Due to efforts to develop new drug arsenals faster to overcome the difficulties of medicinal chemistry (multistage and highly wasteful processes), multicomponent reactions (MCRs) have emerged as a plausible solution. MCRs are convergent reactions in which three or more reagents are combined in one step to yield a single product that contains most of the atoms from the starting materials . Among the advantages of MCRs are their high atom economy and efficiency in bond formation, along with the cost-effectiveness of separating and purifying products . These aspects are aligned with the goal of addressing concerns related to the generation of environmentally hazardous waste . In addition, this type of reaction allows for the efficient discovery of low molecular weight compounds. As a result, most of these compounds are drug-like according to Lipinski's rule of five (Ro5) .

Figure 1: Classical MCRs.

Due to its versatility, one of the most prevalent of these MCRs is the Ugi reaction . This reaction generally combines an isocyanide with an acid, an amine, and an aldehyde or ketone to obtain α-acylaminoamides. Innovation in recent years with alternative reagents, like N-hydroxyimides or nitric acid in place of an acid, N-alkylated hydrazines, or nitrobenzene derivatives (reduced in situ to anilines) instead of amines, and in situ-prepared isocyanides, makes it a versatile method for synthesizing diverse scaffolds .

Figure 2: Different scaffolds that can be formed with the Ugi adduct.

Central nervous system (CNS) diseases are the main cause of disability and the second cause of mortality worldwide, indeed, according to the 2019 World Health Organization report stroke ranked second among the leading causes of disease globally, followed by Alzheimer's disease (AD), and other dementias . CNS diseases can be classified according to the etiological and pathological features into traumatic diseases, such as spinal cord and traumatic brain injuries, neurodegenerative diseases, such as AD and Parkinson’s disease (PD), demyelinating diseases such as multiple sclerosis (MS), etc. .

However, despite advances in the etiology of psychosis indicating both polygenetic and environmental factors, significant gaps remain . Psychosis is a subgroup of severe mental illnesses characterized by delusions, hallucinations, and disorganized behavior. This illness can manifest itself across a spectrum of conditions such as major depressive disorder (MDD), bipolar disorder, delusional and schizophreniform disorder. The prototypical psychotic disorder is schizophrenia, which is a chronic and debilitating condition whose etiology is unclear and about which there are many different hypotheses . In the case of MDD, even though the etiology is unknown, there are several models that have focused on genes, environmental factors, and gene–environment interactions . In relation to epilepsy, the etiology of seizures depends on age. In children, seizures are frequently originated by genetic factors, malformations of cortical evolution, and injuries from perinatal events. In adults lacking an inherited tendency, typical causes include encephalitis or meningitis, traumatic brain injuries, and brain tumors. Finally, in elderhood, seizures are often linked to primary craniocephalic trauma, brain tumors, and neurodegenerative disorders .

This review centers on five neurological disorders where ligands obtained using multicomponent reactions (MCRs) have been identified: Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, and epilepsy. Our goal is not to provide a comprehensive survey but rather to spotlight key studies that address significant CNS disorders, pertinent drug targets, and various MCR methodologies. We have thoughtfully selected representative articles and extend our apologies to authors whose important works may not be included. By focusing on these studies, we aim to present a clear and concise view of current research directions and significant advancements in the field.

The pathogenesis of AD is still not clear but is marked as a multifactorial disease , including a good deal of hypotheses involving the cholinergic hypothesis, glutamate excitotoxicity, tau aggregation, abnormal extracellular accumulation of Aβ peptides, and oxidative stress (OS) .

Alzheimer’s disease (AD) is commonly thought to emerge from a deficiency of the neurotransmitter acetylcholine (ACh) in neuronal and neuromuscular regions, according to the most recognized theory. This deficit may be caused by reduced synthesis or enzymatic function of acetylcholinesterase (AChE) on ACh. Among the five drugs prescribed for AD, four (donepezil, rivastigmine, galantamine, and tacrine) are built upon the cholinergic hypothesis . In contrast, memantine emerges as the only drug available that targets the glutamatergic system for AD, functioning as a non-competitive antagonist of the N-methyl-ᴅ-aspartate (NMDA) receptor to regulate excessive glutamate stimulation . The β-amyloid hypothesis for AD is based on the formation of senile plaques, which are formed after the accumulation of insoluble aggregates of β-amyloid protein, primarily Aβ-42, in the brain. The gene for amyloid precursor protein (APP), found on chromosome 21, undergoes a mutation that causes the production of Aβ-42 instead of Aβ-40. APP, a transmembrane protein, is typically cleaved by α-secretase and γ-secretase, which leads to the formation of soluble Aβ-40. However, when cleaved by β-secretase and γ-secretase, it produces Aβ-42. This form misfolds, leading to the formation of insoluble protein aggregates known as senile plaques, causing toxicity . Oxidative stress occurs when there is an imbalance between prooxidants and antioxidants in the body, leading to damage in various biomolecules like DNA and lipids. Lipid peroxidation and membrane disruption can cause random cross-linking, resulting in cell death and the fragmentation of proteins and enzymes. Elevated concentrations of reactive oxygen species (ROS) from various molecular processes contribute to the oxidation of proteins, nucleic acids, polysaccharides, and lipids. These modifications can impact the structure and biological functions of these molecules, ultimately leading to neuronal death, as observed in conditions like AD .

