Recent advances in the development of active hybrid molecules in the treatment of cardiovascular diseases

Abstract

Multifactorial nature of the underlying pathophysiology of chronic disorders hinders in the effective treatment and management of many complex diseases. The conventional targeted therapies have limited applications due to highly complicated disease etiology. Cardiovascular diseases (CVDs) are the group of disorders of the heart and blood vessels. Currently, there is limited knowledge on the underlying cellular and molecular mechanisms of many of the CVDs due to their complex pathophysiology and co-morbidities. Their management with conventional medications results in failure due to adverse drug reactions and clinical specificity of solo-targeting drug therapy. Therefore, it is critical to introduce an alternative strategy to treat multi-factorial diseases. In the past few years, discovery and use of multi-targeted drug therapy with hybrid molecules have shown promising results with minimal side effects, and thus considered a most effective approach. In this review article, prominent hybrid molecules combining with different active moieties are reported to synergistically and simultaneously block different pathways involved in CVDs. Here, we provide a critical evaluation and discussion on their pharmacology with mechanistic insights and the structure activity relationship. The timely information provided in this article reveals the recent trends of molecular hybridization to the scientific community interested in CVDs and help them in designing the next generation of multi-targeting drug therapeutics.

Keywords: Cardiovascular diseases; Hybrid molecules; Inflammation; Multi-targeted therapeutics; Structure activity relationship.

Fig. 1:. Schematic diagram depicting the multifactorial nature of the cardiovascular diseases (CVDs).

(A) The role of high fat diet, lipopolysaccharide (LPS), and reactive oxygen species (ROS) in CVDs; (B) Cellular pathways in the progression of atherosclerotic plaque and plaque rupture; (C) Pathological role of cyclooxygenase/lipoxygenase enzymes in CVDs; (D) Role and intracellular pathways of voltage-gated calcium channel and the renin-angiotensin-aldosterone system (RAAS) system in CVDs.

Fig. 2:

Design of isatin-aminorhodamine hybrids as selective inhibitors of CLK1/PIM1 kinases. Compounds 1 and 2 are shown with their IC₅₀ values for CLK1 or PIM1.

Fig. 3:

Potent hybrid molecules acting on enzymes in the arachidonic acid metabolism to release inflammatory mediators in CVDs. The IC₅₀ values of each compound from 3 to 19 are shown against epoxide hydrolase, COX-1, COX-2 or 15-LOX and other targets.

Fig. 4:

Hybrid molecules active against oxidative stress, angiotensin-II and ACE enzyme for the treatment of CVDs.

Fig. 5:

Hybrid molecules acting as α- and β-adrenergic receptor blockers in the treatment of CVDs

Fig. 6:

Various hybrid molecules directly inhibiting the pro-inflammatory biomarkers involved in the pathogenesis of CVDs.

Fig. 7:

Various hybrid molecules acting as anti-adipogenic agents and calcium ion channel blockers.

Fig. 8:

Dual acting hybrid molecules in clinical trials for the treatment of CVDs