PYRAZOLE AS A PRIVILEGED HETEROCYCLIC SCAFFOLD: SYNTHETIC INNOVATIONS, STRUCTURE ACTIVITY RELATIONSHIPS, AND TRANSLATIONAL CHALLENGES

Abstract

Pyrazole has been recognized as a privileged structure because of its versatility, desirable physicochemical characteristics, and universal applicability in medicinal chemistry, agricultural chemicals, and functional materials. In this article, the recent progress in pyrazole research has been critically surveyed, focusing on the relationships between molecular structure, synthetic method, and bioactivity or functionality. From a medicinal chemistry perspective, the structure-activity relationship studies have clearly demonstrated that substitution at the C-3, C-5, and N-1 atoms of pyrazole plays a key role in modulating affinity, selectivity, tautomerism, and ADME characteristics. Although pyrazole derivatives have been found to possess potential activity in cancer, inflammation, infectious diseases, and metabolism-related disorders, their translational potential has been hindered by inadequate ADMET characteristics. The review also analyses modern synthetic strategies, such as green, solvent-free reactions, reactions catalysed using microwaves, ultrasonic waves, mechano-chemical reactions, and flow chemistry, which have increased the molecular diversity and reaction efficacies. Although there are concerns related to scalability and reproducibility in laboratory reactions, pyrazole merged with different pharmaceutical scaffolds are stated to be an exciting strategy for developing multi-target drugs in which there exists a large gap between cellular and in vitro efficacies. Further, implications of the emergence of pyrazole-based materials, particularly pyrazole metal–organic frameworks, are also touched upon in this article. It also points out that the role of computing tools in pyrazole-based design is on the upsurge, but docking score predictions must be validated by experimental evidence. In conclusion, this review can be considered an important paper in providing a complete overview on the research on pyrazole, contributing to the field in highlighting many challenges for future developments.