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A
Abd El-Karim, S. S., Y. M. Syam, A. M. El Kerdawy, and T. M. Abdelghany, New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies, , vol. 86, pp. 80 - 96, 2019. AbstractWebsite

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 IC50 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.

Abdel-Mohsen, H. T., M. A. Abdullaziz, A. M. El Kerdawy, F. A. F. Ragab, K. J. Flanagan, A. E. E. Mahmoud, M. M. Ali, H. I. El Diwani, and M. O. Senge, "Targeting Receptor Tyrosine Kinase VEGFR-2 in Hepatocellular Cancer: Rational Design, Synthesis and Biological Evaluation of 1,2-Disubstituted Benzimidazoles", Molecules, vol. 25, no. 4, 2020. AbstractWebsite

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

Abdel-Mohsen, H. T., E. A. Abd El-Meguid, A. M. El Kerdawy, A. E. E. Mahmoud, and M. M. Ali, "Design, synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer", Archiv der PharmazieArchiv der Pharmazie, vol. 353, issue 4: John Wiley & Sons, Ltd, pp. 1900340, 2020. AbstractWebsite

Abstract A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-? 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 IC50 values of 0.19, 0.18, 0.17, and 0.13??M, respectively, against VEGFR-2; IC50 values of 0.28, 0.37, 0.19, and 0.27??M, respectively, against FGFR-1; and IC50 values of 0.07, 0.04, 0.08, and 0.14??M, respectively, against PDGFR-?. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC50 values of 7.83 and 6.58??M, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC50?=?4.33??M. 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.

Abdel-Mohsen, H. T., A. M. El Kerdawy, M. A. Omar, E. Berrino, A. S. Abdelsamie, H. I. El Diwani, and C. T. Supuran, New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis, in vitro biological evaluation, and molecular docking studies, , vol. 28, issue 5, pp. 115329, 2020. AbstractWebsite

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 Ki 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 Zn2+ 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.

Abdel-Mohsen, H. T., M. A. Omar, A. M. El Kerdawy, A. E. E. Mahmoud, M. M. Ali, and H. I. El Diwani, "Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors", European Journal of Medicinal Chemistry, vol. 179, pp. 707 - 722, 2019. AbstractWebsite

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 IC50 = 0.17, 0.12, 0.17 and 0.19 μM, respectively against VEGFR-2 in comparison to sorafenib (I) IC50 = 0.10 μM and regorafenib (II) IC50 = 0.005 μM. While compounds 9c, 9d and 10a showed IC50 = 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 (IC50 = 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 (IC50 = 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%).

Abdullaziz, M. A., H. T. Abdel-Mohsen, A. M. El Kerdawy, F. A. F. Ragab, M. M. Ali, S. M. Abu-bakr, A. S. Girgis, and H. I. El Diwani, "Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors", Eur. J. Med. Chem., vol. 136, pp. 315 - 329, 2017/8/18/. AbstractWebsite

AbstractInhibition 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 (IC50 = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC50 = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 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 (IC50 = 0.64 μM) in comparison to sorafenib (IC50 = 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.

Al-Sanea, M. M., A. Elkamhawy, S. Paik, K. Lee, A. M. El Kerdawy, B. Syed Nasir Abbas, E. Joo Roh, W. M. Eldehna, H. A. H. Elshemy, R. B. Bakr, et al., Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights, , vol. 28, issue 13, pp. 115525, 2020. AbstractWebsite

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 IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 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 SO2 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.

Al-Warhi, T., A. M. El Kerdawy, N. Aljaeed, O. E. Ismael, R. R. Ayyad, W. M. Eldehna, H. A. Abdel-Aziz, and G. H. Al-Ansary, "Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors", Molecules, vol. 25, no. 9, 2020. AbstractWebsite

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 (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f 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 (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s 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 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

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El Kerdawy, A., S. Güssregen, H. Matter, M. Hennemann, and T. Clark, "Quantum Mechanics-based Properties for 3D-QSAR.", J. Chem. Inf. Model., vol. 53, pp. 1486-1502, 2013.
El Kerdawy, A. M., A. A. Osman, and M. A. Zaater, Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors, , vol. 25, issue 6, pp. 171, 2019. AbstractWebsite

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.

