Publications by authors named "Hany E A Ahmed"

35 Publications

Design of molecular hybrids of phthalimide-triazole agents with potent selective MCF-7/HepG2 cytotoxicity: Synthesis, EGFR inhibitory effect, and metabolic stability.

Bioorg Chem 2021 Jun 22;111:104835. Epub 2021 Mar 22.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 11884 Nasr City, Cairo, Egypt.

This study reports an efficient and convenient click chemistry synthesis of a novel series of phthalimide scaffold linked to 1,2,3 triazole ring and terminal lipophilic fragments. Structures of newly synthesized compounds were well characterized by different spectroscopic tools. In vitro MTT cytotoxicity assay was performed comparing the cytotoxic effects of newly synthesized compounds to staurosporine using three different types: human liver cancer cell line (HepG2), Michigan cancer foundation-7 (MCF-7) and human colorectal carcinoma cell line (HCT116). The initial screening showed excellent to moderate anticancer activity for these newly synthesized compounds with high degree of cell line selectivity with micromolar (µM) half maximal inhibitory concentration (IC) values against tumor cells. The SAR analysis of these derivatives confirmed the role of molecular fragments including phthalimide, linker, triazole, and terminal tails in correlation to activity. In addition, enzymatic inhibitory assay against wild type EGFR was performed for the most active compounds to get more details about their mechanism of action. In order to further explore their binding affinities, molecular docking simulation was studied against EGFR site. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. One of the most prominent analogs is (6f) with terminal disubstituted ring and amide linker showed selective MCF-7 cytotoxicity profile with IC 0.22 µM and 79 nM to EGFR target. Extensive structure activity relationship (SAR) analyses were also carried out. The pharmacokinetic profile of (6f) was studied showing good metabolic stability and long duration behavior. This design offered a potent selective anticancer phthalimide-triazole leads for further optimization in cancer drug discovery.
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http://dx.doi.org/10.1016/j.bioorg.2021.104835DOI Listing
June 2021

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

Arch Pharm (Weinheim) 2021 May 9;354(5):e2000449. Epub 2021 Feb 9.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Koum, Egypt.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.
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http://dx.doi.org/10.1002/ardp.202000449DOI Listing
May 2021

Targeted potent antimicrobial benzochromene-based analogues: Synthesis, computational studies, and inhibitory effect against 14α-Demethylase and DNA Gyrase.

Bioorg Chem 2020 12 17;105:104387. Epub 2020 Oct 17.

Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address:

7H-Benzo[7,8]chromeno[2,3-d]pyrimidin-9(8H)-amine (6a,b) have been synthesized via hydrazinolysis of the imidates (5a,b). Polysubstituted chromenotriazolopyrimidine (7a-j), (12a,b) and Schiff base (8a,b) derivatives have also been prepared. The new heterocyclic derivatives were affirmed by spectral data. The target compounds have been screened for antibacterial and antifungal activity. Compounds 6a,b and 7a-c, g,h displayed the most favorable antimicrobial activities in resemblance to the reference antimicrobial agents by IZ range over 24 mm. In addition, MIC, MBC and MFC were also tested and screen for most active compound 6a by 6.25 µg/mL showing bactericidal effect. SAR study revealed that the antimicrobial vitality of the target compounds was safely influenced by the lipophilicity substituents and the calculated log P value. The potent compounds were subjected into in vitro enzyme screening (14α-Demethylase and DNA Gyrase) against both interesting targets and showed good inhibitory profile. Molecular modeling analyses were introduced and discussed focusing on the docking of active compounds into two essential targets, and their ADMET properties were studied.
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http://dx.doi.org/10.1016/j.bioorg.2020.104387DOI Listing
December 2020

Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives.

Arch Pharm (Weinheim) 2021 Feb 20;354(2):e2000277. Epub 2020 Oct 20.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.
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http://dx.doi.org/10.1002/ardp.202000277DOI Listing
February 2021

Novel 1,2,4-triazole derivatives: Design, synthesis, anticancer evaluation, molecular docking, and pharmacokinetic profiling studies.

