Advances in nonclassical phenyl bioisosteres for drug structural optimization.

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Drug Discovery

Background:

• Phenyl rings are common in drugs but can cause poor physicochemical properties.
• Nonclassical phenyl bioisosteres (NPBs) are emerging as alternatives for structural optimization.
• NPBs possess unique steric and physicochemical properties beneficial for drug development.

Purpose of the Study:

• To review the effects of widely reported NPBs on physicochemical properties and biological activities.
• To discuss considerations and practical solutions for using NPBs in structural optimization.
• To highlight NPBs as valuable tools in medicinal chemistry.

Main Methods:

• Literature review of NPBs including bicyclo[1.1.1]pentane (BCP), bicyclo[2.1.1]hexanes (BCH), bicyclo[2.2.2]octane (BCO), cubane (CUB), and closo-carboborane.
• Analysis of reported effects on molecular properties and biological activity.
• Discussion of challenges and solutions in NPB application.

Main Results:

• NPBs significantly alter steric and electronic properties compared to phenyl groups.
• Specific NPBs demonstrate improved solubility, metabolic stability, and target engagement.
• The review identifies key NPBs and their impact on drug candidate profiles.

Conclusions:

• NPBs are effective replacements for phenyl rings in drug design, enhancing molecular properties.
• Careful consideration of NPB selection and application strategies is crucial for successful optimization.
• This review provides a valuable resource for medicinal chemists utilizing NPBs.