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Graphical abstract Highlights • Synthesis of Dithiocarbamate chalcone-based derivatives scaffold. • Antibacterial screening showed equal or higher activity than colistin standard. • 24 with MIC of 8 µg/ml against both Ps12 and K4, MBC of 32 µg/ml against Ps12, 16 µg/ml against K4. • 28 , 34 have DNA binding better than doxurubucin with IC 50 of 27.48 and 30.97 µg/ml respectively. • 20 , 22 , 24 and 25 had good binding affinity to PEA transferase via Thr280. • 28 and 34 showed a clear intercalation between DNA double strands. Abstract New dithiocarbamate chalcone-based derivatives were synthesized, their structures were elucidated using different spectroscopic techniques. They were subjected to antimicrobial screening against selected Gram negative bacteria focusing on microbial resistance. Bacterial resistance was targeted via phosphoethanolamine transferase enzyme. Most of the synthesized compounds showed equal or higher activity to colistin standard. Compound 24 proved to be the most active candidate with MIC of 8 µg/ml against both Ps12 and K4 and MBC of 32 µg/ml against Ps12 and 16 µg/ml against K4 Molecular docking study showed that 20, 22 , 24 and 25 had good binding affinity with active site residues via Thr280. DNA macromolecule was further targeted. Compounds 28 and 34 were recorded to have better DNA binding than doxurubucin with IC 50 of 27.48 and 30.97 µg/ml respectively, suggesting that it could have a role in their higher antibacterial effect. Their docking into DNA has shown a clear intercalation matching with antibacterial data. Pharmacokinetics parameters of active compounds showed that they have better absorption through GIT. [ABSTRACT FROM AUTHOR]

A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques 1H NMR, 13C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 µg/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain Staphylococcus aureus. The products were screened for anti-biofilm activity. Compounds 36, 37, and 38 exhibited promising anti-biofilm activity with IC50 value ranges from 2.4 to 8.6 µg. Molecular modelling was performed suggesting parameters of signalling anti-biofilm mechanism. AspB327 HisB340 (arene-arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds 36, 37, and 38 could be used as good orally absorbed anti-biofilm agents. [ABSTRACT FROM AUTHOR]

One of the major issues affecting worldwide public health is cancer. According to the related occurrence and morbidity statistics, it is becoming more common in both economically developed countries and developing countries. Several diagnostics procedures and early treatment methods are essential in order to reduce the incidence rate of breast cancer. In this article, we introduce several reported strategies of treatment based on the tumor progression and breast cancer (BC) molecular subtypes in order to offer the most personalized treatment for BC patients. [ABSTRACT FROM AUTHOR]

A novel series of nitrogenous heterocycles starting from chalcones including thiazolo[3,2- a ]pyrimidines (20 – 67) , were synthesized. Structure elucidation of the synthesized compounds was attained by the use of 1 H NMR, 13 CC NMR, and Mass spectrometry. The obtained compounds were evaluated for their in vitro anticancer activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Six compounds have passed the 5-log dose level NCI assay. Compounds 34 and 24 proved to be the most active derivatives with GI 50 , TGI, LC 50 of 5.89, 20.0, 66.1% and 5.0, 19.5, 52.5% respectively. Compounds 36 , 39 , 63 showed lesser activity with GI 50 , TGI, LC 50 3.2, 11.8, 38.9%, 3.4, 16.6, 60.3%, 3.5, 17.8, 66.1% respectively. DNA binding assay of synthesized compound were performed. Molecular docking showed that compounds 34, 42, and 60 could effectively fit into the minor groove and selectively bind with AT base pairs. The results could confer the anticancer activity of compounds 24, 34, 36, and 39 in vitro to their abilities to bind at DNA minor groove. [ABSTRACT FROM AUTHOR]

A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC 50 0.02 and 0.01 μM, respectively. Molecular modeling studies concluded that recognition with the key amino acid Phe34 is essential for binding and hence DHFR inhibition. Compounds 34 , 56 and 66 showed broad spectrum antimicrobial activity comparable to Gentamicin and Ciprofloxacin. Compounds 40 and 64 showed broad spectrum antitumor activity toward several tumor cell lines and proved to be 10 fold more active than 5-FU, with GI 50 MG-MID values of 2.2 and 2.4 μM, respectively. [ABSTRACT FROM AUTHOR]

A new series of 7-substituted coumarin scaffolds containing a methyl ester moiety at the C4-position were synthesized and tested for their in vitro anti-proliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using Doxorubicin (DOX) as reference. Compounds 2 and 8 showed noticeable selectivity against MCF-7 with IC50 = 6.0 and 5.8 µM, respectively compared to DOX with IC50 = 5.6 µM. Compounds 10, 12, and 14 exhibited considerable selectivity against Estrogen Negative cells with IC50 = 2.3, 3.5, and 1.9 µM, respectively) compared to DOX with (IC50 = 7.3 µM). The most promising compounds were tested as epidermal growth factor receptor and aromatase (ARO) enzymes inhibitors using erlotinib and exemestane (EXM) as standards, respectively. Results proved that compound 8 elicited the highest inhibitory activity (94.73% of the potency of EXM), while compounds 10 and 12 displayed 97.67% and 81.92% of the potency of Erlotinib, respectively. Further investigation showed that the promising candidates 8, 10, and 12 caused cell cycle arrest at G0–G1 and S phases and induced apoptosis. The mechanistic pathway was confirmed by elevating caspases-9 and Bax/Bcl-2 ratio. A set of in silico methods was also performed including docking, bioavailability ADMET screening and QSAR study [ABSTRACT FROM AUTHOR]

Abstract: A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC50 0.03 μM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors. [Copyright &y& Elsevier]

Abstract: A novel series of 2-acetamido- or 2-propanamido-4-(4-substituted phenyl)-1,3-thiazoles (11–34) was designed and synthesized. Compounds were subjected to National Cancer Institute (NCI) in vitro assessment for their antitumor activity, at a single dose of 10μM. Most of the investigated compounds exhibited broad-spectrum antitumor activity. Compounds 19 and 28 believed to be the most active members in this study, with MG-MID GI50, TGI, and LC50 values of 2.8, 11.4, 44.7; and 3.3, 13.1, 46.8, respectively. Compounds 19 and 28 proved to be nine and sevenfold more active than the standard antitumor drug 5-FU, respectively. [Copyright &y& Elsevier]

