Emerging insights into chemistry and therapeutic potentials of functionalized hexahydroquinolines

Abstract

Quinolines are well-established scaffolds in drug discovery and form the core of many FDA-approved medicines. Among their reduced analogues, hexahydroquinolines (HHQs) have gained increasing attention due to their structural adaptability and broad pharmacological relevance. Research has largely focused on the 1,4,5,6,7,8-hexahydroquinoline framework, although interest in other variants, including 2-oxo derivatives, is steadily growing. This review summarizes recent progress in HHQ chemistry, with emphasis on synthetic strategies and emerging therapeutic applications. Traditional multicomponent reactions such as the Hantzsch, Antaki, and Stankevich methods are discussed alongside more recent green synthetic strategies, including the use of natural and heterogeneous catalysts, catalyst-free protocols, and alternative activation techniques such as ultrasonication. These sustainable protocols often provide improved yields under milder conditions and shorter reaction times. A recurring feature of HHQ synthesis is the preferential formation of 5-oxo derivatives. The mechanistic basis for this structural dominance and the synthetic approaches for the other underexplored HHQ chemotypes are examined. From a biological perspective, HHQs have demonstrated notable activity across several therapeutic areas, including antiprotozoal potential against Plasmodium falciparum , Leishmania species, and Toxoplasma gondii , with several compounds exhibiting dual-stage or transmission-blocking effects. Additional reports also include their usage as modulators of multidrug resistance in cancer cells, antimicrobial, anti-inflammatory, antioxidant, and cardiovascular activities. This review aims to provide a focused and practical reference for researchers engaged in heterocyclic drug design and development involving hexahydroquinoline scaffolds.