Reconnecting the roots of hydrogen sulfide (H₂S) with medicinal chemistry: Lessons accomplished and challenges so far

Previously known for its unpleasant odour and mortality in elevated concentrations, hydrogen sulfide (H₂S) is currently considered a complex molecule having significant physiological advantages. After nitric oxide (NO) and carbon monoxide (CO), H₂S is regarded as the third endogenous gasotransmitter, performing many biological functions in the human body. The essential functions include but are not limited to regulating inflammation, maintaining the redox potential, cellular signalling, and metabolic processes. Moreover, an imbalance in its expression or dysfunction of its precursors and associated enzymes in its biosynthesis leads to multiple pathological conditions, including cancer, diabetes, neurodegenerative disorders, COVID-19, etc. Nonetheless, its upregulation is also reported to dysregulate normal physiological conditions and precipitate different diseases and cancer, thus acting as a "Double-edged sword." Despite this, H₂S is still being widely explored for its therapeutic potential in various disease states. The present review is put forth to focus on hydrogen sulfide's dichotomous properties, emphasising its critical functions and therapeutic applications. This compilation provides a state-of-the-art analysis of the broad application of H₂S donors in developing therapeutic interventions, release mechanisms, and their use in numerous diseases and disorders. Furthermore, various analytical techniques for detecting and quantifying the H₂S release in biological samples via the hybrid donors are also discussed. We herein expect that an in-depth comprehension of the multiple activities of H₂S can aid in discovering novel therapeutic interventions critical for holistic disease management measures in the future.