Abstract: A novel series of 2-acetamido and 2 or 3-propanamido derivatives of 4- or 5-substituted-thiazoles was designed and synthesized. Structure elucidation of the new synthesized compounds was attained by the use of 1H &13C NMR, and Mass spectrometry. Compounds were subjected to NCI in vitro assessment for their antitumor activity, at a single dose of 10μM of test compounds. Compounds bearing straight chain substituent or 4-phenyl function proved to be more active than their branched or 4-methyl congeners. Compounds 37, 41 and 42 exhibited broad spectrum antitumor activity. Compounds 23 and 27 proved lethal while compounds 18, 21, 32 and 37 showed remarkable GI values of 75.5, 69.3, 96.2 and 92.7% to the Leukemia CCRF-CEM cell line, respectively. [Copyright &y& Elsevier]

Benzimidazole derivatives are known to be key players in the development of novel anticancer agents. Herein, we aimed to synthesize novel derivatives to target breast cancer. A new series of benzimidazole derivatives conjugated with either six- and five-membered heterocyclic ring or pyrazanobenzimidazoles and pyridobenzimidazole linkers were synthesized yielding compounds 5–8 and 10–14, respectively. Structure elucidation of the newly synthesized compounds was achieved through microanalytical analyses and different spectroscopic techniques (1H, 13C-APT and 1H–1H COSY and IR) in addition to mass spectrometry. A biological study for the newly synthesized compounds was performed against breast cancer cell lines (MCF-7), and the most active compounds were further subjected to normal Human lung fibroblast (WI38) which indicates their safety. It was found that most of them exhibit high cytotoxic activity against breast cancer (MCF-7) and low cytotoxic activity against normal (WI38) cell lines. Compounds 5, 8, and 12, which possess the highest anti-breast cancer activity against the MCF-7 cell line, were selected for Pin1 inhibition assay using tannic acid as a reference drug control. Compound 8 was examined for its effect on cell cycle progression and its ability to apoptosis induction. Mechanistic evaluation of apoptosis induction was demonstrated by triggering intrinsic apoptotic pathways via inducing ROS accumulation, increasing Bax, decreasing Bcl-2, and activation of caspases 6, 7, and 9. Binding to 15N-labeled Pin1 enzyme was performed using state-of-the-art 15N–1H HSQC NMR experiments to describe targeting breast cancer on a molecular level. In conclusion, the NMR results demonstrated chemical shift perturbation (peak shifting or peak disappearance) upon adding compound 12 indicating potential binding. Molecular docking using 'Molecular Operating Environment' software was extremely useful to elucidate the binding mode of active derivatives via hydrogen bonding. [ABSTRACT FROM AUTHOR]

Clinically approved EFGR inhibitors and the designed target compounds. • New series of novel benzothiazole analogs has been synthesized. • The antitumor activities of the synthesized compounds were conducted 5 different cell line. • Tyrosine kinase inhibition activity was also tested for the synthesized compounds. • Molecular modeling studies have been conducted to rationalize the obtained data and to determine the probable binding mode. • Flexible alignment and surface mapping had explained the different pattern of activity of tested compounds. New benzothiazole-based derivatives were synthesized in the present work with the aim of evaluating their antitumor activity. They were in vitro tested against hepatocellular carcinoma (HepG2), colorectal carcinoma (HCT-116), mammary gland cancer (MCF-7), prostate cancer (PC-3), and epithelioid carcinoma (HeLa). The results of the in vitro antitumor evaluation revealed that the most active compounds were 39 , 40 , 51 , 56 , and 61 exhibiting IC 50 values comparable to the reference drug lapatinib. The most active compounds were further subjected to EGFR inhibitory activity assay to rationalize their potency mode. Notably, the most active antitumor compounds 39 and 40 represented the most potent inhibitors to EGFR with IC 50 values of 24.58 and 30.42 nM respectively in comparison with 17.38 nM for lapatinib as a standard drug. Molecular modeling studies were also conducted for the synthesized compounds, including docking into EGFR active site and surface mapping. Results proved the superior binding of the hydrazone derivatives 39 and 40 with EGFR suggesting them as good candidates for targeted antitumor therapy through EGFR kinase inhibition. [ABSTRACT FROM AUTHOR]

• New benzimidazole hybrids were synthesized as promising anticancer agents. • Compounds 18 and 19 were the most active anticancer agents, with IC 50 range of 5.16–20.35 µM. • TopoII inhibition was tested, compound 18 was found to be the best inhibitor. • Compound 18 showed cell cycle arrest at G1-phase, increasing in the total apoptosis by 72 folds and decreasing in TF-DNA binding in MCF-7 cells. • Molecular docking studies and lipinski's rule were conducted. Two series of new benzimidazole derivatives were designed and synthesized. The antiproliferative activity of the new derivatives was screened against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Relative to Doxorubicin (IC 50 = 6.72 µM), compounds 18 and 19 showed broad spectrum anticancer effect against all the tested cancer cell lines, with IC 50 range of 5.16–20.35 µM, however they were safe to WI-38 normal cells with IC 50 of 32.61 µM and 50.62 µM, respectively. Inspection of human TopoII inhibitory activity disclosed that compound 18 was the most potent (IC 50 = 6.9 µM) compared to Staurosporine (IC 50 = 4.64 µM). Further mechanistic studies implied that compound 18 triggered the apoptotic death of MCF-7 cells via decreasing Bcl-2, activating caspases 8 and 9, and increasing the accumulation of ROS. In addition, it caused cell cycle arrest at the G1-phase and lowered the binding activity of transcription factors' protein to DNA. The biological results were assisted by molecular modeling studies. The physicochemical parameters of compounds 18 and 19 conferred convenient drug-like properties. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Fifteen new 1,4-diphenylpiperazine hybrids were synthetized. • All newly synthesized compounds selectively inhibit h MAO-A enzyme. • Compounds 7 and 8 exhibited preferred inhibitory activities against h MAO-A. • All compounds showed acceptable pharmacokinetics properties. • In silico binding modes of compounds 7 and 8 were revealed by means of molecular docking. Fifteen new diphenylpiperazine hybrids were designed, synthesized and in vitro biologically evaluated against h MAOs enzymes via fluorometric method. All of our new compounds displayed strong inhibitory activities against both two isoforms of h MAOs with IC 50 range of 0.091–16.32 µM. According to selectivity index values, all hybrids showed higher selectivity against h MAO-A over h MAO-B. Compound 8 exhibited the best h MAO-A inhibition activity (IC 50 value = 91 nM, SI = 19.55). With a selectivity index of 31.02 folds over MAO-B, compound 7 was revealed to be the most effective h MAO-A inhibitor. In silico prediction of physicochemical parameters and BBB permeability proved that all of the newly synthesized compounds have favorable pharmacokinetic profiles and acceptable ADME properties and can pass BBB. For clarification and explanation of the biological activity of compounds 7 and 8 , molecular docking simulations were carried out. In light of this, 1,4-diphenylpiperazine analogues can be seen as an encouraging lead to develop safe and effective new drugs for treatment of many disorders such as anxiety and depression by inhibition of h MAO-A enzyme. [ABSTRACT FROM AUTHOR]

