Publications by authors named "Ahmed El Kerdawy"

28 Publications

  • Page 1 of 1

Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities.

Bioorg Chem 2021 Feb 30;107:104569. Epub 2020 Dec 30.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-Raf to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-Raf were consolidated by the inhibition of B-Raf, EGFR and VEGFR-2 with IC in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
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http://dx.doi.org/10.1016/j.bioorg.2020.104569DOI Listing
February 2021

Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and studies.

J Enzyme Inhib Med Chem 2021 Dec;36(1):270-285

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

The serine/threonine protein kinases CDK2 and GSK-3β are key oncotargets in breast cancer cell lines, therefore, in the present study three series of oxindole-benzofuran hybrids were designed and synthesised as dual CDK2/GSK-3β inhibitors targeting breast cancer (, , and ). The -unsubstituted oxindole derivatives, , showed moderate to potent activity on both MCF-7 and T-47D breast cancer cell lines. Compounds showed the most potent cytotoxic activity with IC of 3.41, 3.45 and 2.27 μM, respectively, on MCF-7 and of 3.82, 4.53 and 7.80 μM, respectively, on T-47D cell lines, in comparison to the used reference standard (staurosporine) IC of 4.81 and 4.34 μM, respectively. On the other hand, the -substituted oxindole derivatives, and , showed moderate to weak cytotoxic activity on both breast cancer cell lines. CDK2 and GSK-3β enzyme inhibition assay of revealed that compounds and are showing potent dual CDK2/GSK-3β inhibitory activity with IC of 37.77 and 52.75 nM, respectively, on CDK2 and 32.09 and 40.13 nM, respectively, on GSK-3β. The most potent compounds caused cell cycle arrest in the G2/M phase in MCF-7 cells inducing cell apoptosis because of the CDK2/GSK-3β inhibition. Molecular docking studies showed that the newly synthesised -unsubstituted oxindole hybrids have comparable binding patterns in both CDK2 and GSK-3β. The oxindole ring is accommodated in the hinge region interacting through hydrogen bonding with the backbone CO and NH of the key amino acids Glu81 and Leu83, respectively, in CDK2 and Asp133 and Val135, respectively, in GSK-3β. Whereas, in series and , the -substitutions on the oxindole nucleus hinder the compounds from achieving these key interactions with hinge region amino acids what rationalises their moderate to low anti-proliferative activity.
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http://dx.doi.org/10.1080/14756366.2020.1862101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751407PMC
December 2021

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights.

Bioorg Med Chem 2020 07 25;28(13):115525. Epub 2020 Apr 25.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address:

Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.
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http://dx.doi.org/10.1016/j.bmc.2020.115525DOI Listing
July 2020

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole-Indole Conjugates as Anticancer CDK Inhibitors.

Molecules 2020 Apr 27;25(9). Epub 2020 Apr 27.

Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah 6231, Saudi Arabia.

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole-indole conjugates ( and ) and carbocycle-indole conjugates (, as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole-indole conjugates, except , , and efficiently affected the growth of the human breast cancer MCF-7 (IC: 0.39 ± 0.05-21.40 ± 1.58 μM) and/or MDA-MB-231 (IC: 1.03 ± 0.04-22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds ,) diminished the anti-proliferative activity. In addition, hybrids and displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (, , and ) were investigated for their potential inhibitory action toward CDK4. Hybrids and displayed good CDK4 inhibitory activity with ICs equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids and as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.
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http://dx.doi.org/10.3390/molecules25092031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248897PMC
April 2020

Modulation of endoplasmic reticulum stress response in gut-origin encephalopathy: Impact of vascular endothelial growth factor receptor-2 manipulation.

Life Sci 2020 Jul 8;252:117654. Epub 2020 Apr 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, P.O. Box 11835, Egypt.

Background: Septic encephalopathy, the most frequent complication of sepsis, is orchestrated by a complex interplay of signals that leads to high mortality rates among intensive care unit patients. However, the role of the vascular endothelial growth factor receptor-2 (VEGFR2) in endoplasmic reticulum stress response (ERSR), during septic encephalopathy, is still elusive.

Aim: This study was aimed to examine the effect of an in-house designed/synthesized VEGFR2 antagonist, named WAG4S, on septic encephalopathy using cecal ligation and perforation (CLP).

Main Methods: Rats were intraperitoneally injected with WAG-4S (1 mg/kg/d) for 7 days post-CLP.

