Heterocyclic rings are abundant in natural compounds, active pharmaceutical ingredients, and excipients. Being highly versatile, they are often found as synthetic precursors or (bio)isosteres of troublesome functional groups in medicinal chemistry and more than 80% of biologically active molecules contain at least one heterocycle in their structure. The crucial properties of these privileged scaffolds justify their role in modern drug design and development pipelines, especially in the scaffold-hopping strategy applied to enzyme modulation. Oxygen-, nitrogen-, and sulfur-containing compounds exhibit a wide range of biological activities mimicking natural molecules or endogenous metabolites, thus reinforcing the interactions with the target(s). A large chemical diversity can be obtained by different and innovative synthetic methodologies to broaden the available drug-like chemical space and achieve more robust structure-activity relationships within each scaffold. Moreover, the presence of heteroatoms could provide proper modulation of solubility, lipophilicity, polarity, and hydrogen bonding ability toward biologically active agents, as well as the optimization of their ADME/Tox properties.

The goal of this Research Topic is to highlight alternative synthetic approaches that can overcome issues related to the principles of the 2030 Agenda and those of Green Chemistry. Final compounds can be obtained easily and in high yields but reducing costs and waste material. New drug-like compounds can avoid failures in the drug discovery process and economic waste. These improvements will be disclosed in more interesting and rational papers which can gather attention from pharmaceutical companies and academia. Bioisosteric replacements can improve the success rate to obtain hit compounds for further development. This process can be also corroborated or suggested by in silico techniques.

We welcome Original Research, Review, Mini Review and Perspective articles on themes including, but not limited to:
• Innovative synthesis of bioactive heterocycles
• Drug design strategies for bioactive heterocycles
• In silico investigations of enzyme-heterocycle interactions
• Biological and enzymatic activity screening of heterocyclic compounds
• Hyphenated analytical techniques to characterize heterocycles
• Isolation of heterocyclic compounds from natural matrices

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Recent Advances in the Design of Heterocyclic Modulators of Druggable Enzymes