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC 50 value of 0.01 μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC 50 values of 25.4 and 9.5 μg/ml, respectively. Compounds 15 , 20 , 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13 , 14 , 19 , 20 and 24 against Candida albicans and Aspergillus flavus . Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively. [ABSTRACT FROM AUTHOR]

A series of 3-(2H-1,2,4-triazol-5-yl)-1,3-thiazolidin-4-one derivatives (7c-l) was designed and synthesized. Their structures have been elucidated based on analytical and spectral data. They were evaluated for their antibacterial and antifungal activities. Compound 7h showed the highest activity against all tested strains, except P. vulgaris, with MIC 8 µg/mL and 4 µg/mL against S. aureus and C. albicans, respectively. Furthermore, Compounds 7c, 7h, and 7j demonstrated moderate anti-mycobacterium activity. The binding mode of the synthesized thiazolidinones to bacterial MurB enzyme was also studied. Good interactions between the docked compounds to the MurB active site were observed primarily with Asn83, Arg310, Arg188 and Ser82 amino acid residues. [ABSTRACT FROM AUTHOR]

New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2- a ][1,3]diazepin-3-carboxylate (HIE-124, 3 ), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3 . Compounds 15 (0.78 mmol/kg) and 20 (0.39 mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38 mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABA A . Superposition, flexible alignment and surface mapping of 15 , 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants. [ABSTRACT FROM AUTHOR]

[Display omitted] • Series of new benzimidazole hybrids were synthesized. Antiproliferative activity was assessed against HepG-2, MCF-7, PC-3, HCT-116 and Hela cancer cells. • Compounds 13 , 20 , 21 , 22 and 23 were the most active anticancer agents. • Compound 21 showed the most potent anticancer activity with IC 50 range of 2.82 to 12.59 µM. • Compounds 13 and 20 were found to be the most potent TopoII inhibitors. • Compound 13 showed cell cycle arrest at S -phase, increasing in the total apoptosis by 62.5 folds and decreasing in TF-DNA binding in HepG-2 cells. Molecular docking studies and Lipinski's rule were conducted. Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (1H, 13C NMR, ESI-MS and IR). All hybrids (6 – 23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC 50 range of 2.82 to 12.59 µM, while proving safe towards normal cells WI-38 (IC 50 = 31.89 µM) compared to the reference drug doxorubicin (IC 50 = 6.72 µM). The most active candidates 13 , 20 , 21 , 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC 50 of 6.72 and 8.18 µM respectively compared to staurosporine (IC 50 = 4.64 µM). Further mechanistic studies for compound 13 showed cell cycle arrest at S -phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors' binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20 , and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates. [ABSTRACT FROM AUTHOR]

Design and synthesis of a new series of benzofuran derivatives has been performed. 1H-NMR, 13C-NMR, elemental analysis, and IR were used to confirm the structures of the produced compounds. Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), epithelioid carcinoma cervical cancer (Hela), and human prostate cancer are used to test anticancer activity (PC3). In compared to DOX (4.17–8.87 µM), Compound 8 demonstrated the highest activity against HePG and PC3 cell lines, with an IC50 range of 11–17 µM. Compound 8 inhibited PI3K and VEGFR-2 with IC50 values of 2.21 and 68 nM, respectively, compared to 6.18 nM for compound LY294002 and 31.2 nM for compound sorafenib as PI3K and VEGFR-2 reference inhibitors, selectively. The molecular docking and binding affinity of the generated compounds were estimated and studied computationally utilizing molecular operating environment software as a PI3K and VEGFR-2 inhibitor (MOE). In conclusion, compound 8 exhibited significant action against hepatocellular and cervical cancer cell lines. Mechanistic study showed that it had a dual inhibitory effect against PI3K and VEGFR-2. [ABSTRACT FROM AUTHOR]

In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity. [ABSTRACT FROM AUTHOR]

A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29 , 34 , and 39 proved to be the most active DHFR inhibitors with IC 50 values range of 0.1–0.6 μM. Compounds 28 , 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26 , 33 , 39 , 43 , 44 , 50 , 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1–100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity. [ABSTRACT FROM AUTHOR]

Quorum sensing (QS) plays a vital role in regulation of virulence factors and toxins in Pseudomonas aeruginosa , which can cause serious human infections. Therefore, the QS system in P. aeruginosa may be an important target for pharmacological intervention. Activity of aspirin on the QS system was assessed using a reporter strain assay and confirmed using RT-PCR to test expression of virulence factors and toxins. In addition, molecular modeling techniques including docking, flexible alignment and surface mapping were also applied to further understand aspirin's potential QS inhibition activity. Aspirin (6 mg/ml) showed significant reduction ( p < 0.01) of quorum sensing signals in P. aeruginosa , including expression of elastase, total proteases, and pyocyanin ( p < 0.01) without affecting bacterial viability. Aspirin also significantly reduced organism motility and biofilm production ( p < 0.01) and decreased expression of lasI , lasR , rhlI , rhlR , pqsA and pqsR genes by 38, 72, 69, 72, 74 and 43% respectively. Moreover, the expression of Pseudomonas toxins exoS and exoY was reduced by 47 and 55% respectively. The molecular modeling analysis suggests the QS inhibitory action of aspirin occurs through interaction of aspirin's aryl group and Tyr-88 of the LasR receptor, by strong π–π stacking interactions, which associated with a conformational change of the receptor–aspirin complex. The inhibitory effect of aspirin on virulence factors was specific to P. aeruginosa as aspirin at sub-MIC did not affect the biofilm or motility of Escherichia coli . To summarize, the collective data demonstrate that low concentrations of aspirin inhibit quorum sensing of P. aeruginosa . [ABSTRACT FROM AUTHOR]

