA subdomain IB. Furthermore, the CD experiment results showed conformational changes in the HSA-QTP system. Besides this, the addition of QTP does not affect the esterase-like activity of HSA. This study will help further understand the credible mechanism of transport and delivery of QTP via HSA and design new QTP-based derivatives with greater efficacy.

The interaction between erlotinib (ERL) and bovine serum albumin (BSA) was studied in the presence of quercetin (QUR), a flavonoid with antioxidant properties. Ligands bind to the transport protein BSA resulting in competition between different ligands and displacing a bound ligand, resulting in higher plasma concentrations. Therefore, various spectroscopic experiments were conducted in addition to in silico studies to evaluate the interaction behavior of the BSA-ERL system in the presence and absence of QUR. The quenching curve and binding constants values suggest competition between QUR and ERL to bind to BSA. The binding constant for the BSA-ERL system decreased from 2.07 × 10 4 to 0.02 × 10 2 in the presence of QUR. The interaction of ERL with BSA at Site II is ruled out based on the site marker studies. The suggested Site on BSA for interaction with ERL is Site I. Stability of the BSA-ERL system was established with molecular dynamic simulation studies for both Site I and Site III interaction. In addition, the analysis can significantly help evaluate the effect of various quercetin-containing foods and supplements during the ERL-treatment regimen. In vitro binding evaluation provides a cheaper alternative approach to investigate ligand-protein interaction before clinical studies.

Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC 50 value of 3.2 nM, which is very close to that of sorafenib (IC 50  = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC 50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

The methanolic extract of Argyreia capitiformis stem was examined for anti-inflammatory activities following network pharmacology analysis and molecular docking study. Based on gas chromatography-mass spectrometry (GC-MS) analysis, 49 compounds were identified from the methanolic extract of A. capitiformis stem. A network pharmacology analysis was conducted against the identified compounds, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology analysis of biological processes and molecular functions were performed. Six proteins (IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6) were identified from the KEGG pathway analysis and subjected to molecular docking study. Additionally, six best ligand efficiency compounds and positive control (aspirin) from each protein were evaluated for their stability using the molecular dynamics simulation study. Our study suggested that IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6 proteins may be targeted by compounds in the methanolic extract of A. capitiformis stem to provide anti-inflammatory effects., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Ahmad J. Obaidullah et al.)

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression of tumour propagation. Accordingly, two series of new 3-methylquinoxaline derivatives have been designed and synthesised as VEGFR-2 inhibitors. The synthesised derivatives were evaluated in vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the VEGFR-2 inhibitory activities of the target compounds were estimated to indicate the potential mechanism of their cytotoxicity. To a great extent, the results of VEGFR-2 inhibition were highly correlated with that of cytotoxicity. Compound 27a was the most potent VEGFR-2 inhibitor with IC 50 of 3.2 nM very close to positive control sorafenib (IC 50 = 3.12 nM). Such compound exhibited a strong cytotoxic effect against MCF-7 and HepG2, respectively with IC 50 of 7.7 and 4.5 µM in comparison to sorafenib (IC 50 = 3.51 and 2.17 µM). In addition, compounds 28 , 30f , 30i , and 31b exhibited excellent VEGFR-2 inhibition activities (IC 50 range from 4.2 to 6.1 nM) with promising cytotoxic activity. Cell cycle progression and apoptosis induction were investigated for the most active member 27a . Also, the effect of 27a on the level of caspase-3, caspase-9, and BAX/Bcl-2 ratio was determined. Molecular docking studies were implemented to interpret the binding mode of the target compounds with the VEGFR-2 pocket. Furthermore, toxicity and ADMET calculations were performed for the synthesised compounds to study their pharmacokinetic profiles.

Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24 ) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6 , 9 , 16 , and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5 , 10 , 14 , 15 , 18 , and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI 50 ) of 0.26 µM. Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC 50 ) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC 50 = 0.2 and 0.19 μM, respectively) and HER2 (IC 50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9 , 16 , and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.