Key Findings: In septic animals, VEGFR2 antagonism declined the expression of cortical p-VEGFR2 and p-mammalian target of rapamycin complex-1 (p-mTORC1). It also worsened the behavioral and histopathological alterations beyond CLP. However, and contrary to CLP, WAG-4S decreased the p-protein kinase R-like ER kinase (p-PERK) and eukaryotic initiation factor-2α (p-eIF2α) expression. Moreover, VEGFR2 blockade upregulated the mRNA expression of activating transcription factor-4 (ATF4), binding immunoglobulin protein/glucose-regulated protein-78 (Bip/GRP78), growth arrest and DNA damage-34 (GADD34) and spliced X-box binding protein-1 (XBP1s) above CLP. Similarly, it boosted inositol requiring enzyme-1α (IRE1α) activation and redox imbalance. In the same context, WAG-4S augmented the protein levels of CLP-induced ERSR apoptotic markers, namely C/EBP homologous protein (CHOP/GADD153), c-jun N-terminal kinase (JNK) and caspase-3.

Significance: In conclusion, the PERK/eIF2α axis inhibition, during septic encephalopathy, is VEGFR2-independent, whereas the activated IRE1α/XBP1s/CHOP/JNK/caspase-3 cue promotes the ERSR execution module through VEGFR2 inhibition. This has turned VEGFR2 into a potential therapeutic target for ameliorating such an ailment.
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http://dx.doi.org/10.1016/j.lfs.2020.117654DOI Listing
July 2020

Some 1,3,5-trisubstituted pyrazoline derivatives targeting breast cancer: Design, synthesis, cytotoxic activity, EGFR inhibition and molecular docking.

Bioorg Chem 2020 06 21;99:103780. Epub 2020 Mar 21.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt. Electronic address:

Different 1,3,5-trisubstituted pyrazoline derivatives 2a-c, 3-c, 4a-f, 6a-c, 7a-f and 8a-d were prepared via condensation reaction of the appropriate chalcone 1a-c or 5a-c with various hydrazine derivatives. All compounds were screened for their cytotoxicity against breast MCF-7 cancer cell line and the normal fibroblasts WI-38. Thirteen compounds 2a, 3a, 3c, 4a-d, 6c, 7d, 7e, 8b, 8d and 8f revealed promising cytotoxicity against MCF-7 compared to the reference standard staurosporine and they were safe to the normal fibroblasts WI-38. In addition, compounds 3c, 6c, 7d, 8b and 8d elicited higher cytotoxicity than erlotinib and exhibited promising EGFR inhibitory activity at submicromolar level comparable to that of erlotinib except for compound 8b that may exert its cytotoxicity via another mechanism besides EGFR inhibition. Molecular docking of 3c, 6c, 7d, 8b and 8d in the active site of EGFR confirmed the obtained results.
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http://dx.doi.org/10.1016/j.bioorg.2020.103780DOI Listing
June 2020

Design and Synthesis of some new 2,4,6-trisubstituted quinazoline EGFR inhibitors as targeted anticancer agents.

Bioorg Chem 2020 05 6;98:103726. Epub 2020 Mar 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box, 11562, Egypt.

The present study describes the synthesis of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines starting from 4-chloro derivative VI via the reaction with either phenolic compounds to obtain VIIa-f, IXa-d, 2-amino-6-(un)substituted benzothiazole to produce VIIIa-c or hydrazine hydrate to give X. Reaction of the hydrazino functionality of X with appropriate acid anhydride, acid chloride or aldehyde affords XIa-c, XIIa-c and XIVa-i, respectively. The target compounds were screened for their efficacy as EGFR inhibitors compared to gefitinib. Compounds eliciting superior EGFR inhibitory activity were further screened for their in vitro cytotoxicity against two human cancer cell lines namely: MCF7 (breast) and A549 (lung), in addition to normal fibroblast cell WI38 relative to gefitinib as a reference. Furthermore, compounds that showed potent inhibitory activity on wild-type EGFR were screened against mutant EGFR and assayed for their cytotoxicity against mutant EGFR-expressing cell lines PC9 and HCC827. The unsubstituted benzothiazol-2-amine VIIa showing superior EGFR inhibition (IC = 0.096 µM) and anticancer activity against MCF-7 cell line (IC = 2.49 µM) was subjected to cell cycle analysis and apoptotic assay. Moreover, a molecular docking study was performed to investigate the interaction of some representive compounds with the active site of EGFR- TK.
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http://dx.doi.org/10.1016/j.bioorg.2020.103726DOI Listing
May 2020

Design, synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer.

Arch Pharm (Weinheim) 2020 Apr 11;353(4):e1900340. Epub 2020 Feb 11.

Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt.

A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10, and 12. Compounds 9d, 9f, 9i, and 9k exhibited potent multikinase inhibitory activity with IC values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC  = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib (III), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.
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http://dx.doi.org/10.1002/ardp.201900340DOI Listing
April 2020

New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies.