Abstract: A new series of tetrahydro-quinazoline and tetrahydro-1H-dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC50, 0.004 μM) which is twenty fold more active than methotrexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5-FU, with MG-MID GI50, TGI, and LC50 values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 μM, respectively. Computer modeling studies allowed the identification that methoxy and methyl substituents, the π-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These mark points could be used as template model for further future optimization. [Copyright &y& Elsevier]

Abstract: A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3–0.8 μM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8–41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors. [Copyright &y& Elsevier]

Abstract: A novel series of thiazolo[2,3-b]quinazoline (14–23, 26 and 27), and pyrido[4,3-d]thiazolo[3,2-a]pyrimidine (34–43, 45 and 46) analogues were designed and synthesized. The obtained compounds were evaluated for their in-vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 22, 38, 40 and 41 showed remarkable broad-spectrum antitumor activity. Compounds 22 and 38 are almost nine fold more active than 5-FU, with GI50, TGI, and LC50 values of 2.5, >100, >100; and 2.4, 9.1, 36.2 μM, respectively; while 40 and 41 are almost seven fold more active than 5-FU, with GI50, TGI, and LC50 values of 2.9, 12.4, 46.6 and 3.0, 16.3, 54.0 μM, respectively. [Copyright &y& Elsevier]

[Display omitted] • 21 New 1,4-biphenylpiperazine hybridized derivatives were synthetized. • Most compounds selectively inhibit h MAO-B enzyme. • Compounds 19 and 20 showed best inhibitory activities against h MAO-B. • Compound 20 was found to be selective, mixed competitive, reversible and non-cytotoxic inhibitor. • The most potent compounds showed acceptable pharmacokinetics properties. • In silico binding modes of compounds 19 and 20 were determined using molecular docking. In this study, 21 new 1,4-biphenylpiperazine derivatives were designed, synthesized and evaluated as monoamine oxidase (MAO) inhibitors by in vitro fluorometric method. All these compounds exhibited inhibitory activity against h MAO enzymes, 17 analogues of them showed selectivity towards h MAO-B over h MAO-A enzyme. Compound 20 exhibited the best activity and selectivity towards h MAO-B with IC 50 value of 53 nM and selectivity index of 1122 folds over MAO-A, compared to the reference drugs rasagiline (IC 50 = 66 nM) and selegiline (IC 50 = 40 nM). Kinetic study and reversibility test of the most potent compound (20) revealed that it is reversible and mixed competitive inhibitor (K i value is 17 nM for the inhibition of h MAO-B). Compound 20 was evaluated against normal NIH/3T3 mouse embryonic fibroblast cell lines and it was found that it is non-cytotoxic at its effective concentration against h MAO-B. Moreover, compound 20 and the most potent compounds have acceptable ADME properties and good pharmacokinetics profiles. Molecular docking simulations were performed for explanation and elucidation for the biological activity of compounds 19 and 20. Accordingly, 1,4- biphenylpiperazine derivatives can be considered as a promising lead to produce more potent and safer MAO inhibitors for management of various neurological disorders. [ABSTRACT FROM AUTHOR]

• Synthesis of coumarin-based compounds (3a-l) − 7. • h CAII, h CAIX, and h CAXII isozymes inhibition assays were performed. • Antiproliferative activity in HCT 116 (colorectal) cancer cell line was evaluated. • Computational studies: docking, ADMET, and molecular dynamic simulations were performed. In the current study, unique series of coumarin sulfonate and sulfamate derivatives were synthesized. Their selectivity and inhibitory activity against glaucoma and cancer-associated CAs (h CA II, IX, and XII) were evaluated compared to standard acetazolamide. In addition, the cytotoxic effects of the synthesized compounds on colorectal carcinoma (HCT116) were examined. Generally, structure-activity relationship (SAR) analysis revealed that potent inhibitors bearing zinc binding group (ZBG) dimethyl sulfamate (4a-c) were shown to lack selectivity against three isoforms owing to the classical inhibitory mode of action. The incorporation of aryl or fluoro aryl sulfone moiety in non-sulfamate coumarin derivatives shifted selectivity toward cancer-related isoforms XII and IX, respectively. Para -fluorine substituted derivative 3c with IC 50 value of 0.62 µM exhibited excellent activity and selectivity against h CA IX, while benzene sulfone possessing derivative 3b demonstrated selectivity toward h CA XII with IC 50 value of 0.56 µM. Moreover, coumarin derivatives with ethyl sulfone (3e, 3i , and 6a) reported excellent selectivity toward CAII. In-silico studies were also conducted over selective, potent compounds. Molecular docking studies have shown that potent compounds could interact with the active site by different modes of action. The molecular dynamic analysis confirmed the stability of the protein in the presence of a potent ligand. [Display omitted] [ABSTRACT FROM AUTHOR]

• A new series of thioquinazolinones derivatives was designed and synthesized as HSP90 inhibitors. • Antiproliferative activity against MCF-7, HCT-116 and Hela cell lines showed compounds 5a , 5d and 9h were the most potent HSP90 inhibitors. • Effect of compounds 5a , 5d and 9h on Her2 and HSP70 was evaluated. • Molecular modeling for the most potent HSP90 inhibitors 5a , 5d and 9h was conducted. • Targeting breast cancer, compound 5d induced apoptosis and showed cell cycle arrest at G2/M phase. A new 2-thioquinazolinones series was designed and synthesized as HSP90 inhibitors based on the structure of hit compound VII obtained by virtual screening approach. Their in vitro anti-proliferative activity was evaluated against three human cancer cell lines rich in HSP90 namely; colorectal carcinoma (HCT-116), and cervical carcinoma (Hela), breast carcinoma (MCF-7). Compounds 5a, 5d, 5e and 9h showed a significant broad spectrum anti-proliferative activity against all tested cell lines. They were characterized by potent effect against breast cancer in particular with IC 50 of 11.73, 8.56, 7.35 and 9.48 μM, respectively against Doxorubicin (IC 50 4.17 μM). HSP90 ATPase activity inhibition assay were conducted where compound 5d exhibited the best IC 50 with 1.58 μM compared to Tanespimycin (IC 50 = 2.17 μM). Compounds 5a and 9h showed higher IC 50 values of 3.21 and 3.41 μM, respectively. The effects of 5a, 5d and 9h on Her2 (a client proteins of HSP90) and HSP70 were evaluated in MCF-7 cells. All tested compounds were found to reduce Her2 protein expression levels and induce Hsp70 protein expression levels significantly, emphasizing that antibreast cancer effect is a consequence of HSP90 chaperone inhibition. Cell cycle analysis of MCF-7 cells treated with 5d showed cell cycle arrest at G2/M phase 38.89% and pro-apoptotic activity as indicated by annexin V-FITC staining by 22.42%. Molecular docking studies suggested mode of interaction to HSP90 via hydrogen bonding. ADME properties prediction of the active compounds suggested that they could be used as orally absorbed anticancer drug candidates. [ABSTRACT FROM AUTHOR]