There is an urgent need to design new anticancer agents that can prevent cancer cell proliferation even with minimal side effects. Accordingly, two new series of 3-methylquinoxalin-2(1 H )-one and 3-methylquinoxaline-2-thiol derivatives were designed to act as VEGFR-2 inhibitors. The designed derivatives were synthesised and evaluated in vitro as cytotoxic agents against two human cancer cell lines namely, HepG-2 and MCF-7. Also, the synthesised derivatives were assessed for their VEGFR-2inhibitory effect. The most promising member 11e were further investigated to reach a valuable insight about its apoptotic effect through cell cycle and apoptosis analyses. Moreover, deep investigations were carried out for compound 11e using western-plot analyses to detect its effect against some apoptotic and apoptotic parameters including caspase-9, caspase-3, BAX, and Bcl-2. Many in silico investigations including docking, ADMET, toxicity studies were performed to predict binding affinity, pharmacokinetic, drug likeness, and toxicity of the synthesised compounds. The results revealed that compounds 11e, 11g, 12e, 12g, and 12k exhibited promising cytotoxic activities (IC 50 range is 2.1 - 9.8 µM), comparing to sorafenib (IC 50 = 3.4 and 2.2 µM against MCF-7 and HepG2, respectively). Moreover, 11b, 11f, 11g, 12e, 12f, 12g, and 12k showed the highest VEGFR-2 inhibitory activities (IC 50 range is 2.9 - 5.4 µM), comparing to sorafenib (IC 50 = 3.07 nM). Additionally, compound 11e had good potential to arrest the HepG2 cell growth at G2/M phase and to induce apoptosis by 49.14% compared to the control cells (9.71%). As well, such compound showed a significant increase in the level of caspase-3 (2.34-fold), caspase-9 (2.34-fold), and BAX (3.14-fold), and a significant decrease in Bcl-2 level (3.13-fold). For in silico studies, the synthesised compounds showed binding mode similar to that of the reference compound (sorafenib).

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC 50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC 50 = 16.08-23.67 µM), HCT-116 (IC 50 = 8.81-13.85 µM), and MCF-7 (IC 50 = 8.36-17.28 µM) cell lines. Compounds 2 , 3 , 8 , 10 , and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC 50 = 0.90 µM). Compounds 2 , 3 , 10 , and 11 displayed significant EGFR TK inhibitory activity with IC 50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2 , 3 , 10 , and 11 indicated that they could bind to the active site of EGFR TK.

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3- a :3',4'- c ]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a , 23i , 23j , 23l , and 23n displayed the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a , 23d , 23h , 23i , 23j , 23l , 23 m , and 23n showed the highest VEGFR-2 inhibitory activities with IC 50 values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC 50 = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).

A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 and HepG-2. Compounds 15b and 17b demonstrated a significant antiproliferative effect with IC 50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out for all the tested candidates against VEGFR-2. Compound 17b was the most potent VEGFR-2 inhibitor (IC 50 = 2.7 nM). Mechanistic investigation including cell cycle arrest and apoptosis was performed for compound 17b against HepG-2 cells, and the results revealed that 17b induced cell apoptosis and arrested cell cycle in the G2/M phase. Moreover, apoptosis analyses were conducted for compound 17b to evaluate its apoptotic potential. The results showed upregulation in caspase-3 and caspase-9 levels, and improving the Bax/Bcl-2 ratio by more than 10-fold. Docking studies were performed to determine the possible interaction with the VEGFR-2 active site. Further docking studies were carried out for compound 17b against cytochrome P450 to present such compounds as non-inhibitors. In silico ADMET, toxicity, and physico-chemical properties revealed that most of the synthesized members have acceptable values of drug-likeness. Finally, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties., Competing Interests: There is no conflict of interest. Many thanks for Dr Mohamed R. Elnagar, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt for his valuable technical assistance., (This journal is © The Royal Society of Chemistry.)

Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC 50  = 8.2 and 5.4 µM, respectively), compared to sorafenib (IC 50  = 3.51 and 2.17 µM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC 50  = 3.4 nM) exhibited good activity compared to sorafenib (IC 50  = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro-apoptotic marker (Bax) expression by 2.33-fold and decreased anti-apoptotic (Bcl-2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A new series of bis([1,2,4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and20mshowed promising VEGFR-2 inhibitory activities with IC 50 values of 5.7, 6.7, 3.2, and 3.1 µM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC 50 values ranging from 3.3 to 14.2 µM, comparing to sorafenib (IC 50  = 2.17 and 3.43 µM against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Thirty-five new colchicine binding site inhibitors have been designed and synthesized based on the 1,2,4-triazin-3(2H)-one nucleus. Such molecules were synthesized through a cascade reaction between readily accessible α-amino ketones and phenyl carbazate as a masked N-isocyanate precursor. The synthesized derivatives are cisoid restricted combretastatin A4 analogues containing 1,2,4-triazin-3(2H)-one in place of the olefinic bond, and they have the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesized compounds were evaluated in vitro for their antiproliferative activities against a panel of three human cancer cell lines (MCF-7, HepG-2, and HCT-116), using colchicine as a positive control. Among them, two compounds 5i and 6i demonstrated a significant antiproliferative effect against all cell lines with IC 50 ranging from 8.2 - 18.2 µM. Further investigation was carried out for the most active cytotoxic agents as tubulin polymerization inhibitors. Compounds 5i and 6i effectively inhibited microtubule assembly with IC 50 values ranging from 3.9 to 7.8 µM. Tubulin polymerization assay results were found to be comparable with the cytotoxicity results. The cell cycle analysis revealed significant G2/M cell cycle arrest of the analogue 5i in HepG-2 cells. The most active compounds 4i, 4j, 5 g, 5i and 6i did not induce significant cell death in normal human lung cells Wl-38, suggesting their selectivity against cancer cells. Also, These compounds upregulated the level of active caspase-3 and boosted the levels of the pro-apoptotic protein Bax by five to seven folds in comparison to the control. Moreover, apoptosis analyses were conducted for compound 5i to evaluate its apoptotic potential. Finally, in silico studies were conducted to reveal the probable interaction with the colchicine binding site. ADME prediction study of the designed compounds showed that they are not only with promising tubulin polymerization inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in a contagious respiratory tract infection that has become a global burden since the end of 2019. Notably, fewer patients infected with SARS-CoV-2 progress from acute disease onset to death compared with the progression rate associated with two other coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Several research organizations and pharmaceutical industries have attempted to develop successful vaccine candidates for the prevention of COVID-19. However, increasing evidence indicates that the SARS-CoV-2 genome undergoes frequent mutation; thus, an adequate analysis of the viral strain remains necessary to construct effective vaccines. The current study attempted to design a multi-epitope vaccine by utilizing an approach based on the SARS-CoV-2 structural proteins. We predicted the antigenic T- and B-lymphocyte responses to four structural proteins after screening all structural proteins according to specific characteristics. The predicted epitopes were combined using suitable adjuvants and linkers, and a secondary structure profile indicated that the vaccine shared similar properties with the native protein. Importantly, the molecular docking analysis and molecular dynamics simulations revealed that the constructed vaccine possessed a high affinity for toll-like receptor 4 (TLR4). In addition, multiple descriptors were obtained from the simulation trajectories, including the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration ( R g ), demonstrating the rigid nature and inflexibility of the vaccine and receptor molecules. In addition, codon optimization, based on Escherichia coli K12, was used to determine the GC content and the codon adaptation index (CAI) value, which further followed for the incorporation into the cloning vector pET28+(a). Collectively, these findings suggested that the constructed vaccine could be used to modulate the immune reaction against SARS-CoV-2., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

New series of [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized, and biologically assessed for their anti-proliferative activities against two selected tumor cell lines MCF-7 and HepG2. Comparing to sorafenib (IC 50  = 2.17 ± 0.13 and 3.51 ± 0.21 µM against MCF-7 and HepG2, respectively), compound 25d, 25e, 25i, and 27e exhibited the highest activities against the examined cell lines with IC 50 values extending from 4.1 ± 0.4 to 11.7 ± 1.1 µM. Furthermore, VEGFR-2 inhibitory activities were assessed for all the synthesized compounds as potential mechanisms for their anti-proliferative activities. Compounds 25d, 25e, 25i, and 27e displayed prominent inhibitory efficiency versus VEGFR-2 kinase with IC 50 value ranging from 3.4 ± 0.3 to 6.8 ± 0.5 nM. Fascinatingly, the results of VEGFR-2 inhibitory assays were matched with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited promising VEGFR-2 inhibitory activities. Further studies displayed the ability of compound 25d to induce apoptosis in HepG2 cells and can arrest the growth of such cells at the G2/M phase. Also, compound 25d produced a significant increase in the level of BAX/Bcl-2 ratio (3.8-fold), caspase- 3 (1.8-fold), and caspase-9 (1.9-fold) compared to the control cells. Molecular docking studies were carried out to investigate the possible binding interaction inside the active site of the VEGFR-2., (Copyright © 2021. Published by Elsevier Inc.)