Bioorg Med Chem 2020 03 22;28(5):115329. Epub 2020 Jan 22.

Università degli Studi di Firenze, Department NEUROFARBA - Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy. Electronic address:

In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed K of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs.
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http://dx.doi.org/10.1016/j.bmc.2020.115329DOI Listing
March 2020

Design, synthesis and biological evaluation of novel pyrazole sulfonamide derivatives as dual COX-2/5-LOX inhibitors.

Eur J Med Chem 2020 Mar 16;189:112066. Epub 2020 Jan 16.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt; Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.

The current therapeutic demand focuses more on the discovery of safer NSAIDs rather than exploring more potent alternatives. The dual COX-2/5-LOX inhibition is a promising strategy for designing compounds with an enhanced efficacy, reduced side-effects and a broader anti-inflammatory spectrum in comparison to classical NSAIDs. In the present study, a hybridization strategy was adopted to combine the binding features of the non-selective COX inhibitor "sulindac" and the selective COX-2 inhibitor "celecoxib" which show 5-LOX inhibitory activity with that of licofelone and a celecoxib pyridone analogue which show dual COX-2/5-LOX inhibitory activity to design new series of pyrazole sulfonamide derivatives which, by design, should possess dual COX-2/5-LOX inhibitory activity. All the newly synthesized compounds were initially tested for their potential analgesic activity, then candidates that showed potential analgesic activity, were selected for the subsequent anti-inflammatory activity evaluation, as well as, ulcerogenicity testing. Moreover, in vitro assessment of their COX-1, COX-2 and 5-LOX inhibitory activities were performed. The benzothiophen-2-yl pyrazole carboxylic acid derivative 5b showed the most potent analgesic and anti-inflammatory activities surpassing that of celecoxib and indomethacin. It showed potent COX-1, COX-2 and 5-LOX inhibitory activity with IC of 5.40, 0.01 and 1.78 μM, respectively, showing a selectivity index of 344.56 that was much better than the used reference standards and its parent compounds, confirming its selectivity towards COX-2 over COX-1. The prodrug ester derivatives 6c and 6d showed equipotent activity to their parent compound 5b with no gastric ulcerogenicity. Molecular docking simulations confirmed that the newly synthesized compounds possess the structural features required for binding to the target enzymes COX-2 and 5-LOX.
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http://dx.doi.org/10.1016/j.ejmech.2020.112066DOI Listing
March 2020

Heteroleptic complexes of cocaine/TMEDA with some f block metals: Synthesis, DFT studies, spectral, thermal, cytotoxicity and antimetastatic properties.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Mar 9;229:117938. Epub 2019 Dec 9.

Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt; Egypt Nanotechnology Center, Cairo University, El-Sheikh Zayed, 6(th) October City, Giza 12588, Egypt.

A series of new three heteroleptic complexes of the general formula [Ln(Cn)(TMEDA)Cl(OH)]·2Cl·xHO, (where Ln = La(III), Er(III) and Yb(III), Cn = cocaine and TMEDA = N,N,N',N'-tetramethylethylenediamine) were synthesized, structurally characterized by elemental analysis, spectroscopic methods, molar conductivity and mass spectrometry. Thermal properties of the synthesized complexes and their kinetic thermodynamic parameters were studied. Theoretical calculations including geometry optimization, electronic structure and electronic and thermal energies were carried out using DFT and TD-DFT calculations at B3LYP/LANL2DZ level of theory and the different quantum chemical parameters were calculated. The in vitro antiproliferative activity of the newly synthesized complexes was assessed by MTT assay on MCF-7 and HepG-2 cancer cell lines. Yb(III) complex showed promising cytotoxic activity comparable to that of cisplatin on both cell lines with minimum effect on human normal cells. Further molecular mechanistic investigations showed that Yb(III) complex is an apoptotic inducer as it raises the caspase-3 and caspase-9 cellular level in the MCF-7 cell line. Furthermore, it showed an elevating effect on the level of the tumor suppressor nuclear proteins P21 and P27 concentrations in MCF-7 cells. Moreover, Yb(III) complex hindered the cellular scavenger system of the reactive oxygen species through reducing the glutathione peroxidase (GPx) cellular level imperiling MCF-7 cells by unmanageable oxidative stress. In addition to its cytotoxic effect, Yb(III) complex showed antimetastatic properties as it decreased the cellular levels of matrix metalloproteinases MMP-3 and MMP-9. These results showed that the Yb(III) complex is a promising cytotoxic metal-based agent that exerts its action through various molecular mechanisms with minimum effects on normal cells and with additional antimetastatic properties.
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http://dx.doi.org/10.1016/j.saa.2019.117938DOI Listing
March 2020

Novel 2-arylbenzothiazole DNA gyrase inhibitors: Synthesis, antimicrobial evaluation, QSAR and molecular docking studies.

