El-Masry, R. M., H. H. Kadry, A. T. Taher, and S. M. Abou-Seri, "Comparative Study of the Synthetic Approaches and Biological Activities of the Bioisosteres of 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles over the Past Decade.", Molecules (Basel, Switzerland), vol. 27, issue 9, 2022. Abstract

The bioisosteres of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles are well-known pharmacophores for many medicinally important drugs. Throughout the past 10 years, 1,3,4-oxa-/thiadiazole nuclei have been very attractive to researchers for drug design, synthesis, and the study of their potential activity towards a variety of diseases, including microbial and viral infections, cancer, diabetes, pain, and inflammation. This work is an up-to-date comparative study that identifies the differences between 1,3,4-thiadiazoles and 1,3,4-oxadiazoles concerning their methods of synthesis from different classes of starting compounds under various reaction conditions, as well as their biological activities and structure-activity relationship.

ABDELNABY, R. A. N. A. M., H. E. B. A. S. RATEB, O. Ali, A. S. Saad, R. I. Nadeem, S. M. Abou-Seri, K. M. Amin, N. S. Younis, and R. Abdelhady, "Dual PI3K/Akt Inhibitors Bearing Coumarin-Thiazolidine Pharmacophores as Potential Apoptosis Inducers in MCF-7 Cells.", Pharmaceuticals (Basel, Switzerland), vol. 15, issue 4, 2022. Abstract

Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone () and thiazolidin-4-one moieties () were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, , induced remarkable cytotoxicity (IC of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following treatment. Mechanistically, was found to target the PI3K-α/Akt-1 axis, as evidenced by enzyme inhibition assay results reporting significant inhibition of examined enzymes. These findings were confirmed by Western blot results indicating the ability of to repress levels of Cyclin D1, p-PI3K, and p-Akt. Furthermore, docking studies showed that has a binding affinity with the PI3K binding site higher than the original ligands X6K. Our results suggest that has pharmacological potential as a promising anti-cancer compound by the inhibition of the PI3K/Akt axis.

Khan, I., T. Ganapathi, M. M. - U. - Rehman, M. A. Shareef, G. C. Kumar, and A. Kamal, "New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis.", Bioorganic & medicinal chemistry letters, vol. 44, pp. 128094, 2021. Abstract

To continue the quest of newer anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic cancer cells) with IC value 7.4 μM and 4.3 μM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC = 4.2 μM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate apoptosis by activating caspase 3 and 9 enzymes which was confirmed by Annexin-FITC assay and caspase assay. Moreover, docking study suggested their binding modes and interactions with caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q = 0.631, r = 0.977) and CoMSIA (q = 0.686, r = 0.954) on PANC-1 cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced anticancer activity.

El Hassab, M. A., W. M. Eldehna, S. T. Al-Rashood, A. Alharbi, R. O. Eskandrani, H. M. Alkahtani, E. B. Elkaeed, and S. M. Abou-Seri, "Multi-stage structure-based virtual screening approach towards identification of potential SARS-CoV-2 NSP13 helicase inhibitors.", Journal of enzyme inhibition and medicinal chemistry, vol. 37, issue 1, pp. 563-572, 2022. Abstract

On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound ) bound to NSP13 helicase enzyme, which identified as a potential potent NSP13 helicase inhibitor with binding free energy equals -328.6 ± 9.2 kcal/mol.

Raafat, A., S. Mowafy, S. M. Abouseri, M. A. Fouad, and N. A. Farag, "Lead generation of cysteine based mesenchymal epithelial transition (c-Met) kinase inhibitors: Using structure-based scaffold hopping, 3D-QSAR pharmacophore modeling, virtual screening, molecular docking, and molecular dynamics simulation.", Computers in biology and medicine, vol. 146, pp. 105526, 2022. Abstract

