21 results on '"Mohammed K. Abdel-Hamid"'
Search Results
2. Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo
- Author
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Alireza Shakoori, John B. Bremner, Mohammed K. Abdel-Hamid, Anthony C. Willis, Rachada Haritakun, and Paul A. Keller
- Subjects
allylation ,cascade reactions ,indigo ,nitrogen heterocycles ,rearrangement ,Science ,Organic chemistry ,QD241-441 - Abstract
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
- Published
- 2015
- Full Text
- View/download PDF
3. In Silico Docking, Molecular Dynamics and Binding Energy Insights into the Bolinaquinone-Clathrin Terminal Domain Binding Site
- Author
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Mohammed K. Abdel-Hamid and Adam McCluskey
- Subjects
bolinaquinone ,clathrin terminal domain ,flexible docking ,linear interaction energy ,Organic chemistry ,QD241-441 - Abstract
Clathrin-mediated endocytosis (CME) is a process that regulates selective internalization of important cellular cargo using clathrin-coated vesicles. Perturbation of this process has been linked to many diseases including cancer and neurodegenerative conditions. Chemical proteomics identified the marine metabolite, 2-hydroxy-5-methoxy-3-(((1S,4aS,8aS)-1,4a,5-trimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-2-yl)methyl)cyclohexa- 2,5-diene-1,4-dione (bolinaquinone) as a clathrin inhibitor. While being an attractive medicinal chemistry target, the lack of data about bolinaquinone’s mode of binding to the clathrin enzyme represents a major limitation for its structural optimization. We have used a molecular modeling approach to rationalize the observed activity of bolinaquinone and to predict its mode of binding with the clathrin terminal domain (CTD). The applied protocol started by global rigid-protein docking followed by flexible docking, molecular dynamics and linear interaction energy calculations. The results revealed the potential of bolinaquinone to interact with various pockets within the CTD, including the clathrin-box binding site. The results also highlight the importance of electrostatic contacts over van der Waals interactions for proper binding between bolinaquinone and its possible binding sites. This study provides a novel model that has the potential to allow rapid elaboration of bolinaquinone analogues as a new class of clathrin inhibitors.
- Published
- 2014
- Full Text
- View/download PDF
4. Schiff Bases of Indoline-2,3-dione: Potential Novel Inhibitors of Mycobacterium Tuberculosis (Mtb) DNA Gyrase
- Author
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Jane Thanassi, Michael J. Pucci, Tarek Aboul-Fadl, Hatem A. Abdel-Aziz, Tilal Elsaman, and Mohammed K. Abdel-Hamid
- Subjects
Schiff bases ,Indoline-2,3-dione ,microwave irradiation ,Mycobacterium tuberculosis (Mtb) ,Mtb DNA gyrase ,MOE ,Organic chemistry ,QD241-441 - Abstract
In the present study a series of Schiff bases of indoline-2,3-dione were synthesized and investigated for their Mtb gyrase inhibitory activity. Promising inhibitory activity was demonstrated with some of these derivatives, which exhibited IC50 values ranging from 50–157 mM. The orientation and the ligand-receptor interactions of such molecules within the Mtb DNA gyrase A subunit active site were investigated applying a multi-step docking protocol using Molecular Operating Environment (MOE) and Autodock4 docking software. The results revealed the importance of the isatin moiety and the connecting side chain for strong interactions with the enzyme active site. Among the tested compounds the terminal aromatic ring benzofuran showed the best activity. Promising new leads for developing a novel class of Mtb gyrase inhibitors were obtained from Schiff bases of indoline-2,3-dione.