Bioorg Chem 2019 12 24;93:103373. Epub 2019 Oct 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.

A series of new 2-arylbenzothiazole derivatives (4, 5, 6a-j, 7a-i and 8a,b) was synthesized and tested for their antimicrobial activity against different Gram-positive, Gram-negative bacteria and yeast using ciprofloxacin and fluconazole as positive controls for the antibacterial and antifungal activities, respectively. The target compounds showed stronger inhibitory activity against Gram-negative than Gram-positive bacteria. The minimum inhibitory concentration (MIC) values were determined for those compounds showed zone of inhibition ≥ 13 mm. Based on the MIC values for the tested compounds against E. coli, compounds (4, 5, 6c, 6d, 6g, 6i, 6j, 7b, 7c, 7g and 8a) were selected and tested for their E. coli gyrase inhibitory activity. The tested compounds showed moderate inhibitory activity against E. coli gyrase. Compounds 5, 6c, 6i, 6j and 7b displayed high inhibitory activity against E. coli gyrase with IC values below 10 µM, however, they were less active than ciprofloxacin (E. coli gyrase IC = 1.14 µM). The p-hydroxy-m-methoxy benzothiazole analogue 6c was the most active tested compound (E. coli gyrase IC = 4.85 µM). Quantitative structure-activity relationship (QSAR) study was also implemented for the newly synthesized compounds. The QSAR study indicated that the structural feature that governs the anti-microbial activity for the newly synthesized benzothiazole derivatives is their structural hydrophilic-lipophilic balance what agrees with the chemical intuition where this balance governs their cellular absorption and so their antimicrobial activity. Molecular docking showed that the newly synthesized compounds possess the required structural feature for E. coli gyrase B inhibition through interaction with the key amino acids Asp73 and Gly77.
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http://dx.doi.org/10.1016/j.bioorg.2019.103373DOI Listing
December 2019

Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors.

Eur J Med Chem 2019 Oct 26;179:707-722. Epub 2019 Jun 26.

Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, Cairo, Egypt.

In the present study, we report the discovery of a novel class of substituted 4-amino-2-thiopyrimidines as antiangiogenic and antiproliferative agents. Structural hybridization between 4-substituted aminopyrimidines (VEGFR-2 inhibitors) and 2-thioxopyrimidines (BRAF inhibitors) was carried out to afford substituted 4-amino-2-thiopyrimidines as type II dual VEGFR-2/BRAF inhibitors. Our design strategy was tailored such that the 4-amino-2-thiopyrimidine scaffold is to be accommodated in the central gate area of the inactive DFG-out conformation of both enzymes. On one side, the hydrophobic substituent on the 4-amino group would occupy the hydrophobic back pocket and on the other side the substituent on the sulfide moiety should extend to fit in the hinge region (front pocket). Molecular docking simulations confirmed the ability of the designed compounds to accomplish the key interactions in VEGFR-2 and BRAF active sites. Most of the synthesized substituted 4-amino-2-thiopyrimidines demonstrated potent VEGFR-2 inhibitory activity at submicromolar concentrations. Compounds 8a, 8d, 9c and 9e showed IC = 0.17, 0.12, 0.17 and 0.19 μM, respectively against VEGFR-2 in comparison to sorafenib (I) IC = 0.10 μM and regorafenib (II) IC = 0.005 μM. While compounds 9c, 9d and 10a showed IC = 0.15, 0.22 and 0.11 μM, respectively against BRAF-WT. At 10 μM concentration 9c revealed promising in vitro broad-spectrum antiproliferative activity against cancer cell lines with growth inhibition percent ranging from 10 to 90%. Moreover, compounds 7b, 8d, 9a, 9b, 9c and 9d showed potent activity against MCF7 cell line (IC = 17.18, 17.20, 19.98, 19.61, 13.02 and 16.54 μM, respectively). On the other hand, compounds 9c, 9d and 10d were found to be the most potent compounds against T-47D cell line (IC = 2.18, 8.09 and 4.36 μM, respectively). Studying the effect of the most potent compounds on VEGFR-2 level in MCF7 cell line revealed that 9c and 9d showed inhibition percent of 84 and 80%, respectively, in comparison to sorafenib (I) (% inhibition = 90%).
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http://dx.doi.org/10.1016/j.ejmech.2019.06.063DOI Listing
October 2019

Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors.