Cysteine-based mesenchymal-epithelial transition (c-Met) is a receptor tyrosine kinase that plays a definitive role during cancer progression and was identified as a possible target for anti-angiogenesis drugs. In the present study, different protocols of computer-based drug design were performed. Construction of predictive pharmacophore model using HypoGen algorithm resulted in a validated model of four features of positive ionizable, hydrogen bond acceptor, hydrophobic, and ring aromatic features with a correlation coefficient of 0.87, a configuration cost of 14.95, and a cost difference of 357.92. The model revealed a promising predictive power and had >90% probability of representing true correlation with the activity data. The model was established using Fisher's validation test at the 95% confidence level and test set prediction (r = 0.96), furthermore, the model was validated by mapping of set of compounds undergoing clinical trials as class Ⅱ c-met inhibitors. The generated valid pharmacophore model was then anticipated for virtual screening of three data bases. Moreover, scaffold hopping using replace fragments protocol was implemented. Hits generated were filtered according to Lipinski's rule; 510 selected hits were anatomized and subjected to molecular docking studies into the crystal structure of c-Met kinase. The good correlation between docking scores and ligand pharmacophore mapping fit values provided a reliable foundation for designing new potentially active candidates that may target c-Met kinase. Eventually, eight hits were selected as potential leads. Subsequently, seven (Hits) have displayed a higher dock score and demonstrated key residue interactions with stable molecular dynamics simulation. Therefore, these c-Met kinase inhibitors may further serve as new chemical spaces in designing new compounds.

Abou-Seri, S. M., A. A. M. Eissa, M. G. M. Behery, and F. A. Omar, "Synthesis, in vitro anticancer activity and in silico studies of certain isoxazole-based carboxamides, ureates, and hydrazones as potential inhibitors of VEGFR2.", Bioorganic chemistry, vol. 116, pp. 105334, 2021. Abstract

The ensuing research presents the results of in vitro anticancer activity of novel 28 compounds of isoxazole-based carboxamides 3(a-d); ureates 4(a-g), 5, 6, 7a,b, 8; and hydrazones 9(a-f), 10(a-d), 11a,b as potential inhibitors of VEGFR2. The carboxamides and ureates were synthesized by converting 5-(aryl)-isoxzaole-3-carbohydrazides 1a,b to the corresponding carbonylazides 2a,b followed by treatment with the appropriate amines. The hydrazones were directly obtained through condensation of the carbohydrazide 1a,b with aldehydes and/or ketones. The structures of the target compounds were confirmed by elemental and spectral analyses. A preliminary in vitro anticancer screening of solutions (10M) on 60 cancer cell lines (NCI, USA) revealed that the carboxamide 3c is the most promising growth inhibitor. Explicitly, 3c showed potent anticancer activity at 10µ M against leukemia (HL-60(TB), K-562 and MOLT-4), colon cancer (KM12) and melanoma (LOX IMVI) cell lines with %GI range = 70.79-92.21. Evaluation of growth inhibitory activity of the synthesized compounds against hepatocellular carcinoma (HepG2), that overexpresses VEGFR2, showed superior activity of compounds 8, 10a and 10c with IC in sub micromolar concentrations of 0.84, 0.79 and 0.69 μM, respectively, which is better than that of the reference drug, Sorafenib (IC = 3.99 µM). Moreover, these compounds displayed high selective cytotoxicity for HepG2 cancer cells over the nontumorigenic THLE2 liver cells (SI range = 26.37-38.60) which reflect their safety. The results of VEGFR2 kinase inhibition assay demonstrate that, compounds 8 and 10a are the most active inhibitors with IC = 25.7 and 28.2 nM, respectively, (Sorafenib IC = 28.1 nM). Molecular docking of the synthesized derivatives to VEGFR2 (PDB: 3WZE) showed similar binding modes to that of the co-crystallized ligand, sorafenib. Moreover, the results of computational assessment of ADME and drug-likeness characteristics inspire further investigations of the new isoxazole-based derivatives to afford more potent, safe and orally active VEGFR2 inhibitors as potential anticancer drug candidates.

Elsayed, Z. M., W. M. Eldehna, M. M. Abdel-Aziz, M. A. El Hassab, E. B. Elkaeed, T. Al-Warhi, H. A. Abdel-Aziz, S. M. Abou-Seri, and E. R. Mohammed, "Development of novel isatin-nicotinohydrazide hybrids with potent activity against susceptible/resistant and bronchitis causing-bacteria.", Journal of enzyme inhibition and medicinal chemistry, vol. 36, issue 1, pp. 384-393, 2021. Abstract

