87-48-9Relevant articles and documents
Discovery of Isatin-Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase
Jaiswal, Shivani,Ayyannan, Senthil Raja
, (2021/11/09)
Using ligand-based design strategy, a set of isatin-3-carbohydrazones was designed, synthesized and evaluated for dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition properties. Compound 5-chloro-N′-(5-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 b) emerged as a potent MAGL inhibitor with nanomolar activity (IC50=3.33 nM), while compound 5-chloro-N′-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 j) was the most potent selective FAAH inhibitor (IC50=37 nM). Compound 5-chloro-N′-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 c) showed dual FAAH-MAGL inhibitory activity with an IC50 of 31 and 29 nM respectively. Enzyme kinetics studies revealed that the isatin-based carbohydrazones are reversible inhibitors for both FAAH and MAGL. Further, blood-brain permeability assay confirmed that the lead compounds (13 b, 13 c, 13 g, 13 m and 13 q) are suitable as CNS candidates. Molecular dynamics simulation studies revealed the putative binding modes and key interactions of lead inhibitors within the enzyme active sites. The lead dual FAAH-MAGL inhibitor 13 c showed significant antioxidant activity and neuroprotection in the cell-based cytotoxicity assay. In summary, the study yielded three potent FAAH/MAGL inhibitor compounds (13 b, 13 c and 13 j) with acceptable pharmacokinetic profile and thus can be considered as promising candidates for treating neurological and mood disorders.
Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer's Agents
Patel, Dushyant V.,Patel, Nirav R.,Kanhed, Ashish M.,Teli, Divya M.,Patel, Kishan B.,Gandhi, Pallav M.,Patel, Sagar P.,Chaudhary, Bharat N.,Shah, Dharti B.,Prajapati, Navnit K.,Patel, Kirti V.,Yadav, Mange Ram
, p. 3557 - 3574 (2020/11/18)
The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 μM; BuChE, IC50 value of 0.21 μM), was also found to possess significant self-mediated Aβ1-42 aggregation inhibitory activity (54% at 25 μM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aβ1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.
A rhodium(ii) catalysed domino synthesis of azepino fused diindoles from isatin tethered: N -sulfonyl-1,2,3-triazoles and indoles
Kahar, Nilesh,Jadhav, Pankaj,Reddy, R. V. Ramana,Dawande, Sudam
supporting information, p. 1207 - 1210 (2020/02/04)
An efficient and convenient protocol for the synthesis of a novel class of azepino fused diindoles from isatin tethered N-sulfonyl-1,2,3-triazoles and indoles has been disclosed. The reaction proceeds via denitrogenative aza-vinyl rhodium carbene formation to give a carbonyl ylide, which with indole results in 1,3-dipolar cycloaddition followed by sequential semipinacol rearrangement/ring expansion/oxidation to produce azepino fused diindoles. The reaction shows a broad substrate scope giving up to 81% yield. Furthermore, reversible catalytic hydrogenation and photophysical studies were carried out to demonstrate the application of these molecules.