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Synthetic Approaches to Inhibitors of Isoprenoid Biosynthesis
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Pedro Merino, Loredana Maiuolo, Ignacio Delso, Vincenzo Algieri, Antonio De Nino, Tomas Tejero
The Cu (II)-catalyzed 1,4-conjugate addition of boronic acids (74) and indoles (65) to (64) allowed synthesizing bisphosphonates (75) and (77), respectively, as described in Scheme 2.23 (Andrea et al., 2017). Whereas the reactions with boronic acids proceeded smoothly in toluene, the addition of indoles should be carried out in polar solvents (1,2-dichloroethane or water with sodium dodecyl sulfate). In some cases, the presence of different functional groups on boronic acids or isatin derivatives had a dramatic influence in the chemical yield. Reagents and conditions: (i) Cu(OTf)2 (10 mol%), toluene, 18 h, 70°C. (ii) TMSBr, 18 h, rt; then water, 4 h, rt.
Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
When the two carbonyl oxygen atoms of 1,2-dione moiety are cis-coplanar or fused within a ring structure, such as 1,2-quinones and isatins, demonstrate high specificity towards CES1 over CES2 (Table 9.2). Tanshinones, the natural phenanthrene-quinone compounds isolated from Chinese herb Danshen (De Palma et al., 2008), are found to be potent inhibitors of both CES1 and CES2 (Hatfield et al., 2013). The entrance to the active site gorge in CES1 is considerably smaller, and any substitution introduced to the benzene ring of the 1,2-quinone or isatin should be small enough to ensure the access of the inhibitors to the active cavity (Hyatt et al., 2007a). β-Lapachone with 1,2-dione moiety in cis-coplanar is a potent and reversible CES inhibitor, and demonstrates relatively high specificity towards CES2 over CES1 (Hatfield et al., 2017). 4-Phenoxynaphthalene-1,2-diones demonstrated high selectivity toward CES1 as compared with β-lapachone. The amino analogues (4-phenyl- aminonaphthalene-1,2-diones) with the imino forms were inactive toward human CES when compared with phenoxy analogues, suggesting that the imino group at the C-4 site was unbeneficial for CES inhibition. The potency of N-methylated amino analogues (4-phenyl(methyl)aminonaphthalene-1,2-diones) were equal to the phenoxy analogues and demonstrated selectivity towards CES1. Further investigation on inhibition kinetic analyses and docking simulations showed that the tautomerism of the amino derivatives to the imino forms likely accounts for their loss in biological activity.
Imaging of Hypoxia, Apoptosis, and Inflammation
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Stavros Spiliopoulos, Athanasios Diamantopoulos
The 5-pyrrolidinylsulfonylisatin class of nonpeptidyl caspase inhibitors, which binds to the cysteine residue of the active site of a given caspase, has been used for apoptosis imaging. However, caspase 3 activation does not selectively involve only apoptosis (Spires-Jones et al. 2008). As a result, a 2′-fluoroethyl-1,2,3-triazole with a subnanomolar affinity for caspase 3 has been identified. This agent demonstrates high labeling efficiencies and high in vivo stability, as well as rapid uptake and elimination. At present, PET imaging using 18F-labeled isatin analogues, such as the 18F-labeled isatin 18F-isoprenylcysteine carboxyl methyltransferase 11 (ICMT-11) labeled by click radiochemistry, is under investigation as to determine their role as apoptotic radiotracers (Chen et al. 2009; Nguyen et al. 2009).
Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Moataz A. Shaldam, Hadia Almahli, Andrea Angeli, Rehab Mustafa Badi, Eman F. Khaleel, Abdelrahman I. Zain-Alabdeen, Zainab M. Elsayed, Eslam B. Elkaeed, Rofaida Salem, Claudiu T. Supuran, Wagdy M. Eldehna, Haytham O. Tawfik
Isatin, an endogenic molecule in mammalaian tissues including human, stands for valuable privileged scaffold in drug design and pharmaceutical chemistry10. Isatin-tethered compounds have been found to display various pharmacological effects, in particular carbonic anhydrase11–14 and VEGFR-215–17 inhibitory activities. In the last few years, isatin motif has been exploited to develop several CAIs with effective in vitro and in vivo antitumor activities, such as WEG-10418,19 and compound I20 (Figure 1). In 2019, we reported a new set of N-substituted isatin derivatives as promising CAIs. Among this set, compound II (Figure 1) displayed excellent activity against cancer-related CA IX and XII isoforms; KI = 5.2 and 6.3 nM, respectively. Also, it exerted good VEGFR-2 inhibitory action (IC50= 260.64 nM), as well as effective cell growth inhibitory action on breast cancer cell lines21.
Development of 2-oxindolin-3-ylidene-indole-3-carbohydrazide derivatives as novel apoptotic and anti-proliferative agents towards colorectal cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Wagdy M. Eldehna, Mahmoud F. Abo-Ashour, Tarfah Al-Warhi, Sara T. Al-Rashood, Amal Alharbi, Rezk R. Ayyad, Khayal Al-Khayal, Maha Abdulla, Hatem A. Abdel-Aziz, Rehan Ahmad, Radwan El-Haggar
Isatin (1H-indole-2,3-dione), as a special class in drug design and discovery, represents one of the most favourable scaffolds of heterocyclic systems which possesses many interesting biological activities including anti-SARS-CoV-223, antimicrobial24, anticonvulsant25 and mainly anticancer26–28. Therefore, isatin nucleus was broadly used by our group for the development of diverse effective oxindole-based small molecules (structures I–III29–31, Figure 1) with anticancer activities that target different enzymatic and cellular targets such as inhibition of cancer-related carbonic anhydrase IX isoform32–33, inhibition of different kinases34–35, in addition to apoptosis induction in different human cancer cell lines36–37.
Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zainab M. Elsayed, Wagdy M. Eldehna, Marwa M. Abdel-Aziz, Mahmoud A. El Hassab, Eslam B. Elkaeed, Tarfah Al-Warhi, Hatem A. Abdel-Aziz, Sahar M. Abou-Seri, Eman R. Mohammed
Isatin is a promising endogenous biologically active scaffold. It could be chemically modified to produce various heterocyclic compounds with different biological activities9–14. Isatin based derivatives have revealed promising antibacterial15–17 and anti-TB effects18,19. Moreover, the nicotinohydrazide moiety has a large contribution to the field of medicinal chemistry. It has been incorporated in several active antimicrobial20 and anti-tubercular agents21. In fact, the presence of a hydrazide group can be considered as a significant key for an optimum anti-tubercular activity22. Recently, several research teams adopted molecular hybridisation techniques between isatin and different moieties for the design of new anti-mycobacterial agents23–26, such as isatin-INH hybrids I (Figure 1)25 and isatin-nalidixic acid hybrids II (Figure 1)26. Later, our research team has identified the N-substituted isatin-thiazolidinone hybrid III (Figure 1) as a promising antitubercular agent that produced an effective killing of M. aurum in infected macrophage model with broad-spectrum antimicrobial effect against sensitive and resistant bacterial strains27. SAR study revealed that N-benzylation or N-methylation of the 2-oxindole ring enhanced the activity by 2-4 folds as compared to the N-unsubstituted analogues.