Recent studies highlight OS as an early event in AD pathogenesis, and mitochondria-directed and metabolic antioxidants have shown efficacy in AD mouse models, with ongoing trials for vitamin E and selenium .

Scheme 1: Oxoindole-β-lactam core produced in a U4C-3CR.

Figure 3: Most active oxoindole-β-lactam compounds developed by Brãndao et al. .

Scheme 2: Ugi-azide synthesis of benzofuran, pyrazole and tetrazole hybrids.

Figure 4: The most promising hybrids synthesized via the Ugi-azide multicomponent reaction reported by Kushwaha et al. .

Scheme 3: Four-component Ugi reaction for the synthesis of novel antioxidant compounds.

The antioxidant properties were determined by oxygen radical absorbance capacity assay (ORAC-FL), expressed as Trolox equivalents (TE) and using fluorescein as probe. Additionally, the study investigated the ability of the compounds to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in cells containing the Nrf2/antioxidant response element (ARE).

Figure 5: Most potent antioxidant compounds obtained through the Ugi four-component reaction developed by Pachón-Angona et al. .

Scheme 4: Four-component Ugi reaction to synthesize β-amiloyd aggregation inhibitors.

The procedure involved an Ugi reaction using phenolic building blocks protected as allyl ethers, followed by deprotection, acetylation, and high-yielding solvolysis of the polyacetates. Also, the Ugi reaction gave the best results when imine preformation was implemented. In this preliminary paper, it was observed that the ferulic derived part was highly significant and for this reason, further experiments were conducted by Galante et al. maintaining the carboxylic building block.

Figure 6: The most potential β-amiloyd aggregation inhibitors generated by Galante et al. .

Due to the multifactorial pathogenesis of AD, one of the current drug discovery approaches is the so-called multitarget-directed ligands (MTDLs). In 2015, Benchekroun et al. reported the design, synthesis, and biological evaluation of a new family of ferulic acid–tacrine hybrids (FATHs), using the Ugi reaction. FATHs were selected because tacrine is a well-known cholinesterase (ChE) inhibitor, although it is hepatotoxic, and ferulic acid is a potent antioxidant.

Scheme 5: Four-component Ugi reaction to obtain FATH hybrids and the best candidate synthesized.

In 2016, the same group developed ferulic acid–tacrine–melatonin hybrids (FATMHs) and lipoic acid–tacrine–melatonin hybrids (LATMHs), deciding to incorporate melatonin as a new target for the MTDL . Melatonin has the ability to combat OS, which is a crucial factor in the pathogenesis of AD. Moreover, it plays a neuroprotective role against Aβ-peptides and easily crosses the blood–brain barrier (BBB). Finally, recent research has implicated melatonin in modulating the Nrf2/ARE pathway, a crucial defense mechanism against OS and inflammation.

Scheme 6: Four-component Ugi reaction for the synthesis of FATMH hybrids and the best candidate synthesized.

Scheme 7: Petasis multicomponent reaction to produce pyrazine-based MTDLs.

Figure 7: Best pyrazine-based MTDLs synthesized by Madhav et al. .

The neuroprotective effects of the compounds were assessed in comparison to MK-886 and donepezil, employing a widely accepted tauopathy model in SH-SY5Y cells. Notably, compound 7a was identified as the most promising multitarget-directed ligand in the study, exhibiting superior neuroprotection compared to both MK-886 and the commercial drug donepezil in a cell viability MTT assay. These findings reinforced the theory that developing MTDLs could provide a more effective approach for addressing complex neurodegenerative disorders than conventional single-target strategies.

Knoevenagel-based multicomponent reactions: Several quinazolinone derivatives have already been developed as MTDLs, inspired by natural alkaloids such as deoxyvasicinone and evodiamine with promising inhibition of ChEs and antioxidant and neuroprotective effects against glutamate-induced OS in HT-22 cells .

Scheme 8: Synthesis of BCPOs employing a Knoevenagel-based multicomponent reaction and the best candidate synthesized.

As a result, compound 8a has been identified as a promising derivative potentially useful in further AD drug discovery for its antioxidant activity (4.7 TE in ORAC-FL assay), moderate hAChE inhibition (IC50 = 1.28 μM), and non-toxicity in liver HepG2 cells.

Scheme 9: Hantzsch multicomponent reaction for the synthesis of DHPs as novel MTDLs.

The synthesized DHPs result from the juxtaposition of nimodipine, a well-known calcium channel blocker and melatonin, a reputed antioxidant agent. This approach lies in the known association between increased cytosolic calcium levels and the formation of Aβ peptides, which are implicated in AD pathology. Calcium also regulates kinases involved in the hyperphosphorylation of tau, contributing to neurofibrillary tangles. Meanwhile, melatonin is known for its neuroprotective properties, countering oxidative stress by scavenging radical oxygenated species and exhibiting potent antioxidant capacity .

