Abd-Allah, W. H., E. E. A. Osman, M. A. - E. - M. Anwar, H. N. Attia, and S. M. El Moghazy, Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants, , vol. 98, pp. 103738, 2020. AbstractWebsite

A series of coumarin derivatives 6–8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p < 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.

Youssif, B. G. M., A. M. Mohamed, E. E. A. Osman, O. F. Abou-Ghadir, D. H. Elnaggar, M. H. Abdelrahman, L. Treamblu, and H. A. M. Gomaa, 5-Chlorobenzofuran-2-carboxamides: From allosteric CB1 modulators to potential apoptotic antitumor agents, , vol. 177, pp. 1 - 11, 2019. AbstractWebsite

Cannabinoids as THC and the CB1 allosteric modulator CBD were reported to have antiproliferative activities with no reports for other CB1 allosteric modulators as the 5-chloroindole-2-carboxamide derivatives and their furan congeners. Based on the antiproliferative activity of two 5-chlorobenzofuran-2-carboxamide allosteric CB1 modulators, a series of novel derivatives was designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Some derivatives showed good antiproliferative activities against tumor cells as compounds 8, 15, 21 and 22. The most active compound 15 showed equipotent activity to doxorubicin. Compounds 7, 9, 15, 16, 21 and 22 increased the level of active caspase 3 by 4–8 folds, compared to the control cells in MCF-7 cell line and doxorubicin as a reference drug. Compounds 15 and 21, the most activecaspase-3 inducers, increase the levels of caspase 8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of Cytochrome C levels in MCF-7 cell lines. Compound 15 exhibited cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of MCF-7 cell line. The drug Likeness profile of the synthesized compounds showed that all the compounds were predicted to have high oral absorption complying with different pharmacokinetics filters.

Hisham, M., B. G. M. Youssif, E. E. A. Osman, A. M. Hayallah, and M. A. El-Aziz, Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents, , vol. 176, pp. 117 - 128, 2019. AbstractWebsite

A series of novel xanthine/NO donor hybrids containing 1,3,8-trisubstituted or 1,8-disubstituted xanthine derivatives were designed and synthesized. The synthesized compounds were tested in a cell viability assay using human mammary gland epithelial cell line (MCF-10A) where all the compounds exhibited no cytotoxic effects and more than 90% cell viability at a concentration of 50 μM. The oxime containing compounds 7a-b and 17-24 were more active as antiproliferative agents than their non-oxime congeners 6a-b and 9-16. Hydroxyimino-phenethyl scaffold compounds 17-24 were more active than the hydroxyimino-ethyl phenyl acetamide 7a-b derivatives. Compounds 18–20 and 22-24 exhibited inhibition of EGFR with IC50 ranging from 0.32 to 2.88 μM. Compounds 18-20 and 22-24 increased the level of active caspase 3 by 4–8 folds, compared to the control cells in Panc-1 cell lines compared to doxorubicin as a reference drug. Compounds 18, 22 and 23 were the most caspase-3 inducers. Compounds 22 and 23 increased the levels of caspase-8 and 9 indicating activation of both intrinsic and extrinsic pathways and showed potent induction of Bax, down-regulation of Bcl-2 protein levels and over-expression of cytochrome c levels in Panc-1 human pancreas cancer cells. Compound 23 exhibited mainly cell cycle arrest at the Pre-G1 and G2/M phases in the cell cycle analysis of Panc-1 cell line. The drug likeness profiles of compounds 18-20 and 22-24 were predicted to have good to excellent drug likeness profiles specially compounds 18-20 and 23. Finally molecular docking study was performed at the EGFR active site to suggest thier possible binding mode. The hydroxyimino-phenethyl scaffold compounds 17-24 represent an interesting starting point to optimize their pharmacokinetics and pharmacodynamics profiles.

Moussa, S. A., E. E. A. Osman, N. M. Eid, S. M. Abou-Seri, and S. M. El Moghazy, "Design and synthesis of novel 5-(4-chlorophenyl)furan derivatives with inhibitory activity on tubulin polymerization.", Future medicinal chemistry, vol. 10, issue 16, pp. 1907-1924, 2018 Aug 01. Abstract

AIM: Discovery of novel series of colchicine binding site inhibitors (CBSIs).

