Imidazoles as Serotonin Receptor Modulators for Depression Treatment: Comparison
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Serotoninergic signaling is identified as a crucial player in psychiatric disorders (notably depression), presenting it as a significant therapeutic target for treating such conditions. Inhibitors of serotoninergic signaling (especially selective serotonin reuptake inhibitors (SSRI) or serotonin and norepinephrine reuptake inhibitors (SNRI)) are prominently selected as first-line therapy for the treatment of depression, which benefits via increasing low serotonin levels and norepinephrine by blocking serotonin/norepinephrine reuptake and thereby increasing activity. While developing newer heterocyclic scaffolds to target/modulate the serotonergic systems, imidazole-bearing pharmacophores have emerged. The imidazole-derived pharmacophore already demonstrated unique structural characteristics and an electron-rich environment, ultimately resulting in a diverse range of bioactivities. 

  • imidazole
  • drug discovery
  • antidepressants
  • serotonin reuptake inhibitors
  • structure–activity relationship

1. Introduction

The discovery of serotonin dates back to the mid-19th century, when scientists explored the physiological implications of numerous chemical messengers in the body [1]. Serotonin was first isolated from the blood serum in 1937 by Vialli and Erspamer, Italian scientists. The group identified the highest reservoir of serotonin in the enterochromaffin cells of the gut system. Two other scientists, Rapport and Page, further crystallized the chemical and coined the name ‘serotonin’ in 1945. They and the former scientists found that this very chemical was capable of causing smooth muscle contraction. Owing to this, they named this chemical “serotonin,” derived from two words, ‘sero’ meaning presence in blood serum, and ‘tonin,’ meaning the ability to induce contraction in smooth muscles [2,3][2][3].
Additional research revealed that serotonin high-concentration reservoirs are also located in platelets and the central nervous system, in addition to the enterochromaffin cells of the gut [4]. This chemical was also discovered to modulate numerous physiological processes other than smooth muscle contraction and was found to be involved in regulating mood, sleep, appetite, and pain perception [5]. Later, as the research progressed, scientists were keen to discover the specific receptors through which serotonin exerts its physiological effects. It was in the 1970s that scientists discovered two significant classes of serotonin receptors, viz., 5-HT1 and 5-HT2, that were further divided into numerous subtypes [6]. The discovery of these receptors and their subtypes led to advancements in understanding their molecular biology, unraveling numerous physiological questions associated with their signaling [7]. The research also facilitated the scientist’s ability to explore the impact of serotonin in various pathological and physiological conditions and accordingly develop specific serotonin modulators. These modulators include but are not limited to selective agonists and antagonists, selective serotonin reuptake inhibitors (SSRIs), for treating associated conditions that include mental health conditions, including depression and anxiety disorders [8].
With the advancement in molecular neuroscience in the last 60 years, there has been a paradigm shift in developing antidepressant-based therapies [9]. Numerous studies are underway that attempt to recognize the other orchestrating partners with serotonin in combination with or independently associated with depression. Besides paving the way for new research in depression, the studies also expressed their concerns over the serious fears among the patients prescribed serotonin modulators and overmedicalized for years [10]. The US FDA approves numerous modulators for treating any imbalance in serotonin physiology, including (a) Selective serotonin reuptake inhibitors (SSRIs): Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Vilazodone, and other drugs; (b) Serotonin and norepinephrine reuptake inhibitors (SNRIs): Venlafaxine, Duloxetine, Desvenlafaxine, and other drugs; (c) Tricyclic and tetracyclic antidepressants: Amitriptyline, Imipramine, Nortriptyline, Doxepin. Notably, more than 90% of these drugs belong to the nitrogen heterocyclic categories, which mainly include indole rings (Fluoxetine, Sertraline, Vilazodone, Vortioxetine); Benzimidazole (Vortioxetine); Benzazepine (Tianeptine); Benzothiazepine (Esmirtazapine); and other drugs [11].
Among the known nitrogen-containing heterocycles, imidazole is an essential heterocycle moiety explored for its biological and medicinal attributes. Imidazole is a widely explored five-membered aromatic heterocyclic compound found in synthetic and natural compounds [12]. Imidazole-containing molecules attach to a wide range of therapeutic targets thanks to their unique structural characteristics and electron-rich environment, resulting in a wide range of bioactivities [13,14,15][13][14][15].