El Kerdawy, A., J. S. Murray, P. Politzer, P. Bleiziffer, A. Heßelmann, A. Görling, and T. Clark, "Directional Non-covalent Interactions: Repulsion and Dispersion. ", J. Chem. Theory. Comput., vol. 9, pp. 2264-2275, 2013.
El Kerdawy, A., S. Güssregen, H. Matter, M. Hennemann, and T. Clark, "Quantum-mechanics-based molecular interaction fields for 3D-QSAR", J. Cheminf., vol. 6(Suppl 1), pp. O10, 2014.
El Kerdawy, A., C. R. Wick, M. Hennemann, and T. Clark, "Predicting the Sites and Energies of Non-covalent Intermolecular Interactions Using Local Properties.", J. Chem. Inf. Model., vol. 52, issue 4, pp. 1061-1071, 2012.
El Kerdawy, A., C. S. Tautermann, T. Clark, and T. Fox, "Economical and Accurate Protocol for Calculating Hydrogen-Bond-Acceptor Strengths", J. Chem. Inf. Model., vol. 53, pp. 3262-3272, 2013.
Eldehna, W. M., S. T. Al-Rashood, T. Al-Warhi, R. O. Eskandrani, A. Alharbi, and A. M. El Kerdawy, "Novel oxindole/benzofuran hybrids as potential dual CDK2/GSK-3β inhibitors targeting breast cancer: design, synthesis, biological evaluation, and in silico studies", Journal of Enzyme Inhibition and Medicinal ChemistryJournal of Enzyme Inhibition and Medicinal Chemistry, vol. 36, issue 1: Taylor & Francis, pp. 271 - 286, 2021. AbstractWebsite
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Eldehna, W. M., S. M. Abou-Seri, A. M. El Kerdawy, R. R. Ayyad, A. M. Hamdy, H. A. Ghabbour, M. M. Ali, and D. A. Abou El Ella, "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.", European journal of medicinal chemistry, vol. 113, pp. 50-62, 2016 May 4. Abstract

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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Fouad, M. A., E. H. Tolba, M. A. El-Shal, and A. M. El Kerdawy, "QSRR modeling for the chromatographic retention behavior of some β-lactam antibiotics using forward and firefly variable selection algorithms coupled with multiple linear regression", Journal of Chromatography A, vol. 1549, pp. 51-62, 2018. AbstractWebsite

AbstractThe 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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Ghannam, I. A. Y., E. A. Abd El-Meguid, I. H. Ali, D. H. Sheir, and A. M. El Kerdawy, Novel 2-arylbenzothiazole DNA gyrase inhibitors: Synthesis, antimicrobial evaluation, QSAR and molecular docking studies, , vol. 93, pp. 103373, 2019. AbstractWebsite

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 IC50 values below 10 µM, however, they were less active than ciprofloxacin (E. coli gyrase IC50 = 1.14 µM). The p-hydroxy-m-methoxy benzothiazole analogue 6c was the most active tested compound (E. coli gyrase IC50 = 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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Halawa, A. H., M. A. H. M. O. U. D. M. ELAASSER, A. M. El Kerdawy, A. M. A. I. Abd El-Hady, H. A. Emam, and A. M. El-Agrody, "Anticancer activities, molecular docking and structure–activity relationship of novel synthesized 4H-chromene, and 5H-chromeno[2,3-d]pyrimidine candidates", Medicinal Chemistry Research, vol. 26, no. 10, pp. 2624–2638, Oct, 2017. AbstractWebsite