Arch Pharm (Weinheim) 2020 Dec 6;353(12):e2000170. Epub 2020 Sep 6.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including H nuclear magnetic resonance (NMR) and C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure-activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC value of 5.95 µM. The observed IC values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.
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http://dx.doi.org/10.1002/ardp.202000170DOI Listing
December 2020

Novel scaffold hopping of potent benzothiazole and isatin analogues linked to 1,2,3-triazole fragment that mimic quinazoline epidermal growth factor receptor inhibitors: Synthesis, antitumor and mechanistic analyses.

Bioorg Chem 2020 10 23;103:104133. Epub 2020 Jul 23.

Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah 30002, Saudi Arabia.

A series of benzothiazole/isatin linked to 1,2,3-triazole moiety and terminal sulpha drugs 5a-e and 6a-e were synthesized and evaluated for cytotoxic activity against a panel of cancer cell lines. The novel compounds showed variable IC range of activity and some of them were potent compared to reference drug. The promising compounds were subjected as postulated the mimicry proposal for quinazoline-based EGFR inhibitors for their inhibitory profile against EGFR TK enzyme. That data obtained revealed that most of these compounds were potent EGFR TK inhibitors at nanomolar concentrations. Among these, compounds 5a and 5b showed more potent activity on EGFR compared to erlotinib (IC 103 and 104 versus 67.6 nM). Based upon the results, molecular docking analysis was performed on EGFR receptor and proved the strong contribution of fragments; benzothiazole, isatin, and triazole to the binding ATP pocket. When these selected compounds 5a and 5b were tested in an HepG2 model, they could effectively inhibited tumor growth, strongly induced cancer cell apoptosis, and suppressed cell cycle progression leading to DNA fragmentation. Well-DMET profile of the most active derivatives was presented and compared to the reference drugs. Taken together, we introduced novel triazole-sulpha drug hybrid for the first time as EGFR inhibitors and the results of our studies indicate that the newly discovered inhibitors have significant potential for anticancer treatment.
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http://dx.doi.org/10.1016/j.bioorg.2020.104133DOI Listing
October 2020

Novel molecular discovery of promising amidine-based thiazole analogues as potent dual Matrix Metalloproteinase-2 and 9 inhibitors: Anticancer activity data with prominent cell cycle arrest and DNA fragmentation analysis effects.

Bioorg Chem 2020 08 2;101:103992. Epub 2020 Jun 2.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, 11884 Nasr City, Cairo, Egypt.

Thiazole derivatives are known to possess various biological activities such as antiparasitic, antifungal, antimicrobial and antiproliferative activities. Matrix metalloproteinases (MMPs) are important protease target involved in tumor progression including angiogenesis, tissue invasion, and migration. Therefore, MMPs have also been reported as potential diagnostic and prognostic biomarkers in many types of cancer. Herein, new aryl thiazoles were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines including the invasive MDA-MB-231 line. Some of these compounds showed IC values in the submicromolar range in anti-proliferative assays. In order to examine the relationship between their anticancer activity and MMPs targets, the compounds were evaluated for their inhibitory effects on MMP-2 and 9. That data obtained revealed that most of these compounds were potent dual MMP-2/9 inhibitors at nanomolar concentrations. Among these, 2-(1-(2-(2-((E)-4-iodobenzylidene)hydrazineyl)-4-methylthiazol-5-yl)ethylidene)hydrazine-1-carboximidamide (4a) was the most potent non-selective dual MMP-2/9 inhibitor with inhibitory concentrations of 56 and 38 nM respectively. When compound 4a was tested in an MDA-MB-231, HCT-116, MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibit cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Taken together, the results of our studies indicate that the newly discovered thiazole-based MMP-2/9 inhibitors have significant potential for anticancer treatment.
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http://dx.doi.org/10.1016/j.bioorg.2020.103992DOI Listing
August 2020

Introducing of potent cytotoxic novel 2-(aroylamino)cinnamamide derivatives against colon cancer mediated by dual apoptotic signal activation and oxidative stress.

Bioorg Chem 2020 08 25;101:103953. Epub 2020 May 25.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt.

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 8 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), no inhibition of normal cell lines C-166, and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 45 killed colon cancer cells at IC = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC = 71 µM and 77.6 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part as a result of oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of covalently acting Michael addition compounds that potently kill cancer cells by a defined mechanism, with prominent selectivity profile over non-cancerous cell lines.
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http://dx.doi.org/10.1016/j.bioorg.2020.103953DOI Listing
August 2020

Novel triazolophthalazine-hydrazone hybrids as potential PCAF inhibitors: Design, synthesis, in vitro anticancer evaluation, apoptosis, and molecular docking studies.

