Molecular Variations Based on Isosteric Replacements

Ciapetti, Paola; Giethlen, Bruno

doi:10.1016/b978-0-12-374194-3.00015-9

Cited by 27 publications

(20 citation statements)

References 208 publications

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“…The bioisosteric replacement of a carboxamide with a sulfonamide group is a common design strategy in medicinal chemistry that has been used to improve biological activity, bioavailability, and metabolic stability of drug candidates31. Accordingly, the type I inhibitor was designed by replacing the carboxamide group of compound 1 with a sulfonamide group.…”

Section: Resultsmentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

128

102

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Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.

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Section: Resultsmentioning

confidence: 99%

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Košak¹,

Brus²,

Knez³

et al. 2016

Sci Rep

128

102

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“…Therefore, we decided to replace the ethoxycarbonyl group of 3 (A region) with a potentially more stable five-membered heterocyclic nucleus, the bioisosteric pyrrole, furan, and thiophene moieties. 18 Preliminary modeling studies showed that, with respect to the small/medium linear chain, 15 the five-membered heterocycle at position 2 of the indole nucleus could form new hydrophobic interactions with Lys254 and Leu248 of the colchicine site of tubulin (Supporting Information).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

et al. 2011

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New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.

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“…BuChE may then act as a compensatory mechanism for ACh metabolism, aggravating the toxicity of Aβ 9 . To obtain more metabolically stable cholinomimetic ligands, it is possible to replace the ester group with a series of five-membered rings like oxadiazoles, thiadiazoles, triazoles and tetrazoles 10 . Some researchers have studied thiadiazoles extensively and the compounds bearing thiadiazole moiety have been reported to exhibit significant anticholinesterase activity 11,12 .…”

Section: Introductionmentioning

confidence: 99%