A quartz crystal adsorbent coated with 5,10,15,20-tetrakis(4-methylphenyl) porphyrin was used to examine the complexation phenomenon of three metallic ions [aluminum(III), iron(III) and indium(III)]. The aim is to select the appropriate adsorbate for metalloporphyrin fabrication. The equilibrium adsorption isotherms of tetrakis(4-methylphenyl) porphyrin were performed at four temperatures (from 300 to 330 K) through the quartz crystal microbalance (QCM) method. Subsequently, the experimental data were analyzed in order to develop a thorough explanation of the complexation mechanisms. The experimental results indicated that the aluminum(III) chloride is the adequate material for metalloporphyrin application. Theoretical investigation was established through physics adsorption models in order to analyze the experimental isotherms. The AlCl 3 isotherms were modeled via a single-layer adsorption model which is developed using the ideal gas law. Whereas, the FeCl 3 isotherms were interpreted via a single-layer adsorption which includes the lateral interactions parameters (real gas law), indicating the lowest stability of the formed iron-porphyrin complex. The participation of the chloride ions in the double-layers adsorption of InCl 3 was interpreted via layer by layer formulation. Interestingly, the physicochemical investigation of the three adopted models indicated that the tetrakis(4-methylphenyl) porphyrin adsorption was an endothermic process and that the aluminum(III) chloride can be recommended for an industrial application because it presents the highest adsorption energy (chemical bonds with porphyrins).

This study assessed the anxiolytic and antidepressant activities of a methanol leaves extract of Cnesmone javanica (CV) in Swiss albino mice. The study found a significant increase in the percentage of time spent in the open arms of an elevated plus maze and in the incidence of head dipping in hole-board tests following the administration of 400 mg/kg of CV or 1 mg/kg diazepam. Moreover, a significant ( p < 0.001) dose-dependent reduction was observed in the immobility time following CV (200 and 400 mg/kg) and fluoxetine (20 mg/kg) administration for forced swimming and tail suspension tests. Gas chromatography-mass spectroscopy (GC-MS) analysis identified 62 compounds in CV, consisting primarily of phenols, terpenoids, esters, and other organic compounds. A molecular docking study was performed to assess the anxiolytic and antidepressant effects of 45 selected compounds against human serotonin transporter and potassium channels receptors. Network pharmacology was performed to predict the pathways involved in these neuropharmacological effects. Overall, CV demonstrated significant and dose-dependent anxiolytic and antidepressant effects due to the presence of several bioactive phytoconstituents, which should be further explored using more advanced and in-depth mechanistic research.

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold ( HI 5 ) was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound., Methods: The potential anti-cancerous effect of HI 5 was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies., Results: The results revealed that HI 5 exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of HI 5 was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, HI 5 blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers ( syn and anti ) is responsible for binding affinity and intrinsic activity of HI 5 . However, the molecular dynamic studies have confirmed that the syn -isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity., Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.

Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information., (© 2021 Elsevier Inc. All rights reserved.)

The main mechanism for drug-drug interaction is displacement reaction of ligands from their protein binding sites. The aim of this study was to evaluate anticancer drug sorafenib displacement from the binding site on human serum albumin by commonly used plant flavonoids quercetin and rutin. The interaction between bio-macromolecules and drugs can also cause changes in protein structure and therefore was evaluated in this study by spectroscopic and molecular dynamic simulation techniques. Serum albumin, the main protein in the plasma acts in the disposition of many drugs and therefore, is a model protein for investigating drug/ligand binding and alteration in the spectrophotometric and molecular docking properties of drug/ligand. All the studied ligands sorafenib, quercetin and rutin bind to HSA with different binding affinity. The displacement of ligands from their binding sites was inferred from comparison of quenching and binding constants of binary and ternary systems. Conformational changes in the HSA were found with UV-spectroscopic, circular dichroism, FT-IR and three dimensional studies. The molecular dynamic simulation studies suggest a stable complex formation between HSA and sorafenib. Binding studies for HSA-sorafenib in presence of quercetin and rutin indicated displacement of sorafenib from its binding site., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A new series of N'-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1 H -inden-3-yl) acetohydrazide derivatives (1 - 25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R = 3-methoxyphenyl), 3 (R = 4-dimethylaminophenyl) and 23 (R = 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3 , with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD 50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX-2 gene expression.