Bioorg Chem 2020 07 17;100:103899. Epub 2020 May 17.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt.

Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC values of 5.70, 8.04, 11.15, and 4.25, µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC values of 6.45, 8.63, 12.28, and 7.03 µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC values of 8.13 and 5.31 µM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.
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http://dx.doi.org/10.1016/j.bioorg.2020.103899DOI Listing
July 2020

Design, synthesis, molecular modelling and screening of monoamine oxidase inhibitory activities of novel quinazolyl hydrazine derivatives.

R Soc Open Sci 2020 Apr 22;7(4):200050. Epub 2020 Apr 22.

Biomedical Sciences Research Complex, University of St Andrews, Biomolecular Sciences Building, North Haugh, St Andrews KY16 9ST, UK.

A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide () has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring () decreased inhibition, but a less flexible linker () resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.
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http://dx.doi.org/10.1098/rsos.200050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211837PMC
April 2020

The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase.

Bioorg Chem 2020 06 21;99:103781. Epub 2020 Mar 21.

Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address:

A series of novel 2-Amino-4-Methylthiazole analogs were developed via three-step reaction encompassing hydrazine-1-carboximidamide motif to combat Gram-positive and Gram-negative bacterial and fungal infections. Noticeably, the thiazole-carboximidamide derivatives 4a-d displayed excellent antimicrobial activity and the most efficacious analogue 4d with MIC/MBC values of 0.5 and 4 μg/mL, compared to reference drugs with very low toxicity to mammalian cells, resulting in a prominent selectivity more than 100 folds. Microscopic investigation of 4d biphenyl analogue showed cell wall lysis and promote rapid bactericidal activity though disrupting the bacterial membrane. In addition, an interesting in vitro investigation against GlcN-6-P Synthase Inhibition was done which showed potency in the nanomolar range. Meanwhile, this is the first study deploying a biomimicking strategy to design potent thiazole-carboximidamides that targeting GlcN-6-P Synthase as antimicrobial agents. Importantly, Molecular modeling simulation was done for the most active 4d analogue to study the interaction of this analogue which showed good binding propensity to glucosamine binding site which support the in vitro data.
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http://dx.doi.org/10.1016/j.bioorg.2020.103781DOI Listing
June 2020

S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors.

J Enzyme Inhib Med Chem 2020 Dec;35(1):733-743

Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, Italy.

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 ) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds and showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (Ks; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds and 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 , and 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 , , and 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, and and hCAs isoenzymes. Compounds and , 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 and were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds and were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds -, , and were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors.Compounds , -, were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors.Compounds and 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 , and are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds , and are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31).
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http://dx.doi.org/10.1080/14756366.2020.1742117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144323PMC
December 2020

Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B.

Bioorg Chem 2020 03 10;96:103656. Epub 2020 Feb 10.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, Mansoura, Egypt.

A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.
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http://dx.doi.org/10.1016/j.bioorg.2020.103656DOI Listing
March 2020

Exploring structure-activity relationship of S-substituted 2-mercaptoquinazolin-4(3H)-one including 4-ethylbenzenesulfonamides as human carbonic anhydrase inhibitors.

J Enzyme Inhib Med Chem 2020 Dec;35(1):598-609

Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, Italy.

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 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 with inhibition constants (Ks) ranging from 57.8-740.2 nM. Compounds , , , and showed inhibitory action against hCA II with Ks between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives with K values ranging from 7.1 to 93.6 nM. Compounds , , , , , and also exerted potent inhibitory action against hCA XII (Ks ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds and 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.
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http://dx.doi.org/10.1080/14756366.2020.1722121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034075PMC
December 2020

First example of Azo-Sulfa conjugated chromene moieties: Synthesis, characterization, antimicrobial assessment, docking simulation as potent class I histone deacetylase inhibitors and antitumor agents.

Bioorg Chem 2019 11 5;92:103262. Epub 2019 Sep 5.