• Series of thioquinazolinones analogues was synthesized as HSP90 inhibitors. • Antiproliferative activity was assessed against breast, colon and cervix cells. • Compounds 5b , 5k and 8a were found to be the most potent HSP90 inhibitors. • 5k showed multi-target activity against EGFR, VEGFR-2 and Topoisomerase-2. • Compound 5k caused cell cycle arrest at G2/M phase and induced apoptosis of MCF-7 cells through mitochondrial-mediated pathway. • Molecular docking studies, ADMET analysis and Lipinski's rule were conducted. New series of compounds bearing 2-thioquinazolinone scaffold were designed, synthesized as HSP90 inhibitors. Anti-proliferative activity of the synthesized compounds was evaluated against HCT-116, Hela and MCF-7 cell lines and compound 5k was found to be the most active member of the entire study with IC 50 of 4.47, 7.55 and 4.04 μM, respectively, compared to DOX (IC 50 of 5.23, 5.57 and 4.17 μM, respectively). Most of the tested compounds revealed lower cytotoxicity against normal fibroblast cells WI-38. Compounds 5b, 5k and 8a showed potent HSP90 inhibitory activities with IC 50 values in nanomolar range; 71.32, 25.07 and 56.78 nm, respectively, against Tanespimycin (IC 50 of 86.45 nm). Their HSP90 inhibitory activities were confirmed by their down regulation of HSP90 client protein Her2 and up regulation of chaperone HSP70 levels. Compound 5k had shown potent multi-target inhibitory activities against EGFR, VEGFR-2 and Topoisomerase-2 with IC 50 values in nanomolar range; 38.5, 126.95 and 25.85 nm, respectively. Compound 5k was further evaluated for cell cycle distribution and apoptosis induction on MCF-7 cells using flow cytometry. Compound 5k arrested the cell cycle on MCF-7 at a G2/M phase by 35.06% and induced apoptosis by 19.82%. Mechanistic evaluation of apoptosis induction was studied by following ways triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 6, 7 and 9. Comparative molecular modeling study was performed between active and inactive HSP90 inhibitors. Docking studies into the active site of HSP90 N -terminal domain showed good agreement with the obtained biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated where compound 5k had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed antibreast targeted therapy. [ABSTRACT FROM AUTHOR]

• Synthesis of conjugated benzimidazole ring core 5 – 15 and 22 – 31. • Compounds 5 , 12 , 15 and 25 were the most active antibreast cancer among the synthesized series exhibiting IC 50 < 10 µg/ml. • State–of-the-art 2D NMR binding experiments were performed (15N-1H HSQC). • Compounds 5, 12, and 25 showed chemical shift perturbation and peak disappearance in the HSQC confirming binding to Pin1. • Molecular modeling (docking, contact statistics and surface mapping) elucidated the binding mode of active derivatives. New series of benzimidazole ring core conjugated with either dithiocarbamate or thiopropyl linkers, hybridized with different secondary amines were synthesized; 5 – 15 and 22 – 31 ; respectively. The new compounds were characterized by different spectroscopic techniques (1H, 13C 1D & 2D NMR, ESI-MS and IR). They were screened for in vitro anticancer activity against breast cancer using MCF7 cell line. The results obtained revealed that compounds 5 , 12 , 15 and 25 were the most active among the synthesized series exhibiting IC 50 < 10 µg/ml against DOX. To characterize targeting breast cancer on molecular level, binding to 15N-labeled Pin1 enzyme was conducted using state-of-the-art 2D NMR binding experiments. Results showed promising binding between compounds 5, 12, and 25 by chemical shift perturbation (peak shifting or peak disappearance). Molecular docking study were quite valuable to explain the binding mode of active derivatives via hydrogen bonding. Additional contact preferences and surface mapping studies stated the similarity pattern between active candidates which may pave the way for more precise anti breast cancer target optimization. [ABSTRACT FROM AUTHOR]

• Synthesis of triazoloquinazolines with moderated to good cytotoxic activity against the tested five human cancer cells. • Compounds 7, 8, 12, 19, 20, 21, 24 and 29 were the most active, exhibiting excellent inhibitory activity. • Compounds 8, 19 and 21 exhibited worthy EGFR inhibition activity with IC 50 ranging from 0.69 to 1.8 µM. • Compounds 8, 19 and 21 caused cell cycle arrest at G2/M phase, and induced apoptosis of MCF-7 cells. • Molecular modeling, docking studies, ADMET analysis and Lipinski's rule of five were performed. New series of triazolo[4,3- c ]quinazolines were designed, synthesized and their structures were elucidated using different spectroscopic techniques. They were evaluated for their in vitro antitumor activity against HepG2, MCF-7, PC-3, HCT-116 and HeLa cancer cell lines using MTT assay. It was found that all compounds showed variable in vitro cytotoxicity. Distinct derivatives exhibited higher inhibitory activity against the tested cell lines with IC 50 values ranging from 8.27 to 10.68 µM using DOX standard (IC 50 = 4.17–8.87 µM). In vitro epidermal growth factor receptor (EGFR) inhibition assay was performed. Results revealed that compounds 8 , 19 and 21 exhibited worthy EGFR inhibitory activity with IC 50 values ranging from 0.69 to1.8 µM in comparison to the reference drug Gefitinib (IC 50 = 1.74 µM). Further investigation showed that active candidates 8 , 19 and 21 caused cell cycle arrest at the G2/M phase, and interestingly, induced cell death by apoptosis of MCF-7 cells cumulatively with 7.14, 17.52 and 24.88%, respectively, compared with DOX as a positive reference (29.09%). Molecular modeling studies, including docking, flexible alignment and surface mapping, were also done to study the interaction mode into the active site of EGFR kinase domain. There was a good agreement between modeling results and biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated. Pharmacokinetic parameters showed that compound 8 had more expected penetration through blood brain barrier than Gefitinib. The present work displayed new triazoloquinazoline based derivatives with potent cytotoxicity and promising EGFR inhibition activity. [ABSTRACT FROM AUTHOR]

