Regioselective Synthesis of Benzimidazolic Bioisosteres of Melatonin

Depreux, Patrick; Fourmaintraux, E.; Lesieur, D.; Renard, Pierre

doi:10.1080/00397919408010225

Cited by 4 publications

(12 citation statements)

References 13 publications

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“…The benzimidazole analogue of melatonin is, like the C-6 methoxyl, N-1 side chain analogue, a melatonin agonist [70]. The core 11 was prepared from 3-chloro-4-nitroanisole with the C-3 side chain attached, as shown in Fig.…”

Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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The functions of melatonin, the hormone of the pineal gland, are of considerable current interest. Synthetic melatonin analogues as agonists and antagonists have been explored in some detail and the molecule can be considered as consisting of an indole core, acting mainly as a spacer, and the 5-methoxyl and 3-amidoethyl side chains acting as the functional components, as originally proposed by Heward and Hadley. This review focuses on the synthetic routes to these melatonin analogues, first of the core, then of the substituents that have been attached to the core, and finally those compounds with restricted conformations and those that are chiral. The importance of the various factors involved in the activity of the compounds as agonist or antagonists is indicated, as is the difference in activity of enantiomers.

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Section: Indole Benzo[b]thiophene Benzo[b]furan Benzimidazoles Inmentioning

confidence: 99%

Synthesis of Compounds as Melatonin Agonists and Antagonists

Garratt¹,

Tsotinis

2007

MRMC

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“…We synthesized a series of novel benzimidazoles using convenient routes (Schemes , , , and ). Scheme illustrates the synthesis of compounds 4 , 6 , 7 , and 8a–j using 1-fluoro-4-methoxy-2-nitrobenzene (or 2-fluoro-4-methoxy-1-nitrobenzene) as the starting material, which was combined with ethylenediamine and CuBr 2 to afford the nitroaniline derivative . Acylation of this intermediate with acetic anhydride or acyl halides produced the desired acylated compounds 3a–i in good yields.…”

Section: Resultsmentioning

confidence: 99%

“…Scheme 1 illustrates the synthesis of compounds 4, 6, 7, and 8a−j using 1-fluoro-4methoxy-2-nitrobenzene (or 2-fluoro-4-methoxy-1-nitrobenzene) as the starting material, which was combined with ethylenediamine and CuBr 2 to afford the nitroaniline derivative. 38 Acylation of this intermediate with acetic anhydride or acyl halides produced the desired acylated compounds 3a−i in good yields. Nitro reduction followed by cyclization with formic acid gave exclusively the desired compound 4, as described by Depreux et al 38 Alternatively, the nitro group was reduced with Zn powder/NH 4 HCO 2 in MeOH or Pd/C (10%) in MeOH to provide the desired phenylenediamines 5a−i; 5a was then treated with bis(trichloromethyl)carbonate (BTC) 39,40 to give the 5-membered cyclic urea 6.…”

Section: ■ Resultsmentioning

confidence: 99%

“…HRMS (ESI) m / z calculated C 12 H 15 N 3 O 2 : 233.1164; found [M + H] + 234.1259. The chemical physical data are in agreement to those previously reported …”

Section: Methodsmentioning

confidence: 99%

“…The compound N -[2-(2-ethoxy-6-methoxybenzoimidazol-1-yl)ethyl]acetamide 8a was synthesized as described previously . In a 1000 mL reactor, NCS (292 mmol, 1.1 eq) was added to a solution of the obtained compound 8a (266 mmol, 1.0 eq) in i -PrOH (560 mL) at 20 °C in one portion.…”

Section: Methodsmentioning

confidence: 99%

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Discovery of ACH-000143: A Novel Potent and Peripherally Preferred Melatonin Receptor Agonist that Reduces Liver Triglycerides and Steatosis in Diet-Induced Obese Rats

Ferreira¹,

Azevedo²,

Mascarello³

et al. 2021

J. Med. Chem.

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The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.

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