- Published
- 2011
- Full Text
- View/download PDF
5. Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations
- Author
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Hassab, Mahmoud A. El, primary, Fares, Mohamed, additional, Amin, Mohammed K. Abdel-Hamid, additional, Al-Rashood, Sara T., additional, Alharbi, Amal, additional, Eskandrani, Razan O., additional, Alkahtani, Hamad M., additional, and Eldehna, Wagdy M., additional
- Published
- 2021
- Full Text
- View/download PDF
6. Toward the identification of potential _-ketoamide covalent inhibitors for sars-cov-2 main protease: Fragment-based drug design and mm-pbsa calculations
- Author
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Mahmoud A. El Hassab, Mohamed Fares, Mohammed K. Abdel-Hamid Amin, Sara T. Al-Rashood, Amal Alharbi, Razan O. Eskandrani, Hamad M. Alkahtani, and Wagdy M. Eldehna
- Subjects
Drug ,media_common.quotation_subject ,medicine.medical_treatment ,Bioengineering ,Computational biology ,TP1-1185 ,01 natural sciences ,03 medical and health sciences ,Viral life cycle ,medicine ,Chemical Engineering (miscellaneous) ,QD1-999 ,030304 developmental biology ,media_common ,chemistry.chemical_classification ,0303 health sciences ,Protease ,biology ,SARS-CoV-2 main protease inhibitor ,Process Chemistry and Technology ,Chemical technology ,Active site ,COVID-19 ,molecular docking ,molecular dynamics ,0104 chemical sciences ,Coronavirus ,010404 medicinal & biomolecular chemistry ,Chemistry ,Enzyme ,chemistry ,Docking (molecular) ,Covalent bond ,biology.protein ,structure-based drug design ,Linker ,COVID-19 treatment - Abstract
Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.
- Published
- 2021
7. Small-Molecule Inhibitors of the NusB–NusE Protein–Protein Interaction with Antibiotic Activity
- Author
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Mohammed K. Abdel-Hamid, Christopher P. Gordon, Trieu N. Trinh, Peter J. Lewis, Jennette A. Sakoff, Adam McCluskey, Peter J. Cossar, and Cong Ma
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biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,General Chemical Engineering ,General Chemistry ,Bacillus subtilis ,010402 general chemistry ,medicine.disease_cause ,biology.organism_classification ,01 natural sciences ,Small molecule ,Article ,In vitro ,0104 chemical sciences ,Protein–protein interaction ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QD1-999 ,Biochemistry ,Antitermination ,medicine ,Pharmacophore ,Growth inhibition ,Escherichia coli - Abstract
The NusB–NusE protein–protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified N,N′-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(N-ethyl)urea 1 as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated 1 as a 20 μM potent inhibitor of NusB–NusE. Four focused compound libraries based on 1, comprising 34 compounds in total were designed, synthesized, and evaluated as NusB–NusE PPI inhibitors. Ten analogues displayed NusB–NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative Escherichia coli and Gram-positive Bacillus subtilis species, these analogues showed up to 100% growth inhibition at 200 μM. 2-((Z)-4-(((Z)-4-(4-((E)-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide 22 showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus and ≤51 μg/mL for Gram-negative Pseudomonas aeruginosa and Acinetobacter baumannii, 22 is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with 22, inhibiting the NusB–NusE PPI as proposed.
- Published
- 2017
8. Quinolone-1-(2H)-ones as hedgehog signalling pathway inhibitors
- Author
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Jennette A. Sakoff, Eileen A. McLaughlin, Christopher P. Gordon, V. Pye, Peter J. Cossar, Mohammed K. Abdel-Hamid, Ilana R. Bernstein, Adam McCluskey, and Trieu N. Trinh
- Subjects
0301 basic medicine ,Stereochemistry ,Antineoplastic Agents ,Quinolones ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Line, Tumor ,Humans ,Moiety ,Hedgehog Proteins ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell Proliferation ,Indole test ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Hedgehog signaling pathway ,030104 developmental biology ,chemistry ,Cell culture ,Drug Screening Assays, Antitumor ,Pharmacophore ,Acetamide ,Signal Transduction - Abstract
A series of quinolone-2-(1H)-ones derived from the Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line. A focused SAR study was conducted and revealed core characteristics of the quinolone-2-(1H)-ones required for cytotoxicity. These requirements included a C3-tethered indole moiety, an indole C5-methyl moiety, an aliphatic tail or an ester, as well as an additional aromatic moiety. Further investigation in the SAG-activated Shh-LIGHT2 cell line with the most active analogues: 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(1-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (5), 2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)-N-(pentan-2-yl)acetamide (23) and ethyl (2-(3-cyano-2-oxo-4-phenylquinolin-1(2H)-yl)-2-(5-methyl-1H-indol-3-yl)acetyl)glycinate (24) demonstrated a down regulation of the HSP via a reduction in Gli expression, and in the mRNA levels of Ptch1 and Gli2. Analogues 5, 23 and 24 returned in cell inhibition values of 11.6, 2.9 and 3.1 μM, respectively, making this new HSP-inhibitor pharmacophore amongst the most potent non-Smo targeted inhibitors thus far reported.