In the present investigation, some novel nitro Mannich bases derived from Michael type addition of activated nitro olefin, β‐nitrostyrene with various amines either primary or secondary including some amino sugars were designed and synthesized. The produced Mannich bases have been full characterized through different spectroscopic techniques. Antimicrobial evaluation has been performed against the Gram positive S. aureus and methicillin‐resistant S. aurues (MRSA) infections. 5 of the synthesized compounds represent the best candidates in the biological screening, they have exhibited good activity with MIC values range from 100 to 250 μg/ml. The active agents have been tested for pyruvate kinase inhibition activity with % of inhibition range from 30 to 79 % with IC50 in a nano molar range. They also exhibited significant Pyruvate kinase inhibition in nanomolar range with IC50 of 1066, 662, 1887, 418 and 1128 ng/ml, respectively (versus 196 ng/ml for AZD7545). Molecular docking calculations for active agents were performed. A complete conformational analysis molecular modeling utilizing Gaussian 09 program (HF/DFT) was used to verify the mode of bonding through the optimized geometries as well as essential quantum parameters were calculated using frontier energies (EHOMO & ELUMO) for the active candidates indicating the overall stability of the structure. [ABSTRACT FROM AUTHOR]

Some synthesized antitumor derivatives of thiazole based chalcones including thiazolo[2,3- b ]quinazoline and pyrido[4,3- d ]thiazolo[3,2- a ]pyrimidine analogues were subjected to be tested against standard microbial strains. Compound 18 showed higher activity against both Gram-positive and Gram-negative bacteria with MIC of 1.0, 1.0, 2.0, 2.0 and 4.0 μg/ml against S. aureus , B. subtilis , M. luteus, E. coli and P. aeuroginosa respectively which is better than ampicillin and very relative to ciprofloxacin standards. Moreover, this compound shows a good anti-biofilm activity against the Gram positive bacteria. Molecular docking studies of synthesized compounds against DHFR enzyme were carried out. Interestingly, active anticancer candidates 22,38, 40 and 41 in addition to most active antimicrobial agents 15, 18 and 20 bind to DHFR with nearly the same amino acid residues as MTX especially mentioning Arg28, Arg70, Asn64 and Lys68 which support our hypothesis that these compounds could act as antitumor or antibacterial via DHFR inhibition. Flexible alignment and surface mapping techniques have further provided lipophilic distributions supporting effective binding to DHFR. ADMET calculations for compounds 15, 18 and 20 suggested that they could be good orally absorbed antibacterial agents while compound 38 could be an orally absorbed anticancer agent with diminished toxicity. The results highlight studied thiazole based chalcones as efficient leads for designing new future antibacterial drug candidates. • Testing antimicrobial activity of thiazolo[2,3- b ]quinazoline and pyrido[4,3-d]thiazolo[3,2- a ] pyrimidine analogues. • Molecular docking was used to examine binding of compounds that may act as DHFR inhibitors. • Active antitumor 22,38, 40, 41 and antimicrobial agents 15, 18 and 20 bound to DHFR as MTX. • ADMET calculations proved good oral absobtion for antimicrobial and anticancer agents. [ABSTRACT FROM AUTHOR]

A new series of pyrazole-based derivatives was synthesized. Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line. The DNA-binding activity of the synthesized compounds was evaluated. Compounds 8 , 3 , and 17 showed the most potent activity. • A new series of pyrazole-based derivatives was synthesized. • Their anticancer activity was tested against hepatocellular carcinoma (HepG2) cell line, and their DNA-binding activity was evaluated. • Compounds 8 , 3 , and 17 showed the most potent activity. • Molecular modeling studies were conducted to rationalize the obtained data. • Flexible alignment and surface mapping explained the different pattern of activity of the tested compounds. A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1 H -pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8 , the pyrazolopyrimidine 3 , and the pyrazolylaminothiazolone 17 were the most active with IC 50 values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds. [ABSTRACT FROM AUTHOR]

• New series of 5-Thioxoimidazolidine-2-one has been synthesized. • The anti-inflammatory and the antitumor activities of the synthesized compounds were conducted. • COX-1 and COX-2 inhibitory action were tested for the synthesized compounds. • Molecular modeling studies have been conducted to rationalize the obtained data and to determine the probable binding mode. • Flexible alignment and surface mapping had explained the different pattern of activity of tested compounds. A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N 1 and N 3 was synthesized with high yield and excellent purity by the reaction of different N -arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, 1H NMR, 13C NMR, 1H, 1H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC 50 valves for COX-2 ranged from 0.001 × 10−3 to 0.827 × 10−3 µM while the reference drug has IC 50 40.0 × 10−3 µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes. [ABSTRACT FROM AUTHOR]

Tetrahydroindolocarbazoles (THICZs) with versatile substituents, have been designed, synthesized, structure characterized, then investigated for their in-vitro anticancer screening, urokinase inhibition (uPA) evaluated, DNA-damage determination was further explored. Compounds 5, 8, 10 and 17 displayed the most promising antitumor activities against the breast cancer cell line as compared to the standard drug, doxorubicin with IC 50  = 5.24 ± 0.37, 4.00 ± 0.52, 7.20 ± 0.90 and 9.60 ± 1.10 µg/ml (versus 3.30 ± 0.48 µg/ml for doxorubicin). Compounds 5, 8, 10 and 17 represents the most significant uPA inhibitors of our study with IC 50 of 3.80, 2.70. 4.75, 10.80 (ng/ml) respectively. The expression levels of CDKN2A gene were decreased in 8 , 10 and 17 cell lines as compared to those in positive control samples. Cell lines treated with 5 , 8 , 10 and 17 clearly observed a high score of damaged DNA cells. A deeper examination revealed that our hetroaromatics showed an extensive hydrogen bonding interactions that is required in the S pocket which is important for activity Arg 217, Gly 219, Gly 216, Lys 143 and Ser 190. So we present THICZs as promising uPA inhibitors expected as significant promise for further development as anti-invasiveness drugs. [ABSTRACT FROM AUTHOR]

