Neurodegenerative diseases, ischemic lesions of the central nervous system (CNS), epilepsy, and neuroinflammatory cascades constitute some of the most challenging conditions in modern medical science. The multifactorial nature of their pathogenesis limits the effectiveness of single-target drugs. Consequently, the concept of multi-target medicines is becoming highly relevant. Sulfonic acid derivatives, including taurine, homotaurine, and various sulfobetaine structures, as well as heterocyclic compounds based on pyridine, pyrimidine, and uracil, show great potential as novel multi-target neuroprotectors.

MULTI-TARGET APPROACH

Development of therapeutic agents for central nervous system disorders continues to be one of the most complex objectives in modern pharmacology. Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and epilepsy share a complex pathogenesis that involves oxidative stress, neuroinflammation, mitochondrial dysfunction, neurotransmission disorders, excitotoxicity, and cell death [1, 2]. The conventional ‘one target, one drug’ approach is frequently insufficient for the effective management of such complex diseases. The strategy of Multi-Target Directed Ligands (MTDL) has been actively developed during the recent years. The strategy suggests that it is possible to develop molecules that are capable to produce a simultaneous effect on several key pathogenetic mechanisms [1, 2]. Owing to this approach, therapeutic efficacy can be enhanced, and the risk of drug resistance can be reduced.

The molecules that are capable to concurrently exhibit several types of a pharmacological activity hold considerable value within the scope of multi-target therapeutics. Particularly relevant are sulfonic acid derivatives and nitrogen-containing heterocyclic compounds with a wide range of a biological activity that can modulate various molecular targets of the central nervous system.

TAURINE

While searching for promising frameworks for multitarget agents, endogenous compounds with an established neuroprotective profile evoke inherent interest. Taurine (2-aminoethanesulfonic acid) is such an endogenously produced free amino acid primarily found in the central nervous system (CNS). An extensive amount of data shows that the compound is fundamental to osmoregulation and neuromodulation (including through the GABA system). It also produces a powerful antioxidant, anti-inflammatory and anti-apoptotic effect. Taurine performs osmoregulatory, neuromodulatory, and cytoprotective functions in the nervous system [3]. Taurine performs osmoregulatory, neuromodulatory, and cytoprotective functions in the nervous system [3].

High polarity of taurine, however, limits its permeability through the blood-brain barrier (BBB), whereas a wide range of physiological effects requires a targeted modification to obtain a specific therapeutic effect.

In addition, the main action of taurine is auxiliary and preventive. It is not intended for monotherapy of acute conditions, but plays an important role in maintaining cell health, increasing their resistance to damaging factors and creating favorable conditions for recovery. The effect of taurine on attenuation of apoptosis and its antioxidant activity seem to be crucial for a cytoprotective action. Although these properties are not tissue-specific, taurine is found in particularly high concentrations in tissues exposed to elevated levels of oxidants (for example, in inflammatory cells). It means that taurine may play an important role in reducing inflammation driven by oxidative stress. During the inflammatory process, immune cells release myeloperoxidase (MPO) to generate hypochlorous acid. Taurine subsequently interacts with this acid, effectively neutralizing its toxic effects (:media_ 1;). The reaction results in the formation of a less toxic taurine chloramine (TauCl), which produces antimicrobial and anti-inflammatory effects. Furthermore, taurine chloramine reduces electron loss and decreases the production of superoxide anions by stabilizing mitochondrial membranes [4].

The ischemic stroke model is commonly used to study neuroprotection as it encompasses all major pathogenic pathways such as excitotoxicity, oxidative stress, apoptosis, and inflammation. In 2021, a study investigated the neuroprotective effect of taurine using BV2 microglial cells and a rat model of middle cerebral artery occlusion (MAO) [5]. While delivering taurine through the nose offered no protective effect, the identical dose of Tau-Cl significantly reduced the volume of infarction, improved neurological disorders, and enhanced motor skills. Following middle cerebral artery occlusion (MCAO), neutrophils invaded the brain, and the myeloperoxidase (MPO) they released could help convert taurine into Tau-Cl. The levels of antioxidant enzymes in the brain rose following OCMA treatment, with Tau-Cl further boosted this OCMA-induced increase.

The results suggest that neutrophils move into areas of ischemic brain injury, where taurine is converted to Tau-Cl. This conversion protects brain tissue by neutralizing harmful hypochlorous acid (HOCl) and boosting the production of protective antioxidant enzymes [5].