Joining the global fight against Tuberculosis, the world's most deadly infectious disease, herein we present the design and synthesis of novel isatin-nicotinohydrazide hybrids ( and ) as promising anti-tubercular and antibacterial agents. The anti-tubercular activity of the target hybrids was evaluated against drug-susceptible M. tuberculosis strain (ATCC 27294) where hybrids , and were found to be as potent as INH with MIC = 0.24 µg/mL, also the activity was evaluated against Isoniazid/Streptomycin resistant M. tuberculosis (ATCC 35823) where compounds and showed excellent activity (MIC = 3.9 µg/mL). Moreover, the target hybrids were examined against six bronchitis causing-bacteria. Most derivatives exhibited excellent antibacterial activity. K. pneumonia emerged as the most sensitive strain with MIC range: 0.49-7.81 µg/mL. Furthermore, a molecular docking study has proposed DprE1 as a probable enzymatic target for herein reported isatin-nicotinohydrazide hybrids, and explored the binding interactions within the vicinity of DprE1 active site.

Abdelrahman, M. A., H. S. Ibrahim, A. Nocentini, W. M. Eldehna, A. Bonardi, H. A. Abdel-Aziz, P. Gratteri, S. M. Abou-Seri, and C. T. Supuran, "Novel 3-substituted coumarins as selective human carbonic anhydrase IX and XII inhibitors: Synthesis, biological and molecular dynamics analysis.", European journal of medicinal chemistry, vol. 209, pp. 112897, 2021. Abstract

In this study, diverse series of coumarin derivatives were developed as potential carbonic anhydrase inhibitors (CAIs). A "tail" approach was adopted by selecting the coumarin motif as a tail that is connected to the ZBG benzenesulfonamide moiety via a hydrazine (4a,b) or hydrazide (5a,b) linker. Thereafter, an aryl sulfone tail was incorporated to afford the dual tailed coumarin-sulfonamide arylsulfonehydrazones (13a-d) and hydrazides (14a,b). Then, the ZBG were removed from compounds 13 and 14 to furnish coumarin arylsulfonehydrazones (11a-d) and hydrazides (12a,b). Coumarin-sulfonamides 4 and 5 emerged as non-selective CAIs as they displayed good inhibitory activities toward all the examined CA isozymes (I, II, IX and XII) in the nanomolar ranges. Interestingly, the "dual-tail" approach (compounds 13 and 14) succeeded in achieving a good activity and selectivity toward CA IX/XII over the physiologically dominant CA I/II. In particular, compounds 13d and 14a were the most selective coumarin-sulfonamide counterparts. Concerning non-sulfonamide coumarin derivatives, coumarins 8 exhibited excellent activity and selectivity profiles against the target hCA IX/XII, whereas, coumarins 11 and 12 reported excellent selectivity profile, but they barely inhibited hCA IX/XII with Ks spanning in the micromolar ranges. Furthermore, molecular modelling studies were applied to get a deep focus about the feasible affinities and binding interactions for target coumarin-sulfonamides 4, 5, 13 and 14 with the active site for CA II, IX and XII isoforms.

Alfayomy, A. M., S. A. Abdel-Aziz, A. A. Marzouk, M. S. A. Shaykoon, A. Narumi, H. Konno, S. M. Abou-Seri, and F. A. F. Ragab, "Design and synthesis of pyrimidine-5-carbonitrile hybrids as COX-2 inhibitors: Anti-inflammatory activity, ulcerogenic liability, histopathological and docking studies.", Bioorganic chemistry, vol. 108, pp. 104555, 2021. Abstract

Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC 0.041-0.081 μM, SI 139.74-321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3-48.3, 1 h; 58.4-60.5, 2 h; 70.8-83.2, 3 h; 78.9-89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.

Helwa, A. A., E. M. Gedawy, A. T. Taher, A. K. Ed El-Ansary, and S. M. Abou-Seri, "Synthesis and biological evaluation of novel pyrimidine-5-carbonitriles featuring morpholine moiety as antitumor agents.", Future medicinal chemistry, vol. 12, issue 5, pp. 403-421, 2020. Abstractamira.pdf

Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19 derivatives (, and ) were evaluated for their antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound was evaluated against PI3K (α, β and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Compound possessed remarkable broad spectrum antitumor activity with GI (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66 μM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC - positive apoptotic cells, also increased the level of active caspase-3. Moreover, revealed good safety profile against transformed human liver epithelial-2 (THLE2).