- Published
- 2016
9. Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo
- Author
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John B. Bremner, Mohammed K. Abdel-Hamid, Rachada Haritakun, Paul A. Keller, Alireza Shakoori, and Anthony C. Willis
- Subjects
Olefin fiber ,Allylic rearrangement ,Chemistry ,Stereochemistry ,rearrangement ,Organic Chemistry ,cascade reactions ,Metathesis ,Full Research Paper ,Indigo ,lcsh:QD241-441 ,Claisen rearrangement ,lcsh:Organic chemistry ,Yield (chemistry) ,Rapid access ,lcsh:Q ,indigo ,nitrogen heterocycles ,lcsh:Science ,allylation - Abstract
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
- Published
- 2015
10. Phenothiazine-Derived Antipsychotic Drugs Inhibit Dynamin and Clathrin-Mediated Endocytosis
- Author
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Shannon R. Joseph, James A. Daniel, Phillip J. Robinson, Peter Maamary, Adam McCluskey, Sai Krishnan, Lingbo Hu, Lisa von Kleist, Ainslie Whiting, Volker Haucke, Ngoc Chau, Fiona Simpson, and Mohammed K. Abdel-Hamid
- Subjects
biology ,Cell Biology ,Trifluoperazine ,Receptor-mediated endocytosis ,Pharmacology ,Endocytosis ,Biochemistry ,Clathrin ,Dynamin II ,Cell biology ,Structural Biology ,Amphiphysin ,cardiovascular system ,Genetics ,biology.protein ,medicine ,Chlorpromazine ,Molecular Biology ,Dynamin ,medicine.drug - Abstract
Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2-12 µm range, the most potent being trifluoperazine (IC50 2.6 ± 0.7 µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.
- Published
- 2015
11. 1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity
- Author
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Anna Mariana, Ngoc Chau, Ainslie Whiting, Kylie A. MacGregor, Phillip J. Robinson, Luke R. Odell, Adam McCluskey, and Mohammed K. Abdel-Hamid
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Models, Molecular ,GTP' ,Stereochemistry ,In silico ,Phosphatidylserines ,GTPase ,Endocytosis ,Biochemistry ,Protein Structure, Secondary ,Protein structure ,Cell Line, Tumor ,Humans ,Amines ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,Binding site ,IC50 ,Dynamin I ,Dynamin ,Binding Sites ,Chemistry ,Organic Chemistry ,Clathrin ,Naphthalimides ,Guanosine Triphosphate - Abstract
Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.
- Published
- 2015
12. Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug
- Author
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Rudraraju Srilakshmi Reshma, Bahaa G.M. Youssif, Perumal Yogeeswari, Mohammed K. Abdel-Hamid, Mostafa H. Abdelrahman, Hajjaj H.M. Abdu-Allah, Tarek Aboul-Fadl, and Dharmarajan Sriram
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0301 basic medicine ,Drug ,Stereochemistry ,media_common.quotation_subject ,Triazole ,Antitubercular Agents ,Quantitative Structure-Activity Relationship ,Microbial Sensitivity Tests ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Isoniazid ,Humans ,Cytotoxicity ,Ethambutol ,media_common ,010405 organic chemistry ,Isatin ,Organic Chemistry ,Hydrazones ,Mycobacterium tuberculosis ,Triazoles ,Aminosalicylic Acid ,0104 chemical sciences ,030104 developmental biology ,HEK293 Cells ,chemistry ,Drug Design ,Molecular Medicine ,Rifampin ,Selectivity ,Rifampicin ,medicine.drug - Abstract
The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39–1.5 μg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 µg/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development.
- Published
- 2016
13. Synthesis, molecular modeling and anti-inflammatory screening of new 1,2,3-benzotriazinone derivatives
- Author
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Said A. El-Feky, Zakaria K. Abdel-Samii, Adel A. Rashad, Mohammed K. Abdel-Hamid, Waleed Barakat, and Tarek S. Ibrahim
- Subjects
Molecular model ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Pharmacology toxicology ,Binding pocket ,Oxadiazole ,Combinatorial chemistry ,Anti-inflammatory ,chemistry.chemical_compound ,chemistry ,Docking (molecular) ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Binding site ,Selectivity - Abstract
Several new 4(3H)-1,2,3-benzotriazinone derivatives were synthesized and tested for their anti-inflammatory activity and ulcerogenic effect. A docking study on the COX-2 binding pocket has been carried out for the target compounds to rationalize the possible selectivity. Among the tested compounds, the benzotriazinones linked to either thiadiazole (8) or oxadiazole (9) evoked the highest anti-inflammatory activity as well as the best binding profiles into the COX-2 binding site.