Furthermore, in a rat model of stroke, combination of taurine with other neuroprotective drugs produces a synergistic effect. It significantly reduces infarct size, inhibits apoptosis, and enhances behavioral recovery much better than using any of these agents alone [6]. These data show that taurine has a huge potential as a component of combined treatment regimen.

The extensive pharmacological effect of taurine is proven to be effective against various pathological conditions. Taurine has been demonstrated to inhibit the reduction of sucrose consumption. It successfully prevents spatial memory loss and anxiety, ultimately demonstrating a protective effect against depression-like behaviors in a model of chronic unpredicted soft stress [7]. In addition, this condition causes drops in 5-hydroxytryptamine, dopamine, and norepinephrine; it also elevates glutamate, corticosterone.

In a rat model of depression, pretreatment with taurine preserved the expression levels of fibroblast growth factor-2, vascular endothelial growth factor, and brain-derived neurotropic factor. The antidepressant effect of taurine may be associated with regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stimulation of neurogenesis, survival, and neuron growth in the hippocampus [7]. A review by Nikkhah et al. (2021) examined the hepatoprotective effects of taurine and the underlying mechanisms of its protective action [8]. Studies have explored how taurine affects retinal degenerative diseases. An in vivo study demonstrates that a taurine-rich diet directly helps retinal ganglion cells survive by activating the specific intracellular pathways within these cells [9].

Taurine is considered as a promising supplementary agent for drug-resistant types of epilepsy. Research on animal models indicates that combining this substance with standard antiepileptic drugs can increase seizure control, probably due to the regulation of the GABAergic and glutamatergic systems [10]. A clinical study on taurine in patients with post-infarction cardiosclerosis (PIC) demonstrates that adding taurine to standard therapy improves the effectiveness of treatment in patients without prior revascularization, which is manifested through subjective health markers (reduction of fatigue, complaints of palpitations, severity of shortness of breath, frequency of angina attacks), echocardiographic findings (elevated left ventricular ejection fraction), bathmotropic and chronotropic functions of the myocardium (reduction in the number of ventricular and supraventricular extrasystoles, normalization of heart rate variability), and the lipid profile. It is established that using taurine in combination therapy for PIC is safe and does not cause any unwanted side effects [11].

HOMOTAURINE

Another promising structure for developing neuroprotective drugs is homotaurine (also known as tramiprosate). It is a taurine analog known as 3-aminopropanesulfonic acid, which has an extra CH₂-group in its hydrocarbon chain (fig. 2). This seemingly minor structural change gives this compound unique biological traits, allowing it to be considered as one of the pioneering, multi-target medications in its category for Alzheimer’s disease and mild cognitive impairment [12].

Based on the research reviewed by Manzano et al. (2020), the primary mechanism of its action involves targeting soluble β-amyloid. This inhibits conformational changes and subsequent aggregation of peptides into toxic oligomers and amyloid fibrils. Consequently, tramiprosate is viewed as a potential disease-modifying agent, as it can impact a primary pathological mechanism of Alzheimer’s disease [12]. In addition to the antiamyloid effect, homotaurine shares a structural resemblance with γ-aminobutyric acid (GABA), which allows it to interact with the GABA-ergic system, in particular with GABA-A receptors, which can normalize neuronal excitability and implement additional neuroprotective effects.

Despite the fact that clinical trials have not approved tramiprosate as an independent drug for the treatment of Alzheimer’s disease, the results of preclinical and clinical studies have confirmed its favorable safety profile and the presence of biological activity. The use of homotaurine was accompanied by a decrease in amyloid load, a slowdown in hippocampal atrophy, an improvement in cholinergic neurotransmission, and stabilization of cognitive functions in patients with Alzheimer’s disease and moderate cognitive impairment [12].

The anti-inflammatory effect of homotaurine is confirmed during some clinical and experimental studies. For example, Bossu et al. (2018) have shown in their study that in patients with mild cognitive impairment, who carry the APOE e4 allele, taking homotaurine for 12 months is specifically associated with a decrease in serum levels of the pro-inflammatory cytokine IL-18, which, in turn, is related to an improvement in episodic memory [13]. This demonstrated that homotaurine supplements exhibit anti-inflammatory effects that are linked to better memory function in patients with cognitive impairment, highlighting the central role of chronic neuroinflammation in the pathogenesis of neurodegeneration.