The calcium channel blockade was determined by the measure of Ca2+ influx induced by K+-depolarization in SH-SY5Y neuroblastoma cells, previously loaded with the fluorescent dye Fluo-4AM. On the other hand, the antioxidant activity of the DHPs was evaluated using the ORAC-FL method.

Figure 8: Most active 1,4-dihydropyridines developed by Malek et al. .

Scheme 10: Chromone–donepezil hybrid MTDLs obtained via the Passerini reaction.

Figure 9: Best CDH-based MTDLs as AChE inhibitors synthesized by Malek et al. .

The amyloid hypothesis, which states that β-amyloid (Aβ) aggregates cause the onset and progression of AD, is a leading proposal to explain AD etiology. Based on this hypothesis, compounds that inhibit γ-secretase, one of the enzymes responsible for forming Aβ, are potential therapeutics for AD.

Scheme 11: Replacement of the nitrogen in lactams 11 with an oxygen in 12 to influence hydrogen-bond donating properties and synthesis of the benzodioxepinone derivatives via Passerini reaction.

Scheme 12: MCR 3 + 2 reaction to develop spirooxindole, spiroacenaphthylene, and bisbenzo[b]pyran compounds.

Figure 10: SIRT2 activity of best derivatives obtained by Hasaninejad et al. .

Gewald reaction: Cannabinoid receptors have been proposed as promising neuroprotective targets in several chronic progressive disorders such as AD and PD . Recently, in 2023, Figuerola-Asencio et al. synthesized a series of novel compounds derived from ML192, an antagonist ligand for GRP55. This receptor responds to certain cannabinoids, suggesting it can be part of the endocannabinoid system. GRP55 is extensively distributed throughout the CNS, notably in regions such as peripheral tissues, hippocampus, thalamus, and cerebellum, and in the basal ganglia. The therapeutic potential of GRP55 receptor modulators makes it necessary to search for new selective non-cannabinoid ligands due to the important motor impairment found in mice lacking GPR55 .

Scheme 13: Synthesis of ML192 analogs using the Gewald multicomponent reaction and the best candidate synthesized.

Some of the intermediates of the Gewald reaction were oxidized to provide further exploration of the heterocyclic core. The novel compounds were first evaluated using β-arrestin recruitment assays in CHO (chinese hamster ovary) cells overexpressing human GPR55. These new compounds have been evaluated in competitive binding assays for cannabinoid receptors, but all of them showed to be selective for GPR55 (>4 μM for cannabinoid receptors). Then, the most promising antagonist (14a; IC50 = 0.28 µM) was selected for a G-protein-dependent functional assay, where 14a acted as a weak GPR55 inverse agonist (EC50 = 0.9 µM).

Benzodiazepines are widely used in treating a range of CNS disorders, including epilepsy, muscle relaxation, insomnia, anesthesia, anxiety, and depression . The common coexistence of depression and anxiety may indicate the simultaneous presence of mood and anxiety disorders. Clinical observations imply that benzodiazepines may have utility in treating depression, particularly when accompanied by anxiety. In the initial four weeks of treatment, combining medications proved more effective in reducing depressive symptoms and achieving response and remission of major depression, while showing comparable results in reducing anxiety .

Recent advancements in organic synthesis, particularly through MCRs, have streamlined the synthesis of benzodiazepines, making it more efficient and environmentally friendly . For example, olanzapine as a benzodiazepine-based clinical drug was appropriately and concisely synthesized via MCR .

Over the last twenty years, the Ugi reaction has emerged as a highly considered reaction due to its mild conditions, broad applications, and product diversity. It enables the selective assembly of precursors, facilitating various post-reaction transformations such as deprotection cyclization, 1,3-dipolar cycloaddition, and intramolecular SNAr reactions.

Ugi-4CR/deprotection/cyclization (UDC) strategy: In the UDC approach a protected amine and an electrophilic functional group like esters or ketones are used. Convertible isocyanides can also be employed. Once the Ugi reaction is completed, the protecting group is removed, and the heterocyclic scaffold is subsequently formed .

Scheme 14: Development of 1,5-benzodiazepines via Ugi/deprotection/cyclization (UDC) approach by Xu et al. .

Scheme 15: Synthesis of polysubstituted 1,4-benzodiazepin-3-ones using UDC strategy.

Ugi-4CR/reduction/cyclization (URC) strategy: The URC pathway enables the synthesis of benzodiazepines by using amine surrogates, such as nitro or azide groups, rather than protected amines. Following the Ugi-4CR, the nitro or azide group is reduced to form the amine, leading to a condensation reaction that results in the formation of the benzodiazepine ring .

Scheme 16: Synthetic procedure to obtain 3-carboxamide-1,4-benzodiazepin-5-ones employing Ugi–reduction–cyclization (URC) approach.