MATERIALS & METHODS: Isoxazoline 3a-d, pyrazoline 4a-b, 7a-f and 8a-f, cyclohexenone 9a-b and 10a-b or pyridine derivatives 11a-b were synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity. Most of the compounds displayed potent to moderate antitumor activity against leukemia SR cell line.7c, 7e and 11a were more potent than colchicine with IC of 0.09, 0.05 and 0.06 μM, and percentage inhibition in tubulin polymerization of 95.2, 96.0 and 96.3%, respectively. Compounds 7c and 11a showed cell-cycle arrest at G2/M phase and induced apoptosis and were able to bind the colchicine binding site of tubulin with comparable affinity to colchicine. Docking study showed that these compounds may interact with tubulin exploiting a binding cavity not commonly reported in the binding of CBSI.

CONCLUSION: Compounds 7c and 11a may be considered as promising CBSI based on their excellent activity and favorable drug likeness profile.

Nowar, R. M., E. E. A. Osman, S. M. Abou-Seri, S. M. El Moghazy, and D. A. Abou El Ella, "Design, synthesis and biological evaluation of some novel quinazolinone derivatives as potent apoptotic inducers.", Future medicinal chemistry, vol. 10, issue 10, pp. 1191-1205, 2018 May 01. Abstract

AIM: Novel quinazolinone and triazinoquinazolinone derivatives were designed and synthesized as apoptotic inducers.

METHODOLOGY/RESULTS: Most of the synthesized compounds showed excellent antiproliferative activity against MCF-7 and HCT-116 cell lines, respectively. Compounds 7a, 8a, 8d, 14a and 14d were superior to doxorubicin as activators of caspases 3, 8 and 9 in HCT-116 cell line. The most potent caspase inducers, 8d and 14a showed cell cycle arrest mainly in G1 and S phase, respectively and increased the levels of p53, Bax and the Bax/Bcl-2 ratio compared with doxorubicin in HCT-116 cells with excellent selectivity against CCD-18Co human colon normal cell line.

CONCLUSION: The synthesized compounds can be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways.

Osman, E. E. A., "Analytical investigation of different mathematical approaches utilizing manipulation of ratio spectra.", Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, vol. 188, pp. 469-477, 2018 Jan 05. Abstract

This work represents a comparative study of different approaches of manipulating ratio spectra, applied on a binary mixture of ciprofloxacin HCl and dexamethasone sodium phosphate co-formulated as ear drops. The proposed new spectrophotometric methods are: ratio difference spectrophotometric method (RDSM), amplitude center method (ACM), first derivative of the ratio spectra (1DD) and mean centering of ratio spectra (MCR). The proposed methods were checked using laboratory-prepared mixtures and were successfully applied for the analysis of pharmaceutical formulation containing the cited drugs. The proposed methods were validated according to the ICH guidelines. A comparative study was conducted between those methods regarding simplicity, limitations and sensitivity. The obtained results were statistically compared with those obtained from the reported HPLC method, showing no significant difference with respect to accuracy and precision.

Ahmed, R. I., E. E. A. Osman, F. M. Awadallah, and S. M. El-Moghazy, "Design, synthesis and molecular docking of novel diarylcyclohexenone and diarylindazole derivatives as tubulin polymerization inhibitors.", Journal of enzyme inhibition and medicinal chemistry, vol. 32, issue 1, pp. 176-188, 2017 Dec. Abstract

New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds 4b, 5e and 5f showed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds 4b, 5e and 5f revealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin.[Formula: see text].

El-Moghazy, S. M., R. F. George, E. E. A. Osman, A. A. Elbatrawy, M. Kissova, A. Colombo, E. Crespan, and G. Maga, "Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line.", European journal of medicinal chemistry, vol. 123, pp. 1-13, 2016 Nov 10. Abstract

Some novel 6-substituted pyrazolo[3,4-d]pyrimidines 4, 5, 6a-d, 7a-c, 8 and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines 9a-c, 10a-c, 11, 12a,b, 13a-c and 14 were synthesized and characterized by spectral and elemental analyses. They were screened for their biological activity in vitro against Abl and Src kinases. Compounds 7a and 7b revealed the highest activity against both wild and mutant Abl kinases as well as the Src kinase and the leukemia K-562 cell line. They can be considered as new hits for further structural optimization to obtain better activity.