Medicinal Chemistry Approaches for Multitarget Drugs

Abstract

It has become increasingly well recognized that modulating multiple biological targets in parallel can be beneficial for treating diseases with complex etiologies such as cancer, asthma, and psychiatric diseases. Both screening and knowledge‐based strategies have been used for generating ligands with a specific multitarget profile (designed multiple ligands or DMLs). DML projects are often challenging for medicinal chemists, with the need to appropriately balance affinity for two or more targets while obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. The physicochemical properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued. Since DML projects are resource hungry, an early assessment of the feasibility of any given DML project is essential.

Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia

“…The framework combination strategy has been already successfully applied in drug discovery to develop multifunctional drugs that have been approved for human clinical use. 35 On the basis of this strategy, we have previously successfully identified several series of druglike multifunctional ligands acting on a defined set of serotonin and dopamine receptors, with a representative molecule 1 portrayed in Figure 1 . We found that the superimposition of the selective 5-HT 7 receptor antagonist, SB 258719, with the potent 5-HT 6 receptor antagonist, SB214111, showed a remarkable overlap of the pharmacophore features to yield a common N -(3-(piperidin-1-yl)propyl)benzenesulfonamide fragment, with molecular recognition for both 5-HT 6 and 5-HT 7 receptors.…”

“…In this approach, the degree of framework overlap is systematically increased until the frameworks overlap maximally to give the simplest single molecule, with druglike properties. The framework combination strategy has been already successfully applied in drug discovery to develop multifunctional drugs that have been approved for human clinical use . On the basis of this strategy, we have previously successfully identified several series of druglike multifunctional ligands acting on a defined set of serotonin and dopamine receptors, with a representative molecule 1 portrayed in Figure .…”

Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms

“…Since 2004, Morphy et al. started to systematically review strategies for multifunctional ligands development. − MTDLs are agents that treat multifactorial diseases by interacting with multiple targets involved in pathogenesis . This strategy could avoid many pitfalls. − In Table , the advantages and disadvantages of the above two approaches are discussed.…”

Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer’s and Other Neurodegenerative Diseases

“…The rational design of multitargeted compounds is challenging, especially when attempting to merge multiple molecular frameworks and the corresponding underlying pharmacophores in a single small molecule. 32 However, a series of fungicidal diaryl-pyrazoles (e.g., 1 , Figure 1 ) and -imidazoles (e.g., 2 , Figure 1 ) with known MT-stabilizing activity exhibit tricyclic structures similar to those found in known nonsteroidal anti-inflammatory drugs (NSAIDs) such as the potent COX-1 inhibitor 33 SC560 ( 3 , Figure 1 ) and, to a lesser extent, the dual COX/5-LOX inhibitor 34 licofelone ( 4 , Figure 1 ). Furthermore, molecular docking studies indicated that selected representative examples of these MT-stabilizing imidazoles could fit within the arachidonic acid binding site of COX-1 with a predicted binding energy that is comparable (i.e., within 2 kcal/mol) to that of 3 (see Figure 1 and Supporting Information ).…”

“…The rational design of multitargeted compounds is challenging, especially when attempting to merge multiple molecular frameworks and the corresponding underlying pharmacophores in a single small molecule . However, a series of fungicidal diaryl-pyrazoles (e.g., 1 , Figure ) and -imidazoles (e.g., 2 , Figure ) with known MT-stabilizing activity exhibit tricyclic structures similar to those found in known nonsteroidal anti-inflammatory drugs (NSAIDs) such as the potent COX-1 inhibitor SC560 ( 3 , Figure ) and, to a lesser extent, the dual COX/5-LOX inhibitor licofelone ( 4 , Figure ).…”