Ibrahim, H. S., W. M. Eldehna, A. L. Fallacara, E. R. Ahmed, H. A. Ghabbour, M. A. H. M. O. U. D. M. ELAASSER, M. Botta, S. M. Abou-Seri, and H. A. Abdel-Aziz, "One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors.", Future medicinal chemistry, vol. 10, issue 24, pp. 2771-2789, 2018 Dec. Abstract

AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives.

MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies.

RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.

Abo-Ashour, M. F., W. M. Eldehna, R. F. George, M. M. Abdel-Aziz, M. A. H. M. O. U. D. M. ELAASSER, N. M. Abdelgawad, A. Gupta, S. Bhakta, and S. M. Abou-Seri, "Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents.", European journal of medicinal chemistry, vol. 160, pp. 49-60, 2018 Dec 05. Abstract

In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38 cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98 μg/mL) and antifungal (MIC: 0.49-0.98 μg/mL) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81 μg/mL, respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.

Abo-Ashour, M. F., W. M. Eldehna, A. Nocentini, H. S. Ibrahim, S. Bua, S. M. Abou-Seri, and C. T. Supuran, "Novel hydrazido benzenesulfonamides-isatin conjugates: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies.", European journal of medicinal chemistry, vol. 157, pp. 28-36, 2018 Sep 05. Abstract

As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with Ks in the range of 671.8: 3549.5 nM, hCA II in the range of 36.8: 892.4 nM; hCA IX in the range of 8.9: 264.5 nM, whereas hCA XII in the range of 9.0: 78.1 nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results.

Ismail, R. S. M., S. M. Abou-Seri, W. M. Eldehna, N. S. M. Ismail, S. M. Elgazwi, H. A. Ghabbour, M. S. Ahmed, F. T. Halaweish, and D. A. Abou El Ella, "Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells.", European journal of medicinal chemistry, vol. 155, pp. 782-796, 2018 Jul 15. Abstract

Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC = 3 and 16 μM, respectively), compared to that of Erlotinib (IC = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.

Abo-Ashour, M. F., W. M. Eldehna, R. F. George, M. M. Abdel-Aziz, M. A. H. M. O. U. D. M. ELAASSER, S. M. Abou-Seri, and N. M. Abdelgawad, "Synthesis and biological evaluation of 2-aminothiazole-thiazolidinone conjugates as potential antitubercular agents.", Future medicinal chemistry, vol. 10, issue 12, pp. 1405-1419, 2018 Jun 01. Abstract

AIM: Mycobacterium tuberculosis, which causes tuberculosis, continues to infect millions of the global population, resulting in 1.8 million deaths worldwide in 2015.

METHODOLOGY: Hybrids of 2-amino-4-methylthiazole bearing 5-acetyl/5-ethyl carboxylate functionality with 5-arylidene thiazolidinone moiety (6a-k and 9a-d) were synthesized and screened for antitubercular and antimicrobial activities.

RESULTS & DISCUSSION: 5-ethyl carboxylate derivative 6k revealed half antitubercular activity (minimal inhibitory concentration = 1.56 μg/ml) than the acetyl analog 6c (minimal inhibitory concentration = 0.78 μg/ml), however, it exhibited more potent broad spectrum antibacterial and antifungal activities in addition to its excellent safety profile with high selectivity toward M. tuberculosis over normal human lung cells. Collectively, these data suggested that compound 6k can be considered as an ideal lead compound for further optimization.

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.

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.

Ragab, F. A. F., S. M. Abou-Seri, S. A. Abdel-Aziz, A. M. Alfayomy, and M. Aboelmagd, "Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety.", European journal of medicinal chemistry, vol. 138, pp. 140-151, 2017 Sep 29. Abstractabdallah.pdf

A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Fatma A. Ragab, H. I. Heiba, M. G. El-Gazzar, S. M. Abou-Ser, W. A. El-Sabbaghb, and R. M. El-Haz, "Synthesis of novel thiadiazole derivatives as selective COX-2 inhibitors", Med. Chem. Commun., vol. 7, pp. 2309-2327, 2016. reham_supp.pdf
Ragab, F. A., H. I. Heiba, M. G. El-Gazzar, S. M. Abou-Seri, W. A. El-Sabbagh, and R. M. El-Hazek, "Anti-inflammatory, analgesic and COX-2 inhibitory activity of novel thiadiazoles in irradiated rats.", Journal of photochemistry and photobiology. B, Biology, vol. 166, pp. 285-300, 2017 Jan. Abstractjournal_of_photochemistry__photobiology.pdf

In this work, novel series of pyran, thiophene and thienopyrimidine derivatives based on 2-acetamide-thiadiazole scaffold were designed and synthesized for evaluation as selective COX-2 inhibitors in-vitro and investigated in-vivo as anti-inflammatory and analgesic agents against carrageenan-induced rat paw oedema model in irradiated rats, since its well-known that ionizing radiation plays an important role in exaggerating the inflammatory responses and in enhancing the release of inflammatory mediators in experimental animals. Toxicological studies were carried out to evaluate the ulcerogenic activity, acute toxicity and kidney and liver functions for the most potent compounds. In order to understand the binding mode of the synthesized compounds into the active site of COX-2, docking study was performed. Most of the tested compounds showed high inhibitory ability to COX-2. Among them, thiadiazole derivatives bearing thiophene and thienopyrimidine moieties were the most active derivatives, compound 26 showed extremely high selectivity index (SI) of >555.5μM which is nearly two folds better than celecoxib (>277.7μM), in addition to compounds 3, 16, 17, 21 and 26 with SI in the range of >308.6- >384.6μM. The 4-chlorothieno[2.3-d]pyrimidine derivative of thiadiazole 21 showed the highest anti-inflammatory activity in this study having 24.49% of oedema compared to celecoxib (18.61%) in addition to compounds 17 and 26 with 24.70 and 25.40% of oedema, respectively, while the thiadiazol-2-acetamide derivative 2 was the most potent analgesic compound with the highest nociceptive threshold (85.72g) very close to that of celecoxib (90.23g). These compounds showed high safety margin on gastric mucosa with no ulceration effect. Also the most active in-vivo anti-inflammatory compounds 17, 21 and 26 were found to be non-toxic in experimental rats with normal kidney and liver functions. Docking study of the synthesized compounds showed similar orientation as celecoxib within the active site of COX-2 enzyme and similar ability to emerge deeply in the additional pocket and binding with Arg513 and His90 the key amino acids responsible for selectivity.

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