Advancements in the design and development of pyrazoline-based antimycobacterial agents: an update and future...

Pyrazoline scaffolds have attracted significant interest in medicinal chemistry due to their broad spectrum of pharmacological activities. Pyrazole-based drugs are either already approved or are currently undergoing clinical trials across a range of therapeutic areas. Pyrazolines (Δ²-pyrazolines or 2-pyrazoline or 4,5-dihydropyrazoles) evolved as cyclic analogues of thioacetazone and were explored for enhanced antitubercular activity over the past five decades. The scope of this review focused on how extensively the chemical space around pyrazolines has been explored in relation to their antitubercular activity, rather than presenting a general structure-activity relationship (SAR) account. In this exercise, we covered key molecular modifications, including rationale substitutions and conjugations, aimed at enhancing the potency in general. Additionally, information pertaining to in vitro/in silico target interaction and ADMET studies are also covered. A dedicated section is included to showcase target-oriented strategies (InhA, cytochrome P450 14α-sterol demethylase, and enzymes involved in the mycobactin biosynthesis pathway), recent patents, suggested schemes for reported pyrazolines, and an overview of research methodologies and evaluation models. We believe that this review will enable medicinal chemists to map unexplored chemical space in identifying critical research gaps. This is essential for the rational design and development of potent antitubercular agents against tuberculosis (TB), drug-resistant tuberculosis (DR-TB), and other non-tubercular mycobacterial diseases (NTMD).