314025-86-0Relevant academic research and scientific papers
Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents
Eldehna, Wagdy M.,Abo-Ashour, Mahmoud F.,Nocentini, Alessio,El-Haggar, Radwan S.,Bua, Silvia,Bonardi, Alessandro,Al-Rashood, Sara T.,Hassan, Ghada S.,Gratteri, Paola,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
, p. 147 - 160 (2019)
Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N-alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7–86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192–239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 ± 0.28 and 12.90 ± 0.34 μM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents.
Synthesis and cytostatic evaluation of some 2-(5-substituted-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide
Karki, Subhas S.,Kulkarni, Amol,Teraiya, Nishith,Clercq, Erik De,Balzarini, Jan
, p. 1229 - 1234 (2012/06/04)
Various substituted 2-(5-substituted-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide 4a-g and 2-(5-substituted-1-(4-substituted benzyl)-2-oxoindolin- 3-ylidene)-N-substituted hydrazine carbothioamide 5a-k were synthesized. The compounds were evaluated for their cytostatic activity against human Molt4/C8 and CEM T-lymphocytes as well as murine L1210 leukemia cells. Several of these compounds were endowed with low micromolar 50%-inhibitory concentration (IC50) values, and some were virtually equally potent as melphalan. The most potent inhibitors against the murine leukemia cells were also most inhibitory against human T-lymphocyte tumor cells. 2-(5-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3- ylidene)-N-p-tolylhydrazine carbothioamide (5b) emerged as the most potent cytostatic compound among the tested compounds. The encouraging cytostatic data provide an adequate rationale for further modification of these molecular scaffolds. Springer Science+Business Media, LLC 2010.
Novel, highly potent aldose reductase inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives
Da Settimo, Federico,Primofiore, Giampaolo,Da Settimo, Antonio,La Motta, Concettina,Simorini, Francesca,Novellino, Ettore,Greco, Giovanni,Lavecchia, Antonio,Boldrini, Enrico
, p. 1419 - 1428 (2007/10/03)
Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives were synthesized and tested as a novel class of aldose reductase (ALR2) inhibitors. Each compound was evaluated as a diastereomeric mixture, due to tautomeric equilibria in solution. The parent com