In the present study, a series of 4H-chromene and 5H-chromeno[2,3-d]pyrimidine derivatives was synthesized and evaluated as potential cytotoxic agents. The cytotoxic activities of the target compounds were evaluated against four cancer cell lines MCF-7, HCT-116, HepG-2, and A549 in comparison with vinblastine and colchicine as reference drugs. We explored the structure–activity relationship of 4H-chromenes with modification at the 2-,4- or 7-position, and fused pyrimidine ring at 2,3-position. Most of the screened compounds showed marginal antitumor activity against the different cell lines in comparison to the standard drugs. The structure–activity relationship study revealed that the antitumor activity of the synthesized compounds was significantly affected by the lipophilicity of the substituent at the 2-,4- or 7-position for the 4H-chromenes, and 5,8-position or fused pyrimidine ring at 2,3-positions for 5H-chromeno[2,3-d]pyrimidines. Structure–activity relationship was elaborated with the help of molecular docking studies. The structures of the synthesized compounds were established on the basis of the spectral data, infrared, proton nuclear magnetic resonance, 13-Carbon nuclear magnetic resonance and mass spectroscopic data.

Hassan, R. M., M. E. Aboutabl, M. Bozzi, M. F. El-Behairy, A. M. El Kerdawy, B. Sampaolese, C. Desiderio, F. Vincenzoni, F. Sciandra, and I. A. Y. Ghannam, Discovery of 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids as novel PPARα agonists with anti-hyperlipidemic and antioxidant activities: Design, synthesis and in vitro/in vivo biological evaluation, , vol. 115, pp. 105170, 2021. AbstractWebsite

In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPARα agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPARα agonistic activity showing Emax% values of 50.80 and 90.55%, respectively, and EC50 values of 8.9 and 25.0 μM, respectively, compared to fenofibric acid with Emax = 100% and EC50 = 23.22 μM, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPARα protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPARα active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg).

Hassanein, H. H., H. H. Georgey, M. A. Fouad, A. M. El Kerdawy, and M. F. Said, "Synthesis and molecular docking of new imidazoquinazolinones as analgesic agents and selective COX-2 inhibitors", Future Med. Chem., 2017.
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Ibrahim, H., A. M. El Kerdawy, A. Abdo, and A. Sharaf Eldin, Similarity-based machine learning framework for predicting safety signals of adverse drug–drug interactions, , vol. 26, pp. 100699, 2021. AbstractWebsite

Drug–drug interaction (DDI) is a major public health problem contributing to 30% of the unexpected clinical adverse drug events. Informatics-based studies for DDI signal detection have been evolving in the last decade. We aim at providing a boosted machine learning (ML) framework to predict novel DDI safety signals with high precision. We propose a similarity-based machine learning framework called “SMDIP” using DrugBank as one of the most reliable pharmaceutical knowledge bases. For this study, DrugBank provides the latest drug information in terms of DDIs, targets, enzymes, transporters, and carriers. We computed drug–drug similarities using a Russell–Rao measure for the available biological and structural information on DrugBank for representing the sparse feature space. Logistic regression is adopted to conduct DDI classification with a focus on searching for key similarity predictors. Six types of ML models are deployed on the selected DDI key features. Our study reveals that SMDIP has yielded favourable predictive performance compared to relevant studies with results as follows: AUC 76%, precision 82%, accuracy 79%, recall 62%, specificity 90%, and F-measure 78%. To further confirm the reliability and reproducibility of SMDIP, we investigate SMDIP on an unseen subset of direct-acting-antiviral (DAA) drugs for treating hepatitis C infections. Forty novel DAA DDIs are predicted that show consistency with the pharmacokinetic and pharmacodynamic profiles of these drugs. Furthermore, several reports from the pharmacovigilance literature corroborate our framework results. Those evaluations show that SMDIP is a promising framework for uncovering DDIs, which can be multifariously feasible in drug development, postmarketing surveillance, and public health fields.

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Muehlbacher, M., A. El Kerdawy, C. Kramer, B. Hudson, and T. Clark, "Conformation-Dependent QSPR Models: logP(OW).", J. Chem. Inf. Model., vol. 51, issue 9, pp. 2408-2416, 2011.
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Ragab, F. A., N. A. El-Sayed, A. A. Eissa, and A. M. El Kerdawy, "Synthesis and anticonvulsant activity of certain substituted furochromones, benzofuran and flavone derivatives.", Chem. Pharm. Bull., vol. 58, issue 9, pp. 1148-1156, 2010. 2010_master_paper.pdf
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