The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2- a ][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 ( 30 ) and AAH1 ( 33 ) induced dose-dependent neuromuscular blockade with onset time of 3 and 10 min, ED 50 0.15 and 0.36 mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (P < 0.05). Docking profile of 30 and 33 closely resembles HIE-124 ( 3 ), in α7β2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants. [ABSTRACT FROM AUTHOR]

A new series of 6,7-dihydro-[1,3,4]thiadiazolo[3,2- a ][1,3]diazepine analogues were synthesized, and biological evaluated. Compound GS-62 ( 33 ) exhibited potent in vivo short acting hypnotic activity with onset time, duration of sleep and therapeutic index of 6.4 ± 0.2, 94.8 ± 5.3 min, 6.62, respectively), in comparison to thiopental sodium ( 6 ). Compounds 33 did not show any sign of acute tolerance reported with the maintenance dose of 6 . Meanwhile 33 potentiated the in vivo hypnotic effect of 6 in an equimolar amounts (0.06 mmol) combination showing an onset and duration of 7.5 ± 1.3, 62.5 ± 5.9 min, respectively. This combination allowed the use of lower doses of both drugs to avoid the undesirable side effects. Docking studies revealed favorable interactions and binding to BDZ binding site of the GABA A receptor especially with Arg87, Arg149, and Thr151 amino acid residues. [ABSTRACT FROM AUTHOR]

Investigation of the EtOAc fraction of Tagetes minuta L. (Asteraceae) aerial parts has afforded a new flavonol glucoside, minutaside A (quercetagetin 6- O-(6- O-hexanoyl)- β-D-glucopyranoside) ( 1), together with four known flavonoids: axillarin 7- O- β-D-glucopyranoside ( 2), quercetagetin 3,7-dimethoxy-6- O- β-D-glucopyranoside ( 3), quercetagetin 7-methoxy-6- O- β-D-glucopyranoside ( 4), and quercetagetin 6- O- β-D-glucopyranoside ( 5). Their structures were established by multiple spectroscopic methods in addition to HRESIMS (high-resolution electrospray ionisation mass spectra) and comparison with literature data. The antioxidant and anti-diabetic activities of the isolated flavonoids were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and α-amylase inhibition assays. Compounds 1 and 5 showed significant antioxidant activity (84.1 and 83.0% at a 20 μM dose, respectively). Compounds 1, 4, and 5 exhibited strong α-amylase inhibitory activity compared with acarbose (a reference α-amylase inhibitor). However, 2 and 3 showed moderate activity. Molecular modeling studies of 1- 5 that included docking, flexible alignment, and surface mapping were performed to evaluate their recognition profile α-amylase receptor. In docking simulations, 5 displayed a binding mode similar to that of acarbose in the active site of α-amylase enzyme. [ABSTRACT FROM AUTHOR]

New curcumin analogues have been synthesized and their antioxidant activities were investigated by measuring their free radical scavenging capacities. The in vitro and in vivo antitumor activities of the synthesized compounds on Ehrlich ascites carcinoma (EAC) cell line were evaluated. 4-(4-Chlorophenyl)-2-(5-ethyl-7-(4-methoxybenzylidene)-3-(4-methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2 H -pyrazolo[4,3- c ] pyridin-2-yl)thiazole 7h showed excellent antineoplastic activity in both in vitro and in vivo studies more than that of tested compounds and reference drug, cisplatin. Different molecular modeling studies were performed, where docking of compound 7h into telomerase active site suggested that it could exert its antitumor potential by telomerase inhibition. [ABSTRACT FROM AUTHOR]

A new series of quinazoline analogues was designed and synthesized to get the target compounds 18 – 21 , 30 – 41 , 46 – 53 , and 57 – 76 . The Obtained compounds were evaluated for their anticonvulsant activity using PTZ and picrotoxin convulsive models. Compounds 47 , 63 , 68 and 73 proved to be the most active compounds in this study with a remarkable 100% protection against PTZ induced convulsions. Compounds 47 , 63 , 68 and 73 proved to be 10, 4, 4, and 5 fold more active, respectively than the used positive control sodium valproate. Structure activity correlation concluded valuable pharmacophoric information which confirmed by molecular modeling studies. Molecular docking study of 68 suggested its agonistic behavior toward GABA A receptor. The studied quinazoline analogues could be considered as useful templates for future development and further derivatization. [ABSTRACT FROM AUTHOR]

Targeting enhancer of zeste homolog 2 (EZH2) can represent a hopeful strategy for oncotherapy. Also, the use of PLGA-based nanoparticles as a novel and rate-controlling carrier system was of our concern. Benzimidazole derivatives were synthesized, and their structures were clarified. In vitro antitumor activity was evaluated. Then, a modeling study was performed to investigate the ability of the most active compounds to recognize EZH2 active sites. Compound 30 (Drug) was selected to conduct pre-formulation studies and then it was incorporated into polymeric PLGA nanoparticles (NPs). NPs were then fully characterized to select an optimized formula (NP 4) that subjected to further evaluation regarding antitumor activity and protein expression levels of EZH2 and EpCAM. The results showed the antitumor activity of some synthesized derivatives. Docking outcomes demonstrated that Compound 30 was able to identify EZH2 active sites. NP 4 exhibited promising findings and proved to keep the antitumor activity of Compound 30. HEPG-2 was the most sensitive for both Drug and NP 4. Protein analysis indicated that Drug and NP 4 had targeted EZH2 and the downstream signaling pathway leading to the decline of EpCAM expression. Targeting EZH2 by Compound 30 has potential use in the treatment of cancer especially hepatocellular carcinoma. [Display omitted] • Compound 30 "Drug" had a promising antitumor activity. • Drug-loaded polymeric nanoparticles kept the antitumor activity of the drug. • The drug in its pure and nanoform had targeted EZH2 and EpCAM expression. • Compound 30 can have a prospective role in the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