J Mol Model 2019 May 25;25(6):171. Epub 2019 May 25.

Research and Development Unit, Majecules LLC, 124 Othman Ibn Affan, Al Matar, P.O. Box 11361, Cairo, Egypt.

Considering the emerging importance of glycogen synthase kinase 3 beta (GSK-3β) inhibitors in treatment of Alzheimer's disease, multi-protein structure receptor-based pharmacophore modeling was adopted to generate a 3D pharmacophore model for (GSK-3β) inhibitors. The generated 3D pharmacophore was then validated using a test set of 1235 compounds. The ZINCPharmer web tool was used to virtually screen the public ZINC database using the generated 3D pharmacophore. A set of 12,251 hits was produced and then filtered according to their lead-like properties, predicted central nervous system (CNS) activity, and Pan-assay interference compounds (PAINS) fragments to 630 compounds. Scaffold Hunter was then used to cluster the filtered compounds according to their chemical structure framework. From the different clusters, 123 compounds were selected to cover the whole chemical space of the obtained hits. The SwissADME online tool was then used to filter out the compounds with undesirable pharmacokinetic properties giving a set of 91 compounds with promising predicted pharmacodynamic and pharmacokinetic properties. To confirm their binding capability to the GSK-3β binding site, molecular docking simulations were performed for the final 91 compounds in the GSK-3β binding site. Twenty-five compounds showed acceptable binding poses that bind to the key amino acids in the binding site Asp133 and Val135 with good binding scores. The quinolin-2-one derivative ZINC67773573 was found to be a promising lead for designing new GSK-3β inhibitors for Alzheimer's disease treatment. Graphical abstract A 3D pharmacophore model for the discovery of novel (GSK-3β) inhibitors.
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http://dx.doi.org/10.1007/s00894-019-4032-5DOI Listing
May 2019

New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies.

Bioorg Chem 2019 05 19;86:80-96. Epub 2019 Jan 19.

Department of Pharmacology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, P.O. Box 11787, Egypt.

Motivated by the potential anticancer activity of both coumarin and 2-aminothiazole nuclei, a new set of thiazol-2-yl hydrazono-chromen-2-one analogs were efficiently synthesized aiming to obtain novel hybrids with potential cytotoxic activity. MTT assay investigated the significant potency of all the target compounds against the human cervical cancer cell lines (HeLa cells). Cell cycle analysis showed that the representative compound 8a led to cell cycle cessation at G0/G1 phase indicating that CDK2/E1complex could be the plausible biological target for these newly synthesized compounds. Thus, the most active compounds (7c and 8a-c) were tested for their CDK2 inhibitory activity. The biological results revealed their significant CDK2 inhibitory activity with IC range of 0.022-1.629 nM. Moreover, RT-PCR gene expression assay showed that compound 8a increased the levels of the nuclear CDK2 regulators P21 and P27 by 2.30 and 5.7 folds, respectively. ELISA tequnique showed also that compound 8a led to remarkable activation of caspases-9 and -3 inducing cell apoptosis. QSAR study showed that the charge distribution and molecular hydrophobicity are the structural features affecting cytotoxic activity in this series. Molecular docking study for the most potent cytotoxic compounds (7c and 8a-c) rationalized their superior CDK2 inhibitory activity through their hydrogen bonding and hydrophobic interactions with the key amino acids in the CDK2 binding site. Pharmacokinetic properties prediction of the most potent compounds showed that the newly synthesized compounds are not only with promising antitumor activity but also possess promising pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bioorg.2019.01.026DOI Listing
May 2019

Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides.

Eur J Med Chem 2019 Feb 24;163:37-53. Epub 2018 Nov 24.

Biochemistry Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, Dokki, 12622, Giza, Egypt.

