ChemInform Abstract: Indole‐Phenol Bioisosterism. Synthesis and Antihypertensive Activity of a Pyrrolo Analogue of Labetalol.

Asselin, A. A.; Humber, Leslie G.; Crosilla, D.; Oshiro, G.; Wojdan, A.; Grimes, Daniel T.; Heaslip, Richard J.; Rimele, Thomas J.; Shaw, C. C.

doi:10.1002/chin.198643150

Cited by 3 publications

(3 citation statements)

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“…Examination of the antihypertensive activity of the pyrrolo analogue 71 of labetalol (70, Figure 64), an R-and β-adrenergic receptor antagonist [127][128] provides further evidence for the successful use of the indole phenol bioisosteric replacements. 129 The indolo analogue 71 of labetalol (70) was found to reduce blood pressure in spontaneously hypertensive rats, without causing a decrease in heart rate. The antihypertensive activity of these compounds is related to their ability to hydrogen bond to the adrenergic receptors.…”

Section: Hydroxyl Group Bioisosteresmentioning

confidence: 99%

Bioisosterism: A Rational Approach in Drug Design

1996

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Section: Hydroxyl Group Bioisosteresmentioning

confidence: 99%

Bioisosterism: A Rational Approach in Drug Design

1996

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“…Thus, the free phenol, which is critical for proton ionophore activity, may hinder the accumulation of our closantel-based compounds. Therefore, from this study, three possibilities for enhancing nematode penetrability are taking a prodrug approach by masking the free phenol, the synthesis of other analogues incorporating the functional groups identified in this report, and the synthesis of phenol isosteric scaffolds (e.g., indazole). − …”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Biological Activities of Closantel Analogues: Structural Promiscuity and Its Impact on Onchocerca volvulus

et al. 2011

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Onchocerciasis, or river blindness, is a neglected tropical disease that affects more than 37 million people worldwide, primarily in Africa and Central and South America. We have disclosed evidence that the larval-stage-specific chitinase, OvCHT1, may be a potential biological target for affecting nematode development. On the basis of screening efforts, closantel, a known anthelmintic drug, was discovered as a potent and highly specific OvCHT1 inhibitor. Originally, closantel's anthelmintic mode of action was believed to rely solely on its role as a proton ionophore; thus, the impact of each of its biological activities on O. volvulus L3 molting was investigated. Structure-activity relationship studies on an active closantel fragment are detailed, and remarkably, by use of a simple salicylanilide scaffold, compounds acting only as protonophores or chitinase inhibitors were identified. From these data, unexpected synergistic protonophore and chitinase inhibition activities have also been found to be critical for molting in O. volvulus L3 larvae.

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“…This approach has been useful for determining the nature of the hydrogen bonding between phenol-containing ligands and receptor proteins. [1][2][3][4] For example Asselin et al1 demonstrated that the "indolic" aminotetralin 2a (Figure 1) showed dopaminergic effects and thus mimicked the action of 7-hydroxy-2-(iV^V-dipropylamino)-l,2,3,4-tetrahydronaphthalene (7-OH-DPAT, lb). It was pointed out that, since the lone pairs in the indole nitrogen of 2a cannot participate in a H-bond (due to its contribution to the aromaticity), the indole NH moiety can only participate as a H-bond donor (electron-pair acceptor).…”

Section: Introductionmentioning

confidence: 99%

6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as Potent and Orally Active Serotonin 5-HT1A Receptor Agonists

Stjernlöf¹,

Nilsson²,

Åndersson³

et al. 1994

J. Med. Chem.

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Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).

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ChemInform Abstract: Indole‐Phenol Bioisosterism. Synthesis and Antihypertensive Activity of a Pyrrolo Analogue of Labetalol.

Abstract: Das Pyrrolo‐Analogon (XIa) des Labetalols (XII) wird ausgehend vom N‐Acetylindolin (I) entsprechend dem Formelschema in einer vielstufigen Reaktionssequenz hergestellt.

Cited by 3 publications

References 1 publication

Bioisosterism: A Rational Approach in Drug Design

Bioisosterism: A Rational Approach in Drug Design

Design, Synthesis, and Biological Activities of Closantel Analogues: Structural Promiscuity and Its Impact on Onchocerca volvulus

6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as Potent and Orally Active Serotonin 5-HT1A Receptor Agonists

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