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).

Said, M. A., W. M. Eldehna, A. Nocentini, S. H. Fahim, A. Bonardi, A. A. Elgazar, V. Kryštof, D. H. Soliman, H. A. Abdel-Aziz, P. Gratteri, et al., "Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation.", European journal of medicinal chemistry, vol. 189, pp. 112019, 2020. Abstract

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with Ks ranges 6-67.6 and 10.1-88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC = 6.4, 8.0 and 11.6 μM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.

Abdelrahman, M. A., W. M. Eldehna, A. Nocentini, H. S. Ibrahim, H. Almahli, H. A. Abdel-Aziz, S. M. Abou-Seri, and C. T. Supuran, "Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and biological evaluation.", Journal of enzyme inhibition and medicinal chemistry, vol. 35, issue 1, pp. 298-305, 2020. Abstract

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (,, ,, , and ), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with s spanning in ranges 10.0-97.5 and 10.1-71.8 nM, respectively. Interestingly, arylsulfonehydrazones displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4-250.3 and 26.0-149.9, respectively), and over hCA II (SIs: 19.6-57.1 and 13.0-34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans and possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.

Said, M. A., W. M. Eldehna, A. Nocentini, A. Bonardi, S. H. Fahim, S. Bua, D. H. Soliman, H. A. Abdel-Aziz, P. Gratteri, S. M. Abou-Seri, et al., "Synthesis, biological and molecular dynamics investigations with a series of triazolopyrimidine/triazole-based benzenesulfonamides as novel carbonic anhydrase inhibitors.", European journal of medicinal chemistry, vol. 185, pp. 111843, 2020. Abstract

In the presented work, we report the design and synthesis of different new sets of triazolopyrimidine-based (9a-d) and triazole-based (11a-h, 13a-c, 15a,b, 17a,b and 21a-g) benzenesulfonamides. The newly synthesized sulfonamides were assessed for their inhibitory activities toward four human (h) metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms; hCA I, II, IX and XII. The four examined isoforms were inhibited by the prepared sulfonamides (9a-d, 11a-h, 13a-c, 15a,b, 17a,b and 21a-g) in variable degrees with Ks ranges: 94.4-4953.5 nM for hCA I, 6.9-837.6 nM for hCA II, 3.3-85.0 nM for hCA XI, and 4.4-105.0 nM for hCA XII. In particular, sulfonamides 11e, 21a and 21e emerged as single-digit nanomolar hCA IX and hCA XII inhibitors. Interestingly, triazolopyrimidine-based sulfonamide 9d and triazole-based sulfonamide 21e were found to be the most selective hCA IX inhibitors over hCA I (SI = 100.85 and 210.58, respectively) and hCA II (SI = 18.54 and 38.36, respectively). Thereafter, sulfonamides 9d and 21e were docked into the active site of CAs II, IX and XII, then poses showing the best scoring values and favorable binding interactions were subjected to a MM-GBSA based refinement and, limited to CA IX and XII, to a cycle of 100 ns molecular dynamics.

Abo-Ashour, M. F., W. M. Eldehna, A. Nocentini, A. Bonardi, S. Bua, H. S. Ibrahim, M. A. H. M. O. U. D. M. ELAASSER, V. Kryštof, R. Jorda, P. Gratteri, et al., "3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights.", European journal of medicinal chemistry, vol. 184, pp. 111768, 2019. Abstract

Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with K range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.

El-Sayed, N. A. - E., A. E. - S. Farag, M. A. F. Ezzat, H. Akincioglu, İ. Gülçin, and S. M. Abou-Seri, "Design, synthesis, in vitro and in vivo evaluation of novel pyrrolizine-based compounds with potential activity as cholinesterase inhibitors and anti-Alzheimer's agents.", Bioorganic chemistry, vol. 93, pp. 103312, 2019. Abstract

Novel series of pyrrolizine based compounds (4-6 and 9-11) were designed, synthesized and evaluated as potential anti-Alzheimer agents. Most of the tested compounds showed selectivity to hAChE over hBChE and effectively inhibited self-induced amyloid beta aggregation in vitro. Among these derivatives, compound 10 displayed high selectivity towards hAChE (Ki = 1.47 ± 0.63 μM for hAChE and Ki = 40.15 ± 3.31 μM for hBChE). However, compound 11 displayed dual inhibitory effect against hAChE and hBChE at submicromolar range (Ki = 0.40 ± 0.03 and 0.129 ± 0.009 μM, respectively). Kinetic studies of the new ligands showed competitive type inhibition for both hAChE and hBChE. Moreover, compounds 10 and 11 showed lower or comparable cytotoxicity to donepezil against human neuroblastoma (SH-SY5Y) and normal human hepatic (THLE2) cell lines. In vivo studies confirmed that both compounds were able to improve cognitive dysfunction of scopolamine-induced AD mice. Finally, molecular docking simulation of compounds 10 and 11 in hAChE active site showed good agreement with the obtained pharmaco-biological results.

Abo-Ashour, M. F., W. M. Eldehna, A. Nocentini, H. S. Ibrahim, S. Bua, H. A. Abdel-Aziz, S. M. Abou-Seri, and C. T. Supuran, "Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies.", Bioorganic chemistry, vol. 87, pp. 794-802, 2019. Abstract

In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a-d, 12a-d, 16a-c and 17a-d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a-d and 12a-d) in variable degrees with the following K ranges: 162.6-7136 nM for hCA I, 9.0-833.6 nM for hCA II, 7.9-153.0 nM for hCA IX, and 9.4-94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (Ks = 8.3 and 7.9 nM, respectively) than SLC-0111 (K = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.

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