• Compounds 8 , 9 and 11 were the most active anticancer with IC50 < 10 µg/ml against 4 cell lines. • Compounds 8 and 9 showed very good inhibition activity of PI3K and computational study elucidate their activity. • Targeting MCF-7 cell line, compounds 8 and 9 induced apoptosis and showed cell cycle arrest at G2/M phase. • Antimicrobial activity of new compounds was assessed against Gram-positive, Gram-negative and fungi. • Antiquorum-sensing activity of new series was assessed using Chromobacterium violaceum . A new series of benzofuran derivatives has been designed and synthesized. The structures of the synthesized compounds have been confirmed by the use of 1H NMR, 13C NMR, 2D 1H–1H NOESY NMR, and IR. Anticancer activity is evaluated against Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), Epitheliod carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 8 , 9 , and 11 showed the highest activity towards the four cell lines with an IC 50 range of 8.49–16.72 µM, 6.55–13.14 µM and 4–8.99 µM respectively in comparison to DOX (4.17–8.87 µM). Phosphatidylinositol-3-kinases (PI3K) inhibition was evaluated against the most active anticancer compounds 8 , 9 and 11. Compounds 8 , 9 and 11 showed good inhibitory activity against PI3Kα with IC 50 values 4.1, 7.8, and 20.5 µM, respectively in comparison to 6.18 µM for the reference compound LY294002. In addition, activity of compounds 8 and 9 on cell cycle arrest and induction of apoptosis in different phases of MCF-7 cells were assessed and detected pre-G1 apoptosis and cell growth arrest at G2/M. Also, both extrinsic and intrinsic apoptosis in MCF-7 cells induced by compounds 8 and 9. Molecular docking, binding affinity surface mapping, and contact preference of the synthesized compounds 8 , 9 and 11 against PI3K were estimated and studied computationally using molecular operating environment software (MOE) and showed good interaction with essential residues for inhibition Val851. In addition, antimicrobial activity was evaluated against gram positive isolates as Staphylococcus aureus and Bacillus cereus, gram negative isolate as Escherichia coli , Pseudomonas aeruginosa and antifungal potential against Candida albicans. Compound 17 showed outstanding anti Gram-positive activity with MIC values 8 and 256 µg/mL in Staphylococcus aureus and Bacillus cereus respectively. Also, compounds 15 , 17 , 18 and 21 showed good anti Gram-negative activity with MIC value 512 µg/mL for all compounds. In addition, the state-of-art quorum sensing (QS) inhibiting effects were detected using Chromobacterium violaceum and compounds 7 , 9 , 10 , 11 , and 12 showed good QS inhibition (3, 3, 5, 2, and 7 mm). [ABSTRACT FROM AUTHOR]

• New series of thiazolopyrimidine derivatives has been synthesized. • Antitumor screening according to NCI protocol against 60 different cell lines has been performed. • DNA binding affinity of the synthesized compounds has been calculated. • Predicted ADMET data for the target compounds were also estimated. • Molecular modeling study has been conducted. In the present study, new series of thiazolopyrimidine derivatives was synthesized as purine analogs. The structures of the products were confirmed through spectroscopic techniques such as NMR and mass spectrometry. In addition, the synthesized compounds were evaluated as antitumor active agent through NCI screening protocol against 60 different cell lines under 9 different panels. Furthermore, DNA binding activity of the compounds was also evaluated. The results revealed that compound 35 proved to be the most active member of the tested series and it is promoted to the 5-dose testing where it gives GI 50 , TGI and LC 50 values of 1.07, 6.61, 34.7 μM respectively. Furthermore, it also proved to have a good DNA binding activity with value that is comparable with that produced by doxorubicin which was used as positive standard. In addition, compound 27 was proved to be the most active DNA binding agent with binding affinity 28.38 ± 1.1. The pharmacokinetic properties were also calculated. Molecular docking studies suggested binding mode of compounds 27 and 35 to DNA minor groove via hydrogen bonding interaction. The anticancer activity of compounds 27 and 35 may be attributed to DNA binding. [ABSTRACT FROM AUTHOR]

• A series of polycyclic skeleton of truxene and triazatruxene analogs has been synthesized. • The synthesized candidates have been evaluated for antitumor and DNA binding activities. • Compounds 2 and 8 proved to be the most active ones among the other target compounds and confirmed by Molecular modeling studies. A series of polycyclic skeleton of truxene and triazatruxene analogs has been synthesized and evaluated for antitumor and DNA binding activities. The synthesized structures were confirmed by different spectroscopic techniques such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The antitumor screening was performed adopting the NCI protocol against 60 different cell lines. Compounds 2 and 8 proved to be the most active ones among the other target compounds. In a trial to investigate the mechanism of action of the target compounds, DNA binding activity was also investigated. Compounds 3f , 4 – 8 exhibited good binding activity explaining their mechanism. In addition, molecular modeling studies were also performed for more clearance of the data obtained from the biological screening. [ABSTRACT FROM AUTHOR]

• New series of tetrahydroindolocarbazole derivatives has been synthesized. • Compound 11 expressed GI% values of 99.9% against MCF7 breast cancer cell line compared to Doxurubucin. • Compound 11 showed a remarkable decrease of uPA level to 3.5 ng/ml compared to DOX. • Compounds 5, 11 and 15 showed significant decrease in expression of MTAP and CDKN2A. • Compounds 5, 11 showed remarkable binding uPA active site via hydrogen binding interactions. A series of some new tetrahydroindolocarbazole derivatives has been synthesized. The structure of the synthesized compounds has been confirmed by different spectroscopic techniques such as IR, NMR, elemental analysis and mass spectrometry. The target compounds were evaluated for their antitumor activity against breast cancer cell line MCF-7, their GI% and their LC 50 have been determined. Six of the synthesized compounds exhibited GI% values against MCF-7 cell lines exceeding 70 % ranging from 71.9 to 85.0 % in addition that compound 11 expressed GI% values of 99.9% and considered the most active derivatives among the synthesized ones. Compound 11 showed a remarkable decrease of u PA level to 3.5 ng/ml compared to DOX. Compound 5, 11 and 15 showed significant decrease in expression of MTAP and CDKN2A, in addition to a remarkable decrease in DNA damage comet assay method. Molecular modeling studies were performed to interpretate the behavior of active ligands as uPA inhibitors. [ABSTRACT FROM AUTHOR]