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2-20 ) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (K I s; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12-17 , and 19-20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27-195 and 3.2-19, respectively, while compounds 12 , 14-17 , and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48-158 and 5.4-31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20 , which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.HighlightsQuinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised.The new molecules potently inhibited the hCA isoforms I, II, IV, and IX.Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 12 - 17 , 19 , and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds 12 , 14 - 17 , 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12-17 , and 19-20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12 , 14-17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2-13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2-13 with inhibition constants (K I s) ranging from 57.8-740.2 nM. Compounds 2 , 3 , 4 , and 12 showed inhibitory action against hCA II with K I s between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2-13 with K I values ranging from 7.1 to 93.6 nM. Compounds 2 , 3 , 4 , 8 , 9 , and 12 also exerted potent inhibitory action against hCA XII (K I s ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a , 4b , 6b , 7b , 13 , and 14 had the most potent antitumor activity (IC 50 range: 5.13-17.95 μM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a , 4b , 7b , and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC 50 values: 2.01 and 6.72 μM, respectively) compared with celecoxib (IC 50 =6.44 μM). Compounds 4b and 13 potently inhibited COX-2 (IC 50 values: 1.08 and 1.88 μM, respectively) comparable to that of celecoxib (IC 50 =0.68 μM). Compounds 4a , 7b , and 13 inhibited PDE4B (IC 50 values: 5.62, 5.65, and 3.98 μM, respectively) compared with the reference drug roflumilast (IC 50 =1.55 μM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

Cyclic imides containing 3-benzenesulfonamide, oxime, and β-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides ( 2-4 , and 9 ), oximes ( 11-13 ), and β-phenylalanine derivative ( 18 ) showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4 , 9 , 12 , 13 , and 18 possessed ED 50 of 35.4-45.3 mg kg -1 relative to that of celecoxib (34.1 mg kg -1 ). For the cytotoxic evaluation, the selected derivatives 2-6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 μM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide ( 2-5 , and 9 ), acetophenone oxime ( 11-14 , 18 , and 19 ) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. β-Phenylalanine derivatives 21-24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.