Additional information about the anti-inflammatory and immunomodulatory potential of homotaurine was obtained in a study by Tian et al. (2021). They used an experimental model of multiple sclerosis. The authors showed that homotaurine therapy, when started after the first signs of the disease appear, helps to prevent the autoimmune response from spreading throughout the central nervous system. In particular, the drug blocked the process of epitopic spread associated with disease progression, and suppressed the reactivity of proinflammatory Th17 and Th1 cells directed against newly identified myelin antigens. Moreover, antigen-presenting cells isolated from animals treated with homotaurine demonstrated a reduced ability to induce the proliferation of autoantigen-specific T-lymphocytes. The results obtained indicate the ability of homotaurine to modulate both innate and adaptive immune mechanisms of neuroinflammation, which significantly expands the prospects for its use not only in Alzheimer’s disease, but also in other autoimmune and neurodegenerative diseases of the central nervous system accompanied by a chronic inflammatory process [14].

Clinical studies of the neuroprotective effect of homotaurine were conducted by Spalletta et al. (2016), who assessed its effect on structural and cognitive parameters in patients with amnesic mild cognitive impairment. The authors found that long-term intake of homotaurine was associated with a slowdown in age-related and pathological changes in the medial temporal regions of the brain, primarily in structures that play a key role in memory processes. Morphometric analysis revealed a link between homotaurine therapy and preservation of the volume of individual areas of the hippocampus and temporal cortex, whereas a neuropsychological examination demonstrated an improvement in episodic memory. Especially pronounced effects were noted in tests evaluating the ability to reproduce recently learned information, which shows that the functional activity of hippocampal networks is preserved [15]. The data obtained suggest that homotaurine has not only an anti-amyloid effect, but also helps maintain the structural integrity of brain regions most susceptible to damage during the initial phases of neurodegeneration.

Modern studies of the pathogenesis of Alzheimer’s disease show that oligomeric forms of beta-amyloid (Aß) are vital to bodily functions. It is known that accumulation of Aß-oligomers is accompanied by an imbalance of the processes of excitation and inhibition in the cerebral cortex, as well as the development of cholinergic insufficiency. To assess the effect of homotaurine on neurophysiological parameters, the study by Martorana et al. (2014) investigated the mechanisms of cortical plasticity, including the processes of long-term potentiation and long-term depression, as well as afferent inhibition with short latency, which is a marker of the functional state of the cholinergic system. It was shown that homotaurine treatment did not cause significant changes in markers of long-term potentiation and long-term depression. At the same time, significant changes in short-latency afferent inhibition were observed in patients, which indicated the effect of the drug on the mechanisms of cholinergic neurotransmission [16]. The identified effects may be related to the ability of homotaurine to modulate GABA-ergic transmission in the cerebral cortex. Such regulation of inhibitory activity potentially helps to restore the disturbed balance between excitatory and inhibitory processes and indirectly improves the functioning of the cholinergic system.

According to the review by Meera and co-authors (2023), taurine and homotaurine are potential endogenous modulators of GABAA receptors. At the same time, homotaurine demonstrates high affinity for these receptors and is able to effectively activate them at concentrations comparable to physiological ones. Experimental studies have shown that the compound induces GABAA receptor-mediated currents in neurons and competes for binding to the high-affinity radioligand [3H] muscimol, which confirms its direct interaction with the receptor complex [17]. The ability of homotaurine to target extrasynaptic GABAA receptors containing the δ-subunit is particularly significant. Activation of these receptors ensures the development of sustained tonic inhibition, which helps to reduce the overall excitability of neural networks and increase the resistance of neurons to damaging effects. Increased inhibitory processes may limit the effects of glutamate-induced excitotoxicity, which is a major driver of nerve cell death in neurodegenerative disorders and ischemic injuries. Thus, the ability of homotaurine to regulate GABAergic signals is a key piece of its multi-target mechanism, producing neuroprotective, anticonvulsant, and cognitive-preserving effects [17].

HETEROCYCLIC COMPOUNDS AS PHARMACOPHORES OF MULTITARGETED NEUROPROTECTORS

Despite taurine and homotaurine are promising substances, it is still important to search for new structural platforms that can preserve neuroprotective properties and simultaneously improve BBB permeability and metabolic stability. The desire to overcome these limitations has enabled the active use of heterocyclic frameworks in medicinal chemistry. Pyridine, pyrimidine and uracil are ideal platforms for multitargeted molecules due to their structural rigidity, the ability to a variety of chemical modifications and a wide profile of interactions with biological targets. In such compounds, the neuroprotective pharmacophore binds to the heterocycle, modifying the final molecule’s lipophilicity, electronics, and overall pharmacological activity.