Chemistry Department, Faculty of Science, Taibah University, 30002, Al-Madinah Al-Munawarah, Saudi Arabia; Chemistry Department, Faculty of Science, Al-Azhar University, 11884 Nasr City, Cairo, Egypt. Electronic address:

This report presents the development of a novel and primary model of sulfonamide compounds encompassing a chromene azo motif with the intent of becoming applicable for drug candidates in the cases of drug-resistant pathogens. The novel molecules (7a-n) have been synthesized via a two-step reaction. First, 4-((2, 4-dihydroxyphenyl)diazenyl)benzenesulfonamide (3a-e) were obtained through the reaction of their corresponding diazotized 4-aminobenzenesulfonamides (1a-e) with resorcinol, followed by the heterocyclization of 3a-e with arylidenemalononitriles (6a-d). Upon structural identification, the newly synthesized compounds were evaluated for their antibacterial and antifungal activities. Moreover, their cytotoxic screening was performed against three cancer cell lines: HCT-116, HepG-2, and MCF-7. Further examinations were comprised of the inhibitory effect analyses of the novel sulfonamide/chromene derivatives against the HDAC classes and the Tubulin polymerization in order to discern the prime antitumor drug candidates.
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http://dx.doi.org/10.1016/j.bioorg.2019.103262DOI Listing
November 2019

Synthesis, Biological Evaluation, and Molecular Docking of Novel Thiazoles and [1,3,4]Thiadiazoles Incorporating Sulfonamide Group as DHFR Inhibitors.

Chem Biodivers 2018 Sep 16;15(9):e1800231. Epub 2018 Aug 16.

Pharmaceutics and Pharmaceutical Technology Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawaraha, 41477, Saudi Arabia.

2-(1-{4-[(4-Methylphenyl)sulfonamido]phenyl}ethylidene)thiosemicarbazide (3) was exploited as a starting material for the synthesis of two novel series of 5-arylazo-2-hydrazonothiazoles 6a - 6j and 2-hydrazono[1,3,4]thiadiazoles 10a - 10d, incorporating sulfonamide group, through its reactions with appropriate hydrazonoyl halides. The structures of the newly synthesized products were confirmed by spectral and elemental analyses. Also, the antimicrobial, anticancer, and DHFR inhibition potency for two series of thiazoles and [1,3,4]thiadiazoles were evaluated and explained by molecular docking studies and SAR analysis.
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http://dx.doi.org/10.1002/cbdv.201800231DOI Listing
September 2018

Introducing novel potent anticancer agents of 1H-benzo[f]chromene scaffolds, targeting c-Src kinase enzyme with MDA-MB-231 cell line anti-invasion effect.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1074-1088

c Chemistry Department, Faculty of Science , Al-Azhar University , Cairo , Egypt.

In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a-h and 6a-h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, H NMR,  C NMR,  C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2. Vinblastine and Doxorubicin have been used as positive controls in the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activity against the three cancer cell lines. Moreover, these molecules exhibited weak cytotoxicity on the HFL-1 line, which suggested that they might be ideal anticancer candidates. The SAR study of the new benzochromene compounds verified that the substituents on the phenyl ring of 1H-benzo[f]chromene nucleus, accompanied with the presence of bromine atom or methoxy group at the 8-position, increases the ability of these molecules against the different cell lines. Due to their high anti-proliferative activity, compounds 4c and 6e were selected to be examined their proficiency to inhibit the invasiveness of the highly sensitive and invasive breast cancer cell line, MDA-MB-231. The anti-invasion behaviour of these molecules against the highly sensitive, non-oestrogen, and progesterone MDA-MB-231 cell line gave rise to their decreasing metastatic effect compared to the reference drug. Furthermore, this report explores the apoptotic mechanistic pathway of the cytotoxicity of the target compounds and reveals that most of these compounds enhance the Caspase 3/7 activity that could be considered as potential anticancer agents.
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http://dx.doi.org/10.1080/14756366.2018.1476503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022228PMC
December 2018

Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects.

Int J Mol Sci 2018 06 11;19(6). Epub 2018 Jun 11.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.

A series of new fluoroquinazolinone ⁻ and ⁻ derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds (IC = 0.35 ± 0.01 µM), (IC = 0.71 ± 0.01 µM), (IC = 0.89 ± 0.02 µM) and (IC = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC = 0.97 ± 0.02 µM) against MCF-7. Compounds (IC = 0.28 ± 0.02 µM), (IC = 0.38 ± 0.01 µM), (IC = 0.94 ± 0.07 µM) and (IC = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated.
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http://dx.doi.org/10.3390/ijms19061731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032053PMC
June 2018

The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization.

