Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis

Kanhed, Ashish M.; Sinha, Anshuman; Machhi, Jatin; Tripathi, Ashutosh; Parikh, Zalak S.; Pillai, Prakash; Giridhar, Rajani; Yadav, Mange Ram

doi:10.1016/j.bioorg.2015.05.005

Cited by 22 publications

(12 citation statements)

References 28 publications

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“…Yield 50% (2.9 g); brown liquid; 1 N-(3-Methylbenzyl)benzene-1,2-diamine (5c). 101 Purified by column chromatography using hexanes and ethyl acetate in a 4:1 ratio as eluants using general procedure A. Yield 60% (636 mg from 5.0 mmol scale of corresponding benzyl bromide); brown liquid; 1 H NMR (300 MHz, CDCl 3 ) δ 7.34−7.20 (m, 3H), 7.14 (d, J = 7.1 Hz, 1H), 6.90−6.81 (m, 1H), 6.81−6.68 (m, 3H), 4.30 (s, 2H), 3.41 (s, 1H), 2.40 (s, 3H); 13 C{ 1 H} NMR (75 MHz, CDCl 3 ) δ 139.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates

et al. 2020

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Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono-and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O 2 and FeCl 3 •6H 2 O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N′-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe 3+ . The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV−vis and EPR) studies suggest a mechanism involving metal−substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates

et al. 2020

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“…The ability of the synthesized compounds to inhibit ChEs was evaluated using Ellman’s method as presented in our earlier reports. ,, Tacrine and donepezil were used as standard compounds.…”

Section: Experimental Sectionmentioning

confidence: 99%

“…Chloro-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino-[5,6-b] indol-3-amine(51). The title compound(51) was synthesized from sulfone (41, 0.5 g, 1.77 mmol) and 6-(pyrrolidin-1-yl)hexan-1-amine (3.01 g, 17.7 mmol) as per Method D. Yellow solid (yield: 0.46 g, 70%); mp >250 °C; IR (KBr, cm−1 ): 3421, 3075, 2930, 1618, 1547, 1365, 1142, 1107, 816; 1 H NMR (DMSO-d 6 ): δ 11.84 (bs, 1H, −NH), 8.02 (d, J = 2.2 Hz, 1H, ArH), 7.43 (dd, J = 8.5, 2.2 Hz, 1H, ArH), 7.36 (d, J = 8.5 Hz, 1H, ArH), 3.34−3.42 (m, 2H, −NHCH 2 ), 2.42−2.54 (m, 6H, −NCH 2 ), 1.59−1.71 (m, 4H,−NCH 2 CH 2 ), 1.52−1.57 (m, 2H, −NCH 2 CH 2 ), 1.39−1.45 (m, 2H, −NHCH 2 CH 2 ), 1.25−1.34 (m, 4H, −CH 2 ); MS (m/z): 373 [M] + , 375 [M + 2] + ; RP-HPLC: purity = 96.7%, t R = 4.08 min. 5.2.5b.…”

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confidence: 99%

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

Patel

Kanhed

et al. 2020

ACS Chem. Neurosci.

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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.

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“…The enzyme inhibition activity of the test compounds was performed adopting the method of Ellman et al as described in our earlier report . AChE from human erythrocytes and BuChE from equine serum, 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB-Ellman’s reagent), acetylthiocholine iodide (ATCI), and butyrylthiocholine iodide (BTCI) were purchased from Sigma.…”

Section: Experimental Proceduresmentioning

confidence: 99%

Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

et al. 2016

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A novel series of hybrid molecules were designed and synthesized by fusing the pharmacophoric features of cholinesterase inhibitor donepezil and diarylthiazole as potential multitarget-directed ligands for the treatment of Alzheimer's disease (AD). The compounds showed significant in vitro anticholinesterase (anti-ChE) activity, the most potent compound (44) among them showing the highest activity (IC50 value of 0.30 ± 0.01 μM) for AChE and (1.84 ± 0.03 μM) for BuChE. Compound 44 showed mixed inhibition of AChE in the enzyme kinetic studies. Some compounds exhibited moderate to high inhibition of AChE-induced Aβ1-42 aggregation and noticeable in vitro antioxidant and antiapoptotic properties. Compound 44 showed significant in vivo anti-ChE and antioxidant activities. Furthermore, compound 44 demonstrated in vivo neuroprotection by decreasing Aβ1-42-induced toxicity by attenuating abnormal levels of Aβ1-42, p-Tau, cleaved caspase-3, and cleaved PARP proteins. Compound 44 exhibited good oral absorption and was well tolerated up to 2000 mg/kg, po, dose without showing toxic effects.

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Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis

Cited by 22 publications

References 28 publications

1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates

1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates

Further Studies on Triazinoindoles as Potential Novel Multitarget-Directed Anti-Alzheimer’s Agents

Benzylpiperidine-Linked Diarylthiazoles as Potential Anti-Alzheimer’s Agents: Synthesis and Biological Evaluation

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