PYRIDINE DERIVATIVES

The pyridine fragment is one of the most common drug scaffolds, due to its ability to be substituted in several positions, solubility, basicity, ability to form hydrogen bonds, π-π interactions, and coordination with metal ions [18]. Pyridine carboxamides with multitarget properties are highly valuable for neuroprotective pharmacology. The results of molecular modeling show their capacity to simultaneously interact with multiple central nervous system protein targets. So, Shah et al. (2020) performed molecular docking of pyridine carboxamide derivatives, potential antipsychotics to simultaneously inhibit dopamine D2 and serotonin 5-HT2A receptors, which plays a vital role in managing schizophrenia. The docking results at both receptors outperformed the standard drug, Risperidone [19].

One of the most promising areas of modern medical chemistry is the creation of hybrid molecules combining several pharmacophore fragments in one structure. Zwitterionic structures combining a pyridine cycle with a sulfonate group represent one example (fig. 3) [20, 21]. These compounds, which carry formal positive and negative charges within one molecule, have unique physicochemical properties (high solubility in water, specific behavior in solutions). Because of their diverse biological effects, these structures can now be explored as CNS enzyme regulators or ion channel modulators [20].

PYRIMIDINE DERIVATIVES

The pyrimidine cycle is one of the most important structural fragments of natural biomolecules. It is also part of nucleic acids, which explains the high scientific interest in its derivatives as sources of new medicines. Pyrimidine compounds have a wide range of pharmacological activity, including anticonvulsant, anti-inflammatory, antidepressant, antimicrobial and antitumor effects. Such a variety of biological effects is associated with the ability of the pyrimidine core to interact with various molecular targets and serve as a convenient platform for creating multi-targeted drugs [22].

Condensed pyrimidine derivatives are of great importance to neuropharmacology. Bafail and Samman (2024) showed that some polycondensated pyrimidine structures exhibit a pronounced antiparkinsonian and anti-inflammatory activity. One of the proposed mechanisms of their action is inhibition of monoamine oxidase B (MAO-B), an enzyme that facilitates the degradation of dopamine within the CNS. Suppression of MAO-B activity boosts dopamine levels and slows down the progression of neurodegenerative diseases like Parkinson’s disease. In addition, the combination of antioxidant, anti-inflammatory, and neuromodulating properties makes these compounds promising candidates for development of multitargeted neuroprotectors capable of simultaneously affecting several links in the pathogenesis of neurodegenerative diseases [23].

Due to their exceptional biocompatibility, uracil-based compounds play a major role among pyrimidine derivatives. In the study of Semenov and et al. (2020), a number of new uracil derivatives were synthesized. They could effectively inhibit acetylcholinesterase, turning into potential candidates for the treatment of Alzheimer’s disease. An important feature of these compounds is the possibility of combining anticholinesterase activity with additional neuroprotective effects, essential for comprehensively targeting the various mechanisms underlying the disease pathogenesis. [24]. In addition, uracil derivatives have pronounced antioxidant properties. Murinov and coauthors (2019) have shown that chemical modification of the uracil core makes it possible to obtain compounds capable of exhibiting both pro-oxidant and antioxidant activity, depending on the structural features. This enables the precise creation of molecules that can lessen oxidative stress, a primary cause of neuron damage in neurodegenerative disorders [25]. There are many biologically active compounds based on the uracil fragment with pronounced pharmacological properties, which indicates the wide possibilities of a structural modification of this heterocycle without loss of biological activity [26]. For example, Ramesh and et al. (2020) emphasize in their review that uracil derivatives exhibit antioxidant, anti-inflammatory, antimicrobial, antitumor, and neuroprotective effects [27].

The multi-target approach is turning into one of the key strategies of modern neuropharmacology. Sulfonic acid derivatives, primarily taurine and homotaurine, exhibit a wide range of neuroprotective effects, including antioxidant, anti-inflammatory, and neuromodulatory effects. At the same time, heterocyclic compounds based on pyridine, pyrimidine, and uracil represent promising platforms for designing new drugs. The most promising approach is synthesizing hybrid molecules that merge sulfonate and heterocyclic pharmacophores. Such compounds are capable of providing a comprehensive effect on various links in the pathogenesis of neurodegenerative diseases and can become the basis new-generation neuroprotectors. In addition, synthesis of fundamentally new classes of compounds, such as picolinamide sulfobetaines or uracyl benzamides, enables the discovery of previously unknown mechanisms of action. Modern development of computer modeling, molecular docking methods and artificial intelligence significantly accelerates the search for multi-target compounds. Focus should be placed on compounds that can simultaneously target neuroinflammation, oxidative stress, and impaired neurotransmitter transmission, which are the foundational causes of most neurodegenerative diseases.