Pursuing on our efforts regarding development of novel multikinase inhibitors, herein we report the design and synthesis of novel 2-indolinone-based ureides 6a-u and amides 10a-j. In this work we adopt a hybridization strategy between type IIA PTK inhibitor (sorafenib) and type IIB PTK inhibitors (sunitinib and nintedanib). This was implemented via linking the indolinone core, in both sunitinib and nintedanib, which is well-fitted in the hinge region in the kinase domain front cleft and the biaryl urea extension, in sorafenib, which is accommodated in the gate area and the hydrophobic back pocket. Molecular docking of the designed hybrid compounds in VEGFR-2 and FGFR-1 active sites revealed, as planned, their ability to establish the binding interactions achieved by both original type IIA and type IIB inhibitors. The designed compounds were evaluated for their multikinase inhibitory activity towards VEGFR-2, PDGFR-b and FGFR-1 and anti-proliferative activity towards HepG2, MCF-7, A549 and A498 cancer cell lines. The ureido analogue 6u emerged as the most potent multikinase inhibitor in the ureido series with VEGFR-2, FGFR-1 and PDGFR-b IC of 0.18, 0.23 and 0.10 μM, respectively. Whereas, the amido congener 10j emerged as the most potent multikinase inhibitor in the amide series with VEGFR-2, FGFR-1 and PDGFR-b IC of 0.28, 0.46 and 0.09 μM, respectively. While, indolinone 6u was the most potent derivative towards HepG2 cells (IC = 2.67 ± 0.14 μM), 6r stood out as the most potent indolinone against A498 cells (IC = 0.78 ± 0.02 μM). Additionally, the target indolinones displayed non-significant cytotoxic impact towards human normal melanocyte (HFB4). ADME prediction study of the designed compounds showed that they are not only with promising multikinase inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties. Compounds 6r and 10j are revealed to be the best compounds in terms of multikinase activity and pharmacokinetics.
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http://dx.doi.org/10.1016/j.ejmech.2018.11.061DOI Listing
February 2019

QSRR modeling for the chromatographic retention behavior of some β-lactam antibiotics using forward and firefly variable selection algorithms coupled with multiple linear regression.

J Chromatogr A 2018 May 21;1549:51-62. Epub 2018 Mar 21.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, P.O. Box 11562, Egypt; Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.

The justified continuous emerging of new β-lactam antibiotics provokes the need for developing suitable analytical methods that accelerate and facilitate their analysis. A face central composite experimental design was adopted using different levels of phosphate buffer pH, acetonitrile percentage at zero time and after 15 min in a gradient program to obtain the optimum chromatographic conditions for the elution of 31 β-lactam antibiotics. Retention factors were used as the target property to build two QSRR models utilizing the conventional forward selection and the advanced nature-inspired firefly algorithm for descriptor selection, coupled with multiple linear regression. The obtained models showed high performance in both internal and external validation indicating their robustness and predictive ability. Williams-Hotelling test and student's t-test showed that there is no statistical significant difference between the models' results. Y-randomization validation showed that the obtained models are due to significant correlation between the selected molecular descriptors and the analytes' chromatographic retention. These results indicate that the generated FS-MLR and FFA-MLR models are showing comparable quality on both the training and validation levels. They also gave comparable information about the molecular features that influence the retention behavior of β-lactams under the current chromatographic conditions. We can conclude that in some cases simple conventional feature selection algorithm can be used to generate robust and predictive models comparable to that are generated using advanced ones.
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http://dx.doi.org/10.1016/j.chroma.2018.03.042DOI Listing
May 2018

Design, synthesis, and molecular docking of novel indole scaffold-based VEGFR-2 inhibitors as targeted anticancer agents.

Arch Pharm (Weinheim) 2018 Feb 11;351(2). Epub 2018 Jan 11.

National Research Centre, Pharmaceutical and Drug Industries Research Division, Chemistry of Natural and Microbial Products Department, Cairo, Egypt.

A series of new indole derivatives 1-18 was synthesized and tested for their cytotoxic activity on a panel of 60 tumor cell lines. Additionally, molecular docking was carried out to study their binding pattern and binding affinity in the VEGFR-2 active site using sorafenib as a reference VEGFR-2 inhibitor. Based on the molecular docking results, compounds 5a, 5b, 6, 7, 14b, 18b, and 18c were selected to be evaluated for their VEGFR-2 inhibitory activity. Compound 18b exhibited a broad-spectrum antiproliferative activity on 47 cell lines, with GI % ranging from 31 to 82.5%. Moreover, compound 18b was the most potent VEGFR-2 inhibitor with an IC value of 0.07 μM, which is more potent than that of sorafenib (0.09 μM). A molecular docking study attributed the promising activity of this series to their hydrophobic interaction with the VEGFR-2 binding site hydrophobic side chains and their hydrogen bonding interaction with the key amino acids Glu885 and/or Asp1046.
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http://dx.doi.org/10.1002/ardp.201700299DOI Listing
February 2018

Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors.

Eur J Med Chem 2017 Aug 26;136:315-329. Epub 2017 Apr 26.

Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Dokki, Cairo, Egypt.

Inhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC = 31.16 μM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92-96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC = 0.64 μM) in comparison to sorafenib (IC = 0.1 μM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.
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http://dx.doi.org/10.1016/j.ejmech.2017.04.068DOI Listing
August 2017

Synthesis and molecular docking of new imidazoquinazolinones as analgesic agents and selective COX-2 inhibitors.

Future Med Chem 2017 04 10;9(6):553-578. Epub 2017 Apr 10.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

Aim: The discovery of new generation of selective COX-2 inhibitors with potential analgesic and anti-inflammatory activity and minimal side effects is a major interest.