The in vitro cytotoxicity of some substituted quinazolinones, 1-15, was evaluated using NCI (10 µM) in a full NCI 59-cell line panel assay. Relative to the reference drug, imatinib (PCE = 20/59), compounds 3, 4, 7, 9, and 10 exhibited remarkable antitumor activity against the tested cell lines, with positive cytotoxic effects (PCE) of 29/59, 18/59, 17/59, 44/59, and 24/59 respectively. Enzymatic inhibitory assay conducted on 3, 4, 9, and 10 as the most potent antitumor agents against EGFR, HER2 and CDK9 kinases, and COX-2 enzyme. Compound 3 possessed good COX-2 inhibitory activity (IC 50  = 0.775 μM) compared to the reference drug, celecoxib (IC 50  = 0.153 μM). Compounds 4 and 9 were closely potent to the reference compounds against EGFR and (HER2) tyrosine kinases, with IC 50 values of 90.17 (and 131.39 for HER2) for 4 and 145.35 (and 129.07 for HER2) nM for 9; the reference drugs in this case, namely, gefitinib and erlotinib, exhibited IC 50 values of 55.58 (90) and 110 (79.28) nM against the EGFR and (HER2) tyrosine kinases, respectively. Compound 4 was approximately similar potent against CDK9 kinase (IC 50  = 67.04 nM) like the reference compound, dinaciclib (IC 50  = 53.12 nM). Compound 9 induced cytotoxicity in the MCF-7 cell line (GI % at 10.0 μM = 47%) through pre-G1 apoptosis, thereby inhibiting cell growth at the G2/M phase. Molecular docking models of 3 and 4 with COX-2, EGFR, and CDK9 were conducted to determine their binding mode within the putative binding pockets., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (K Is ) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: K Is , 250.0 and 5080 nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (K Is , 8.9-51.5 nM); they were almost equally potent to AAZ (K I , 12.0 nM) and had superior potency to SLC-0111 (K I , 960.0 nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with K I values of 3.9-36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (K Is , 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with K I values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (K Is , 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff's bases 4-18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a-8a with inhibition constants (K I ) in the range 93.5-428.1 nM (AAZ and SLC-0111: K I , 250.0 and 5080.0 nM, respectively). Compounds 4a-8a proved to be effective hCA II inhibitors, with K I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K I , 12.0 and 960.0 nM, respectively). Compounds 4a-8a effectively inhibited hCA IX, with K I in the range 8.5-24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K I , 25.0 and 45.0 nM, respectively). Compounds 4a-8a displayed effective hCA XII inhibitory activity with K I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K I , 5.7 and 4.5 nM, respectively). However, compounds 9b-13b and 14c-18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Carbonic anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10-29, 31, 32, 35, 36, and 45-51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14, 15, 17, 19, 20, 21, 24, 25, 28, 29, 31, 35, 45, 47, 49, and 51 with inhibition constant (K I s) values of 39.4-354.7 nM that were nearly equivalent or even greater than that of AAZ (K I , 250.0 nM). Compounds 15, 20, 24, 28, 29, 45 and 47 proved to have inhibitory activities against hCA II with (K I s, 0.73-16.5 nM) that were similar or improved to that of AAZ (K I , 12.0 nM). Compounds 13-29, 31-32, and 45-51 displayed potent hCA IX inhibitory activities (K I s, 1.6-32.2 nM) that were more effective than or nearly equal to AAZ (K I , 25.0 nM). Compounds 14, 15, 20, 21, 26, 45, and 47 exerted potent hCA XII inhibitory activities (K I s, 5.2-9.2 nM), indicating similar CAI activities as compared to that of AAZ (K I , 5.7 nM)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Carbonic anhydrases (CA, EC 4.2.1.1) are Zinc metalloenzymes and are present throughout most living organisms. Among the catalytically active isoforms are the cytosolic CA I and II, and tumor-associated CA IX and CA XII. The carbonic anhydrase (CA) inhibitory activities of newly synthesized pyrazoline-linked benzenesulfonamides 18-33 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared with that of acetazolamide (AAZ), a standard inhibitor. Potent inhibitory activity against hCA I was exerted by compounds 18-25, with inhibition constant (K I ) values of 87.8-244.1 nM, which were greater than that of AAZ (K I , 250.0 nM). Compounds 19, 21, 22, 29, 30, and 32 were proven to have inhibitory activities against hCA IX with K I values (5.5-37.0 nM) that were more effective than or nearly equal to that of AAZ (K I , 25.0 nM). Compounds 20-22, and 30 exerted potent inhibitory activities (K I s, 7.1-10.1 nM) against hCA XII, in comparison with AAZ (K I , 5.7 nM)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A synthesized and promising biologically hypoglycemic compound 5,6-Dichloro-2-[2-(pyridin-2-yl)ethyl]isoindoline-1,3-dione ( 5e ) was studied for its binding to a model protein (bovine serum albumin; BSA) by spectroscopic and molecular simulation approaches. Fluorescence studies revealed that 5e quenched BSA's intrinsic fluorescence by static quenching. The experiments were performed at three different temperatures and the quenching constants and binding constants were evaluated. Stern-Volmer constant (K sv ) values decreased from 1.36 × 10 4 to 1.20 × 10 4 as the temperature increased suggesting static quenching involvement in the interaction. Decreased binding constants from 1.70 × 10 4 to 4.57 × 10 3 at higher temperatures indicated instability of the complex at rising temperatures. Site I (subdomain IIA) of BSA was found to interact with 5e . The thermodynamic results showed the binding interaction was spontaneous and enthalpy driven. The secondary structure alterations in BSA due to interaction with 5e were studied by UV-visible, synchronous fluorescence, and three-dimensional fluorescence spectra. The results indicate the 5e binds effectively to the BSA and thus, this study can be useful in further exploring the pharmacokinetics and pharmacodynamics of 5e .