Int J Mol Sci 2018 Jan 30;19(2). Epub 2018 Jan 30.

Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.

Some novel anthranilate diamides derivatives -, - and - were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, ¹H nuclear magnetic resonance (NMR) and C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out.
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http://dx.doi.org/10.3390/ijms19020408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855630PMC
January 2018

Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]-quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects.

Molecules 2017 Dec 27;23(1). Epub 2017 Dec 27.

Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.

A series of hybrid of triazoloquinoxaline-chalcone derivatives - were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like -, and - exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC values in the 1.65 to 34.28 µM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives -, , and could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 µM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds and displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.
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http://dx.doi.org/10.3390/molecules23010048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943945PMC
December 2017

Design, synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents.

Bioorg Chem 2018 02 2;76:332-342. Epub 2017 Dec 2.

The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.
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http://dx.doi.org/10.1016/j.bioorg.2017.11.019DOI Listing
February 2018

Neuroprotective effect of berberine against environmental heavy metals-induced neurotoxicity and Alzheimer's-like disease in rats.

Food Chem Toxicol 2018 Jan 21;111:432-444. Epub 2017 Nov 21.

Biochemistry Department, Faculty of Science, Alexandria University Alexandria, Egypt.

Heavy metals are reported as neurodegenerative disorders progenitor. They play a role in the precipitation of abnormal β-amyloid protein and hyper-phosphorylated tau, the main hallmarks of Alzheimer's disease (AD). The present study aimed to validate the heavy metals-induced Alzheimer's-like disease in rats as an experimental model of AD and explore the therapeutic effect of berberine via tracking its effect on the oxidative stress-inflammatory pathway. Alzheimer's-like disease was induced in rats orally by a mixture of aluminium, cadmium and fluoride for three months, followed by berberine treatment for another one month. Berberine significantly improved the cognitive behaviors in Morris water maze test and offered a protective effect against heavy metals-induced memory impairment. Docking results showed that berberine inhibited AChE, COX-2 and TACE. Matching with in silico study, berberine downregulated the AChE expression and inhibited its activity in the brain tissues. Also, it normalized the production of TNF- α, IL-12, IL-6 and IL-1β. Moreover, it evoked the production of antioxidant Aβ40 and inhibited the formation of Aβ42, responsible for the aggregations of amyloid-β plaques. Histopathological examination confirmed the neuroprotective effect of berberine. The present data advocate the possible beneficial effect of berberine as therapeutic modality for Alzheimer's disease via its antiinflammatory/antioxidant mechanism.
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http://dx.doi.org/10.1016/j.fct.2017.11.025DOI Listing
January 2018

Structure-activity relationships and molecular docking studies of chromene and chromene based azo chromophores: A novel series of potent antimicrobial and anticancer agents.

EXCLI J 2017 19;16:868-902. Epub 2017 Jun 19.

Chemistry Department, Faculty of Science, University of Prince Edward Island, Charlottetown, Prince Edward Island C1A 4P3, Canada.

The design of novel materials with significant biological properties is a main target in drug design research. Chromene compounds represent an interesting medicinal scaffold in drug replacement systems. This report illustrates a successful synthesis and characterization of two novel series of compounds using multi-component reactions. The synthesis of the first example of azo chromophores containing chromene moieties has also been established using the same methodology. The antimicrobial activity of the new molecules has been tested against seven human pathogens including two Gm+ve, two Gm-ve bacteria, and four fungi, and the results of the inhibition zones with minimum inhibitory concentrations were reported as compared to reference drugs. All the designed compounds showed significant potent antimicrobial activities, among of them, four potent compounds , , , and showed promising MIC from 0.007 to 3.9 µg/mL. In addition, antiproliferative analysis against three target cell lines was examined for the novel compounds. Compounds , , , and possessed significant antiproliferative activity against three cell lines with an IC of 0.3 to 2 µg/mL. Apoptotic analysis was performed for the most potent compounds via caspase enzyme activity assays as a potential mechanism for their antiproliferative effects. Finally, the computational 2D QSAR and docking simulations were accomplished for structure-activity relationship analyses.
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http://dx.doi.org/10.17179/excli2017-356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547389PMC
June 2017

Rational design, synthesis, pharmacophore modeling, and docking studies for identification of novel potent DNA-PK inhibitors.

