Synthesis of Nitrogen‐Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog
8 affiliations
- 1Faculty of Pharmaceutical Sciences of Ribeirão Preto Department of Pharmaceutical Sciences University of Sao Paulo Ribeirão Preto Brazil
- 2Department of Chemistry KU Leuven Leuven Belgium
- 3School of Pharmacy University of East Anglia Norwich Norfolk
- 4Translational Neuropsychiatry Unit Department of Clinical Medicine Aarhus University Aarhus Denmark
- 5Departamento de Produtos Farmacêuticos Faculdade de Farmácia Universidade Federal de Minas Gerais Belo Horizonte Brazil
- 6Faculty of Pharmaceutical Sciences University of Sao Paulo São Paulo Brazil
- 7Institute of Advanced Studies of the University of São Paulo University of São Paulo São Paulo SP Brazil
- 8Department of Biomedicine Aarhus University Aarhus Denmark
Abstract
Heteroaromatic ring systems play a crucial role in drug development because they modulate physicochemical properties and expand the range of molecular interactions compared to non‐heterocyclic aromatic rings. They are also widely represented among approved drugs. Among heteroatoms, nitrogen is the most prevalent in the diverse scaffold space of heterocyclic drugs, including those generated by fragment‐based drug discovery approach. In this work, we show the synthesis of a set of novel or underexplored nitrogen heterocyclic fragments, obtained in three to five steps in moderate yields. In total, 12 fused [6,6] saturated/unsaturated bicycles were synthesized, which fulfill the general rule of fragment‐like compounds. These heterocycles increased the fragment space of the CRAFT library and showed potential application in scaffold‐hopping strategies for drug design. As a proof of concept, 2,6‐naphthyridin‐3‐ol 2 was used to replace the 7‐hydroxy‐3,4‐dihydroquinolin‐2(1H)‐one core of aripiprazole 41, generating 3‐(4‐(4‐(2,3‐dichlorophenyl)piperazin‐1‐yl)butoxy)‐2,6‐naphthyridine 40, that effectively blocked cocaine‐induced hyperactivity in rodents at 20 mg/kg without inducing catalepsy, displaying a pharmacological profile similar to aripiprazole and demonstrating promising antipsychotic potential.
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BibTeX
@article{price2026synthesis,
title = {{Synthesis of Nitrogen‐Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog}},
author = {Temitayo Omowumi Alegbejo Price and Pieterjan Winant and Paulo Eliandro da Silva Júnior and Shaiani Maria Gil de Melo and Pedro Henrique Gobira and Julia Possamai Gimenes and Pedro Tenório Teixeira Fernandes Leite and Vinícius Gonçalves Maltarollo and Gustavo Henrique Goulart Trossini and A. Ganesan and Sâmia Regiane Lourenço Joca and Wim Dehaen and Flavio da Silva Emery},
journal = {Chemmedchem},
year = {2026},
month = oct,
doi = {10.1002/cmdc.70505},
url = {https://doi.org/10.1002/cmdc.70505},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthesis of Nitrogen‐Containing Heterocyclic Scaffolds and Applications in Scaffold Hopping: Development of an Aripiprazole Analog
AU - Temitayo Omowumi Alegbejo Price
AU - Pieterjan Winant
AU - Paulo Eliandro da Silva Júnior
AU - Shaiani Maria Gil de Melo
AU - Pedro Henrique Gobira
AU - Julia Possamai Gimenes
AU - Pedro Tenório Teixeira Fernandes Leite
AU - Vinícius Gonçalves Maltarollo
AU - Gustavo Henrique Goulart Trossini
AU - A. Ganesan
AU - Sâmia Regiane Lourenço Joca
AU - Wim Dehaen
AU - Flavio da Silva Emery
PY - 2026
DA - 2026/10/01
JO - Chemmedchem
DO - 10.1002/cmdc.70505
UR - https://doi.org/10.1002/cmdc.70505
AB - Heteroaromatic ring systems play a crucial role in drug development because they modulate physicochemical properties and expand the range of molecular interactions compared to non‐heterocyclic aromatic rings. They are also widely represented among approved drugs. Among heteroatoms, nitrogen is the most prevalent in the diverse scaffold space of heterocyclic drugs, including those generated by fragment‐based drug discovery approach. In this work, we show the synthesis of a set of novel or underexplored nitrogen heterocyclic fragments, obtained in three to five steps in moderate yields. In total, 12 fused [6,6] saturated/unsaturated bicycles were synthesized, which fulfill the general rule of fragment‐like compounds. These heterocycles increased the fragment space of the CRAFT library and showed potential application in scaffold‐hopping strategies for drug design. As a proof of concept, 2,6‐naphthyridin‐3‐ol 2 was used to replace the 7‐hydroxy‐3,4‐dihydroquinolin‐2(1H)‐one core of aripiprazole 41, generating 3‐(4‐(4‐(2,3‐dichlorophenyl)piperazin‐1‐yl)butoxy)‐2,6‐naphthyridine 40, that effectively blocked cocaine‐induced hyperactivity in rodents at 20 mg/kg without inducing catalepsy, displaying a pharmacological profile similar to aripiprazole and demonstrating promising antipsychotic potential.
SN - 1860-7179
SN - 1860-7187
ER -