- Published
- 2012
14. Novel spiro and fused heterocycles from the allylation of indigo
- Author
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Allan H. White, John B. Bremner, Brian W. Skelton, Paul A. Keller, Jonathan Coates, Yasmine S. Torkamani, Mohammed K. Abdel-Hamid, Anthony C. Willis, and Celia Miländer
- Subjects
chemistry.chemical_classification ,Chemical structure ,Organic Chemistry ,One-pot synthesis ,Biochemistry ,Combinatorial chemistry ,Indigo ,chemistry.chemical_compound ,Cascade reaction ,chemistry ,Indigo carmine ,Heterocyclic compound ,Microwave heating ,Drug Discovery ,Microwave irradiation ,Organic chemistry - Abstract
The allylation of indigo results in the one-step synthesis of two unique complex heterocyclic systems: a spiroindoline–pyridoindolone arising from the addition of three allyl moieties and a fused pyridoindolo-azepinoindolone generated from the addition and subsequent cyclisation of two allyl moieties. The structures of these novel heterocycles are assigned unambiguously using extensive NMR experiments and by X-ray crystallographic analysis. The distribution of the products is influenced by the use of thermal versus microwave heating.
- Published
- 2009
15. ChemInform Abstract: Further Exploration of the Heterocyclic Diversity Accessible from the Allylation Chemistry of Indigo
- Author
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John B. Bremner, Mohammed K. Abdel-Hamid, Anthony C. Willis, Paul A. Keller, Rachada Haritakun, and Alireza Shakoori
- Subjects
Claisen rearrangement ,Olefin fiber ,Allylic rearrangement ,Chemistry ,Stereochemistry ,Yield (chemistry) ,Rapid access ,General Medicine ,Metathesis ,Indigo - Abstract
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
- Published
- 2015
16. Phenothiazine-derived antipsychotic drugs inhibit dynamin and clathrin-mediated endocytosis
- Author
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James A, Daniel, Ngoc, Chau, Mohammed K, Abdel-Hamid, Lingbo, Hu, Lisa, von Kleist, Ainslie, Whiting, Sai, Krishnan, Peter, Maamary, Shannon R, Joseph, Fiona, Simpson, Volker, Haucke, Adam, McCluskey, and Phillip J, Robinson
- Subjects
Dynamins ,Phenothiazines ,Cell Line, Tumor ,Transferrin ,Humans ,Clathrin-Coated Vesicles ,Clathrin ,Endocytosis ,Antipsychotic Agents - Abstract
Chlorpromazine is a phenothiazine-derived antipsychotic drug (APD) that inhibits clathrin-mediated endocytosis (CME) in cells by an unknown mechanism. We examined whether its action and that of other APDs might be mediated by the GTPase activity of dynamin. Eight of eight phenothiazine-derived APDs inhibited dynamin I (dynI) in the 2-12 µm range, the most potent being trifluoperazine (IC50 2.6 ± 0.7 µm). They also inhibited dynamin II (dynII) at similar concentrations. Typical and atypical APDs not based on the phenothiazine scaffold were 8- to 10-fold less potent (haloperidol and clozapine) or were inactive (droperidol, olanzapine and risperidone). Kinetic analysis showed that phenothiazine-derived APDs were lipid competitive, while haloperidol was uncompetitive with lipid. Accordingly, phenothiazine-derived APDs inhibited dynI GTPase activity stimulated by lipids but not by various SH3 domains. All dynamin-active APDs also inhibited transferrin (Tfn) CME in cells at related potencies. Structure-activity relationships (SAR) revealed dynamin inhibition to be conferred by a substituent group containing a terminal tertiary amino group at the N2 position. Chlorpromazine was previously proposed to target AP-2 recruitment in the formation of clathrin-coated vesicles (CCV). However, neither chlorpromazine nor thioridazine affected AP-2 interaction with amphiphysin or clathrin. Super-resolution microscopy revealed that chlorpromazine blocks neither clathrin recruitment by AP-2, nor AP-2 recruitment, showing that CME inhibition occurs downstream of CCV formation. Overall, potent dynamin inhibition is a shared characteristic of phenothiazine-derived APDs, but not other typical or atypical APDs, and the data indicate that dynamin is their likely in-cell target in endocytosis.