Materials & Methods: Novel imidazole and imidazo[1,5-a]quinazoline derivatives were prepared and evaluated for their analgesic and anti-inflammatory activities. COX-1/COX-2 isozyme selectivity testing and molecular docking were performed. Key physicochemical parameters were calculated.

Results: All tested compounds exhibited significant activities compared with indomethacin as reference drug. Pharmacological evaluation showed that compounds 3c and 14c possess promising analgesic activity, pronouncing anti-inflammatory effect and reasonable COX-2 selectivity. Molecular docking attributed their good activity to their hydrogen bonding interaction with key amino acids in COX isozymes Arg120, Tyr355 and Ser530. Most compounds obeyed 'Lipinski's rule of five' and possess promising pharmacokinetic properties.
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http://dx.doi.org/10.4155/fmc-2016-0240DOI Listing
April 2017

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database.

Sci Rep 2017 03 10;7:44201. Epub 2017 Mar 10.

Computer Chemistry Center, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstr. 25, 91052 Erlangen, Germany.

The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a K value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.
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http://dx.doi.org/10.1038/srep44201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345022PMC
March 2017

Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives.

Eur J Med Chem 2016 May 15;113:50-62. Epub 2016 Feb 15.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt.

A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 μM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 μM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 μM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 μM).
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http://dx.doi.org/10.1016/j.ejmech.2016.02.029DOI Listing
May 2016

Economical and accurate protocol for calculating hydrogen-bond-acceptor strengths.

J Chem Inf Model 2013 Dec 11;53(12):3262-72. Epub 2013 Dec 11.

Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg , Nägelsbachstraße 25, 91052 Erlangen, Germany.

A series of density functional/basis set combinations and second-order Møller-Plesset calculations have been used to test their ability to reproduce the trends observed experimentally for the strengths of hydrogen-bond acceptors in order to identify computationally efficient techniques for routine use in the computational drug-design process. The effects of functionals, basis sets, counterpoise corrections, and constraints on the optimized geometries were tested and analyzed, and recommendations (M06-2X/cc-pVDZ and X3LYP/cc-pVDZ with single-point counterpoise corrections or X3LYP/aug-cc-pVDZ without counterpoise) were made for suitable moderately high-throughput techniques.
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http://dx.doi.org/10.1021/ci4006222DOI Listing
December 2013

Quantum mechanics-based properties for 3D-QSAR.

J Chem Inf Model 2013 Jun 5;53(6):1486-502. Epub 2013 Jun 5.

Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052 Erlangen, Germany.

We have used a set of four local properties based on semiempirical molecular orbital calculations (electron density (ρ), hydrogen bond donor field (HDF), hydrogen bond acceptor field (HAF), and molecular lipophilicity potential (MLP)) for 3D-QSAR studies to overcome the limitations of the current force field-based molecular interaction fields (MIFs). These properties can be calculated rapidly and are thus amenable to high-throughput industrial applications. Their statistical performance was compared with that of conventional 3D-QSAR approaches using nine data sets (angiotensin converting enzyme inhibitors (ACE), acetylcholinesterase inhibitors (AchE), benzodiazepine receptor ligands (BZR), cyclooxygenase-2 inhibitors (COX2), dihydrofolate reductase inhibitors (DHFR), glycogen phosphorylase b inhibitors (GPB), thermolysin inhibitors (THER), thrombin inhibitors (THR), and serine protease factor Xa inhibitors (fXa)). The 3D-QSAR models generated were tested thoroughly for robustness and predictive ability. The average performance of the quantum mechanical molecular interaction field (QM-MIF) models for the nine data sets is better than that of the conventional force field-based MIFs. In the individual data sets, the QM-MIF models always perform better than, or as well as, the conventional approaches. It is particularly encouraging that the relative performance of the QM-MIF models improves in the external validation. In addition, the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation. QM-MIF contour maps reproduce the features important for ligand binding for the example data set (factor Xa inhibitors), demonstrating the intuitive chemical interpretability of QM-MIFs.
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http://dx.doi.org/10.1021/ci400181bDOI Listing
June 2013

Directional Noncovalent Interactions: Repulsion and Dispersion.

J Chem Theory Comput 2013 May 24;9(5):2264-75. Epub 2013 Apr 24.

Computer-Chemie-Centrum, Department Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstrasse 25, 91052 Erlangen, Germany.