Bioorg Chem 2017 06 2;72:234-247. Epub 2017 May 2.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia; Department of Pharmaceutical and Medicinal Chemistry, Pharmacy College, Misr University for Science and Technology, Cairo, Egypt.

Drugs of cancer based upon ionizing radiation or chemotherapeutic treatment may affect breaking of DNA double strand in cell. DNA-PK enzyme has emerged as an attractive target for drug discovery efforts toward DNA repair pathways. Hence, the search for potent and selective DNA-PK inhibitors has particularly considered state-of-the art and several series of inhibitors have been designed. In this article, a novel benchmark DNA-PK database of 43 compounds was built and described. Ligand-based approaches including pharmacophore and QSAR modeling were applied and novel models were introduced and analyzed for predicting activity test for DNA-PK drug candidates. Based upon the modeling results, we gave a report of synthesis of fifteen novel 2-((8-methyl-2-morpholino-4-oxo-4H-benzo[e][1,3]oxazin-7-yl)oxy)acetamide derivatives and in vitro evaluation for DNA-PK inhibitory and antiproliferative activities. These fifteen compounds overall are satisfied with Lipinski's rule of five. The biological testing of target compounds showed five promising active compounds 7c, 7d, 7f, 9e and 9f with micromolar DNA-PK activity range from 0.25 to 5µM. In addition, SAR of the compounds activity was investigated and confirmed that the terminal aryl moiety was found to be quite crucial for DNA-PK activity. Moreover flexible docking simulation was done for the potent compounds into the putative binding site of the 3D homology model of DNA-PK enzyme and the probable interaction model between DNA-PK and the ligands was investigated and interpreted.
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http://dx.doi.org/10.1016/j.bioorg.2017.04.014DOI Listing
June 2017

Synthesis, Modelling, and Anticonvulsant Studies of New Quinazolines Showing Three Highly Active Compounds with Low Toxicity and High Affinity to the GABA-A Receptor.

Molecules 2017 Jan 24;22(2). Epub 2017 Jan 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.

Some novel fluorinated quinazolines (-) were designed and synthesized to be evaluated for their anticonvulsant activity and their neurotoxicity. Structures of all newly synthesized compounds were confirmed by their infrared (IR), mass spectrometry (MS) spectra, ¹H nuclear magnetic resonance (NMR), C-NMR, and elemental analysis (CHN). The anticonvulsant activity was evaluated by a subcutaneous pentylenetetrazole (scPTZ) test and maximal electroshock (MES)-induced seizure test, while neurotoxicity was evaluated by a rotorod test. The molecular docking was performed for all newly-synthesized compounds to assess their binding affinities to the GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticonvulsant activity for all newly-synthesized compounds. Compounds , , and showed the highest binding affinities toward the GABA-A receptor, along with the highest anticonvulsant activities in experimental mice. These compounds also showed low neurotoxicity and low toxicity in the median lethal dose test compared to the reference drugs. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and explain the possible mechanism for anticonvulsant action. The most active compounds might be used as leads for future modification and optimization.
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http://dx.doi.org/10.3390/molecules22020188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155771PMC
January 2017

New ursane triterpenoids from Ficus pandurata and their binding affinity for human cannabinoid and opioid receptors.

Arch Pharm Res 2016 Jul 27;39(7):897-911. Epub 2016 Jun 27.

National Center for Natural Products Research, and Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS, 38677, USA.