- Published
- 2014
17. Development of quinone analogues as dynamin GTPase inhibitors
- Author
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Mohammed K. Abdel-Hamid, Adam McCluskey, Ainslie Whiting, Kylie A. MacGregor, Ngoc Chau, Phillip J. Robinson, and Luke R. Odell
- Subjects
GTP' ,Stereochemistry ,Protein Conformation ,Drug Evaluation, Preclinical ,GTPase ,Endocytosis ,Cell Line ,GTP Phosphohydrolases ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,Binding site ,Enzyme Inhibitors ,Dynamin I ,Dynamin ,Pharmacology ,Chemistry ,Organic Chemistry ,Quinones ,General Medicine ,Benzoquinone ,Naphthoquinone ,Clathrin ,Quinone ,Molecular Docking Simulation - Abstract
Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.
- Published
- 2014
18. Contributors
- Author
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Mohammed K. Abdel-Hamid, Ashraf M. Abdel-Megeed, Marudai Balasubramanian, Daniel L. Comins, William R. Dolbier, Nilmi Fernando, Liangfeng Fu, Gordon W. Gribble, Paul A. Keller, Qi-Xian Lin, R. Murugan, Shirish Paranjpe, Eric F.V. Scriven, Lucjan Strekowski, Sergey Tsukanov, Paul Watts, and Charlotte Wiles
- Published
- 2013
19. Ring Synthesis
- Author
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Mohammed K. Abdel-Hamid, Ashraf M. Abdel-Megeed, and Paul A. Keller
- Subjects
Chemistry ,Stereochemistry ,Ring (chemistry) - Published
- 2013
20. 3,5-disubstituted thiadiazine-2-thiones: new cell-cycle inhibitors
- Author
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Tarek Aboul-Fadl, Mohammed K. Abdel-Hamid, Awwad A. Radwan, Abdullah A. Al-Badr, and Abdullah Al-Dhfyan
- Subjects
Models, Molecular ,Molecular model ,Thiadiazines ,Chemistry ,Stereochemistry ,Organic Chemistry ,Cell Cycle ,Biological activity ,Epithelial Cells ,Cell Cycle Checkpoints ,Cell cycle ,Combinatorial chemistry ,In vitro ,Cell Line, Tumor ,Drug Discovery ,Cancer cell ,Lipophilicity ,Molecular Medicine ,Moiety ,Humans ,Pharmacophore - Abstract
Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC(50) = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.
- Published
- 2011
21. Design, synthesis, and docking studies of new 1,3,4-thiadiazole-2-thione derivatives with carbonic anhydrase inhibitory activity
- Author
-
Nawal A. El-Koussi, Atef A. Abdel-Hafez, Claudiu T. Supuran, Nadia M. Mahfouz, Alessio Innocenti, and Mohammed K. Abdel-Hamid
- Subjects
Models, Molecular ,Carbonic Anhydrase I ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Chemical synthesis ,Carbonic Anhydrase II ,chemistry.chemical_compound ,Structure-Activity Relationship ,Carbonic Anhydrase IV ,Carbonic anhydrase ,Drug Discovery ,Thiadiazoles ,Humans ,Carbonic Anhydrase Inhibitors ,Molecular Biology ,Semicarbazone ,chemistry.chemical_classification ,Semicarbazide ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Active site ,Thiones ,Protein Structure, Tertiary ,Enzyme ,Docking (molecular) ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine - Abstract
A new series of 1,3,4-thiadiazole-2-thione derivatives have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiones, showed inhibition constants in the range of 2.55-222 microM, against hCA II in the range of 2.0-433 microM, and against hCA IX in the range of 1.25-148 microM. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the tumor-associated hCA IX with K(I) value of 1.25 microM, being the first non-sulfonamide type inhibitor of such activity. This result is rather important taking into consideration the known antitumor activity of thiones. In addition, docking of the tested compounds into CA II active site was performed in order to predict the affinity and orientation of these compounds at the isozyme active site. The results showed similar orientation of the target compounds at CA II active site compared with reported sulfonamide type CAIs with the thione group acting as a zinc-binding moiety.
- Published
- 2007
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