Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

Agnese C. Pippione; Franco Dosio; Alex Ducime; Antonella Federico; Katia Martina; Stefano Sainas; Bente Frølund; Major Gooyit; Kim D. Janda; Donatella Boschi; Marco L. Lolli

doi:10.1039/c5md00182j

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

Agnese C. Pippione^*, Franco Dosio, Alex Ducime, Antonella Federico, Katia Martina, Stefano Sainas, Bente Frølund, Major Gooyit, Kim D. Janda, Donatella Boschi, Marco L. Lolli

^*Corresponding author af dette arbejde

31 Citationer (Scopus)

Abstract

Bioisosterism and scaffold hopping are two widely used approaches in medicinal chemistry for the purpose of lead optimization. The study highlights the physicochemical properties of the 4-hydroxy-1,2,3-triazole scaffold, a less investigated heterocyclic system. Synthetic strategies to obtain different N-substituted 4-hydroxy-1,2,3-triazole isomers are presented, and their role as possible isosteres of the carboxylic acid is discussed. The aim is to use this system to modulate the acidic moieties present in lead compounds and, at the same time, to regiodirect substituents in set directions, through targeted substitution on the three nitrogen atoms of the triazole ring. Through this approach, compounds having enhanced binding affinity, will be sought. Two examples of bioisosteric applications of this moiety are presented. In the first example, a classical bioisosteric approach mimicking the distal (S)-glutamic acid carboxyl group using the 4-hydroxy-1,2,3-triazole moiety is applied, to obtain two promising glutamate analogs. In the second example, a scaffold hopping approach is applied, replacing the phenolic moiety present in MDG-1-33A, a potent inhibitor of Onchocerca volvulus chitinase, with the 4-hydroxy-1,2,3-triazole scaffold. The 4-hydroxy-1,2,3-triazole system appears to be useful and versatile in drug design.

Originalsprog	Engelsk
Tidsskrift	MedChemComm
Vol/bind	6
Udgave nummer	7
Sider (fra-til)	1285-1292
Antal sider	8
ISSN	2040-2503
DOI	https://doi.org/10.1039/c5md00182j
Status	Udgivet - 1 jul. 2015

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Pippione, A. C., Dosio, F., Ducime, A., Federico, A., Martina, K., Sainas, S., Frølund, B., Gooyit, M., Janda, K. D., Boschi, D., & Lolli, M. L. (2015). Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches. MedChemComm, 6(7), 1285-1292. https://doi.org/10.1039/c5md00182j

Pippione, AC, Dosio, F, Ducime, A, Federico, A, Martina, K, Sainas, S, Frølund, B, Gooyit, M, Janda, KD, Boschi, D & Lolli, ML 2015, 'Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches', MedChemComm, bind 6, nr. 7, s. 1285-1292. https://doi.org/10.1039/c5md00182j

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abstract = "Bioisosterism and scaffold hopping are two widely used approaches in medicinal chemistry for the purpose of lead optimization. The study highlights the physicochemical properties of the 4-hydroxy-1,2,3-triazole scaffold, a less investigated heterocyclic system. Synthetic strategies to obtain different N-substituted 4-hydroxy-1,2,3-triazole isomers are presented, and their role as possible isosteres of the carboxylic acid is discussed. The aim is to use this system to modulate the acidic moieties present in lead compounds and, at the same time, to regiodirect substituents in set directions, through targeted substitution on the three nitrogen atoms of the triazole ring. Through this approach, compounds having enhanced binding affinity, will be sought. Two examples of bioisosteric applications of this moiety are presented. In the first example, a classical bioisosteric approach mimicking the distal (S)-glutamic acid carboxyl group using the 4-hydroxy-1,2,3-triazole moiety is applied, to obtain two promising glutamate analogs. In the second example, a scaffold hopping approach is applied, replacing the phenolic moiety present in MDG-1-33A, a potent inhibitor of Onchocerca volvulus chitinase, with the 4-hydroxy-1,2,3-triazole scaffold. The 4-hydroxy-1,2,3-triazole system appears to be useful and versatile in drug design.",

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AU - Ducime, Alex

AU - Federico, Antonella

AU - Martina, Katia

AU - Sainas, Stefano

AU - Frølund, Bente

AU - Gooyit, Major

AU - Janda, Kim D.

AU - Boschi, Donatella

AU - Lolli, Marco L.

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AB - Bioisosterism and scaffold hopping are two widely used approaches in medicinal chemistry for the purpose of lead optimization. The study highlights the physicochemical properties of the 4-hydroxy-1,2,3-triazole scaffold, a less investigated heterocyclic system. Synthetic strategies to obtain different N-substituted 4-hydroxy-1,2,3-triazole isomers are presented, and their role as possible isosteres of the carboxylic acid is discussed. The aim is to use this system to modulate the acidic moieties present in lead compounds and, at the same time, to regiodirect substituents in set directions, through targeted substitution on the three nitrogen atoms of the triazole ring. Through this approach, compounds having enhanced binding affinity, will be sought. Two examples of bioisosteric applications of this moiety are presented. In the first example, a classical bioisosteric approach mimicking the distal (S)-glutamic acid carboxyl group using the 4-hydroxy-1,2,3-triazole moiety is applied, to obtain two promising glutamate analogs. In the second example, a scaffold hopping approach is applied, replacing the phenolic moiety present in MDG-1-33A, a potent inhibitor of Onchocerca volvulus chitinase, with the 4-hydroxy-1,2,3-triazole scaffold. The 4-hydroxy-1,2,3-triazole system appears to be useful and versatile in drug design.

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Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

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