Phytochemical investigation of Ficus pandurata Hance (Moraceae) fruits has led to the isolation of two new triterpenoids, ficupanduratin A [1β-hydroxy-3β-acetoxy-11α-methoxy-urs-12-ene] (11) and ficupanduratin B [21α-hydroxy-3β-acetoxy-11α-methoxy-urs-12-ene] (17), along with 20 known compounds: α-amyrin acetate (1), α-amyrin (2), 3β-acetoxy-20-taraxasten-22-one (3), 3β-acetoxy-11α-methoxy-olean-12-ene (4), 3β-acetoxy-11α-methoxy-12-ursene (5), 11-oxo-α-amyrin acetate (6), 11-oxo-β-amyrin acetate (7), palmitic acid (8), stigmast-4,22-diene-3,6-dione (9), stigmast-4-ene-3,6-dione (10), stigmasterol (12), β-sitosterol (13), stigmast-22-ene-3,6-dione (14), stigmastane-3,6-dione (15), 3β,21β-dihydroxy-11α-methoxy-olean-12-ene (16), 3β-hydroxy-11α-methoxyurs-12-ene (18), 6-hydroxystigmast-4,22-diene-3-one (19), 6-hydroxystigmast-4-ene-3-one (20), 11α,21α-dihydroxy-3β-acetoxy-urs-12-ene (21), and β-sitosterol-3-O-β-D-glucopyranoside (22). Compound 21 is reported for the first time from a natural source. The structures of the 20 compounds were elucidated on the basis of IR, 1D ((1)H and (13)C), 2D ((1)H-(1)H COSY, HSQC, HMBC and NOESY) NMR and MS spectroscopic data, in addition to comparison with literature data. The isolated compounds were evaluated for their anti-microbial, anti-malarial, anti-leishmanial, and cytotoxic activities. In addition, their radioligand displacement affinity on opioid and cannabinoid receptors was assessed. Compounds 4, 11, and 15 exhibited good affinity towards the CB2 receptor, with displacement values of 69.7, 62.5 and 86.5 %, respectively. Furthermore, the binding mode of the active compounds in the active site of the CB2 cannabinoid receptors was investigated through molecular modelling.
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http://dx.doi.org/10.1007/s12272-016-0784-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590819PMC
July 2016

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits.

Molecules 2016 Jan 30;21(2):175. Epub 2016 Jan 30.

Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, P. O. Box 30039, Al-Madinah Al-Munawarah 41477, Saudi Arabia.

The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool 'Emergent Self-Organizing Maps' for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity.
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http://dx.doi.org/10.3390/molecules21020175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272978PMC
January 2016

Discovery of novel phthalimide analogs: Synthesis, antimicrobial and antitubercular screening with molecular docking studies.

EXCLI J 2016 6;15:781-796. Epub 2016 Dec 6.

Chemistry Department, Faculty of Science, Taibah University, 30002, Al-Madinah Al-Munawarah, Saudi Arabia.

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives ( and ) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds , and (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes.
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http://dx.doi.org/10.17179/excli2016-654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318679PMC
December 2016

Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats.

Evid Based Complement Alternat Med 2015 20;2015:361847. Epub 2015 Oct 20.

Medical Biotechnology Department, Genetic Engineering & Biotechnology Research Institute, City for Scientific Research & Technology Applications, Alexandria, Egypt.

Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ 40) and increased beta-amyloid42 (Aβ 42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity.
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http://dx.doi.org/10.1155/2015/361847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630388PMC
November 2015

Design and evaluation of bonded atom pair descriptors.

J Chem Inf Model 2010 Apr;50(4):487-99

Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universitat Bonn, Dahlmannstrasse 2, D-53113 Bonn, Germany.

Atom pairs have been among the first systematically derived fragment-type topological descriptors and have been one of the origins of two-dimensional fingerprint searching. These descriptors continue to be popular and widely used to this date. Herein we introduce a new type of atom pair descriptors, bonded atom pairs, that exclusively capture short-range atom environment information and, thus, depart in their design from other topological descriptors that enumerate bond paths of varying length. Bonded atom pairs combine different types of structural information including element type, hybridization state, aliphatic/aromatic character, and cyclic/acyclic arrangement. Systematic design led to a set of 117 bonded atom pairs, all of which exist in synthetic compounds. A further expanded bonded atom pair set accounting for specific halogen atoms and including a total of 159 descriptors is also provided. Atom pair distribution and frequency analysis in sets of compounds having different selectivity reveals that both conventional and bonded atom pairs capture complementary structural information. In similarity searching, bonded atom pairs meet or exceed the performance of standard atom pairs and structural fragment fingerprints. The complementary nature of structural information captured by atom pairs of different design is also reflected by individual search calculations. Taken together, our findings indicate that bonded atom pairs extend the current repertoire of topological molecular descriptors.
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http://dx.doi.org/10.1021/ci900512gDOI Listing
April 2010