The interaction energies between an argon atom and the dihalogens Br2, BrCl, and BrF have been investigated using frozen core CCSD(T)(fc)/aug-cc-pVQZ calculations as reference values for other levels of theory. The potential-energy hypersurfaces show two types of minima: (1) collinear with the dihalogen bond and (2) in a bridging position. The former represent the most stable minima for these systems, and their binding energies decrease in the order Br > Cl > F. Isotropic atom-atom potentials cannot reproduce this binding pattern. Of the other levels of theory, CCSD(T)(fc)/aug-cc-pVTZ reproduces the reference data very well, as does MP2(fc)/aug-cc-pVDZ, which performs better than MP2 with the larger basis sets (aug-cc-pVQZ and aug-cc-pvTZ). B3LYP-D3 and M06-2X reproduce the binding patterns moderately well despite the former using an isotropic dispersion potential correction. B3LYP-D3(bj) performs even better. The success of the B3LYP-D3 methods is because polar flattening of the halogens allows the argon atom to approach more closely in the direction collinear with the bond, so that the sum of dispersion potential and repulsion is still negative at shorter distances than normally possible and the minimum is deeper at the van der Waals distance. Core polarization functions in the basis set and including the core orbitals in the CCSD(T)(full) calculations lead to a uniform decrease of approximately 20% in the magnitudes of the calculated interaction energies. The EXXRPA+@EXX (exact exchange random phase approximation) orbital-dependent density functional also gives interaction energies that correlate well with the highest level of theory but are approximately 10% low. The newly developed EXXRPA+@dRPA functional represents a systematic improvement on EXXRPA+@EXX.
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http://dx.doi.org/10.1021/ct400185fDOI Listing
May 2013

Predicting the sites and energies of noncovalent intermolecular interactions using local properties.

J Chem Inf Model 2012 Apr 13;52(4):1061-71. Epub 2012 Apr 13.

Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nägelsbachstraβe 25, 91052 Erlangen, Germany.

Feed-forward artificial neural nets have been used to recognize H-bond donor and acceptor sites on drug-like molecules based on local properties (electron density, molecular electrostatic potential and local ionization energy, electron affinity, and polarizability) calculated at grid points around the molecule. Interaction energies for training were obtained from B97-D and ωB97X-D/aug-cc-pVDZ density-functional theory calculations on a series of model central molecules and H-bond acceptor and donor probes constrained to the grid points used for training. The resulting models provide maps of both classical and unusual H- and halogen-bonding sites. Note that these reactions result even though only classical H-bond donors and acceptors were used as probes around the central molecules. Some examples demonstrate the ability of the models to take the electronics of the central molecule into consideration and to provide semiquantitative estimates of interaction energies at low computational cost.
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http://dx.doi.org/10.1021/ci300095xDOI Listing
April 2012

Conformation-dependent QSPR models: logPOW.

J Chem Inf Model 2011 Sep 29;51(9):2408-16. Epub 2011 Aug 29.

Computer-Chemie-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Quantitative structure-property relationships for predicting the water-octanol partition coefficient, logP(OW), are reported. The models are based on local properties calculated at the standard isodensity surface using semiempirical molecular orbital theory and use descriptors obtained as the areas of the surface found in each bin in a predefined binning scheme. The effect of conformation is taken into account but was found to have little effect on the predictive power of the models. A detailed error analysis suggests that the accuracy of the models is limited by that of the experimental data and that the best possible performance is approximately ±0.5 log units. The models yield a local hydrophobicity function at the surface of the molecules.
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http://dx.doi.org/10.1021/ci200276vDOI Listing
September 2011

Synthesis and anticonvulsant activity of certain substituted furochromone, benzofuran and flavone derivatives.

Chem Pharm Bull (Tokyo) 2010 Sep;58(9):1148-56

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

Synthesis of furochromone, 2-phenylchromone (flavone) and benzofuran derivatives substituted with thiosemicarbazide or thiazolidin-4-one moieties were accomplished. All the newly synthesized compounds were tested for their anticonvulsant activity in both subcutaneous pentylenetetrazole induced seizures (scPTZ) and maximal electric shock induced seizures (MES) tests using valproic acid and phenytoin respectively as reference standards. The most active compounds in scPTZ model were 1c, 2b, 5a and 7e showing 100% protection at 300 mg/kg upon intraperitoneal administration. Also, the effect of pre-treatment of three of the most active compounds (1c, 2b, 5a) on 4-amino pyridine-induced lethality in mice was investigated. Pre-treatment with these compounds significantly increased the latency for clonic and tonic seizures and prevented 4-amino pyridine induced death. Hence, this provides evidence for anticonvulsant activity of these compounds, and a neuroprotective activity for them. The structure-activity relationship was studied based on the obtained data.
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http://dx.doi.org/10.1248/cpb.58.1148DOI Listing
September 2010