Spirocyclic compounds as innovative tools in drug discovery for medicinal chemists

Author(s)

Varela, Marina T. ; Dias, Gleiston G. ; de Oliveira, Luiz Fernando N. ; de Oliveira, Ramon G. ; Aguiar, Francielle D. ; Nogueira, Joao Pedro ; Cruz, Luiza R. ; Dias, Luiz C.

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 287, p. 23-pg., 2025-04-05.

Abstract

The occurrence of spirocyclic motifs in clinical candidates and approved drugs is on the rise. This is related to the improvement of drug-like properties that can be achieved by introducing this sp3-rich system into bioactive compounds. Given the increasing number of synthetic methodologies and building blocks available, spirocycles are becoming widely accessible to medicinal chemists. From restricting conformation to induce a better fit with the target, to modulation of physicochemical and pharmacokinetic properties, spirocycles are being used to address several challenges in drug discovery. This review covers general aspects of the chemistry of spirocycles, highlighting some key strategies for their preparation. As reported in publications over the past five years, we demonstrate that, beyond the exploration of structure-activity relationships (SAR) in medicinal chemistry, the use of spirocycles is an attractive approach for enhancing properties such as potency, selectivity, physicochemistry, and pharmacokinetics. (AU)

• FAPESP's process: 22/13110-8 - Optimization of Leading Compounds for the Treatment of Tropical Parasitic Diseases in Collaboration with the Drugs for Neglected Diseases Initiative (DNDi)
• Grantee: João Pedro Nogueira Bonesconto
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/50655-9 - FAPESP/MMV/DNDi/UNICAMP/USP Consortium to discover new drugs for the treatment of tropical parasitic diseases
• Grantee: Luiz Carlos Dias
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• FAPESP's process: 22/10577-2 - Drug discovery of pre-clinical candidates for Chagas Disease at the MINDI consortium
• Grantee: Gleiston Gonçalves Dias
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 23/10723-1 - Drug discovery of pre-clinical candidates for Chagas Disease
• Grantee: Marina Themoteo Varela
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/24344-4 - Optimization of lead compounds for treatment of tropical parasitic diseases in collaboration with the Drugs for Neglected Diseases Initiative (DNDi)
• Grantee: Ramon Guerra de Oliveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/10715-9 - Design, synthesis and optimization of compounds containing the spirochromane core for the treatment of Chagas disease
• Grantee: Luiz Fernando Nascimento de Oliveira
• Support Opportunities: Scholarships in Brazil - Master