The imidazole ring, as a heterocycle, is part of essential amino acids, including histidine (a histamine precursor). It is widely used in drugs such as antifungal agents (ketoconazole, clotrimazole) [16], antihistamines (cimetidine) [15], COX-inhibitors [17], as well as in other diseases (for example, anticancer [18], antibacterial, antitubercular [19], anti-inflammatory [20], antineuropathic [21], anti-Alzheimer [22,23][22][23], antihypertensive [24], antiviral [25], anti-obesity [26], and antiparasitic activity [27]). Significantly, due to facile structural substituting availability on the imidazole ring, various derived molecules were exploited for gaining potent anticancer activities, for example, topoisomerase inhibitors (as imine-amide imidazole conjugates targeting liver and lung cancer cells) [28]. Additionally, they have been employed in naturally derived compounds, such as MIM1 [29], Meiogynins [30,31[30][31][32],32], and synthetically designed Mcl-1 inhibitors (as in the form of imidazolidine-2,4-dione for chronic myelogenous leukemia cells, prostatic cancer cells, and breast cancer cells [33,34][33][34]). Furthermore, these compounds have been investigated for their potential in targeting insulin-linked cancer cells (insulin receptor-A and IGF-1R and their heterodimers [35,36][35][36]). They have also been explored for hormonal-based targeting of cancer cells (estrogen-based drugs targeting breast cancer [37,38,39,40,41][37][38][39][40][41]).
The application of imidazole rings is not limited to small molecule-based medicinal chemistry; aspects of coordination chemistry and targeted synthesis (with chemical biology applications) were explored as well. For example, medicinal coordination chemistry utilizing elements of supramolecular chemistry has recently gained interest [42]. In coordination chemistry, the imidazole ring presented broad applications with its superlative chemical feasibility, such as lone pairs of nitrogen in imidazole being available to facilitate making coordinate bonds with central metals, as observed in nature (in some of the essential biomolecules, hemoglobin, and hemocyanin), encouraging researchers to develop metal-containing medicinal compounds. The imidazole derivatized coordinate compounds additionally exhibit more advantages, such as lower incidences of cellular resistance, increased therapeutic efficacy, selective cellular targeting [13], and probing, as broadly summarized: (A) Imidazole-based supermolecules as anticancer agents (alkylating agents [43], noble metal complexes with anticancer activities [44[44][45],45], light-activated cytotoxicity of ruthenium-metal complexes [46]). (B) Imidazole-based coordinate compounds for organelles and cellular detection: (a) Boron pyridyl imidazole complex with a characteristic of twisted intra-molecular charge transfer (TICT) does specific detection of BSA levels (identifying denatured BSA versus native BSA) [47]; (b) Imidazole containing dinuclear Ru (II) complex is a lysosome-specific probe, accumulating (specifically) in the lysosomes and therefore assisting in identifying the HeLa cells from healthy HEK293 cells [48]; (c) Gram-negative bacteria differentiated from Gram-positive bacteria using imidazole containing dibenzimidazole-substituted pyridine [49]. (C) Cellular biomolecular and metal detection and probing: (a) Imidazole containing diphenyl derivatives [50] and anthraquinones detected the biological mercaptans (cysteine, homocysteine, and glutathione) levels [51]. (b) Imidazole containing fluorescent sensors detected approximately 4.70 × 10−7 mol/L adenine levels [52]. (c) Fluorescent probe-conjugated imidazole–pyridine pharmacophore structures demonstrated high sensitivity at a molar concentration of 3.38 μM for Ag (I), applicable to liver cellular imaging [53]. (d) Thiophene-derivatized imidazoles as on–off fluorescent reversible chemosensors detecting intracellular Pd (II) ions in living cells (to a level of 20 μg/mL) [54]. (e) Fluorescent probe-based peptide receptors detected intracellular Cu (I) ions in the Golgi apparatus (even in living A549 cells) [55]. (f) Tripyridyl imidazole molecule as a dual sensing probe of Hg (II) (pH 6–8) and Cu (II) (pH 3–11) ions detecting at 0.77 and 1.58 μM, respectively [56]. (g) Ruthenium (II) complexes containing imidazole as 1O2-responsive fluorescent probes as an “on–off”-type fluorescent pH sensor (pKa1 = 1.12 ± 0.15, pKa2 = 6.90 ± 0.24, pKa1* = 1.09, and pKa2* = 6.92) [57]. (h) Fluorescein dye containing imidazole as a colorimetric and fluorescent chemical sensor for fluoride detection with an application in live cells [58]. (i) Cu (II) complexed Bipyridyl imidazole derivative selectively detected the HS− ions and was used to develop a fluorescence microplate assay [59]. (j) Fluorescent zinc complexes presented a high-potential HS−/H2S fluorescence sensor and detection probes at cellular levels [60]. (k) Ir (III) containing a methylene-bridged benzimidazole-substituted complex displayed a high selectivity for pyrophosphate ions (H2P2O72−) with lower cellular HeLA cell toxicity [61]. (l) Fluorescent-active benzimidazole derivatives have high selectivity toward aqueous solubilized Ag (I) within (<30 s) [62]. (m) A reversible naphthalimide-based probe detected Hg (II) ions in a phosphate buffer over a wide pH range (7.0–10.0), which is highly applicable in biological experiments [63]. (n) Imidazolyl Schiff bases exhibit Zn (II) detection as low as 6.78 × 10−9 M compared to the recommended sensitivity detection according to the World Health Organization’s drinking water guidelines (7.6 × 10−5 M) [64]. (o) Imidazole-based anthracene structure detection limit of Zn (II): 1.0 × 10−9 M [65]. (p) Tridentate dibenzimidazole–pyridines have a detection limit of 3.09 × 10−7 M toward Zn (II) ions [66]. (q) Imidazole-based supermolecules as probes for Cu (II) detection (allyl-substituted imidazole derivative with a detection limit for cupric ion (Cu2+) of 1.01 nM [67]; dibenzimidazole derivative with a detection limit of 0.094 μM within a 1 s time period [68]; tetraphenyl ethylene-functionalized aryl imidazole-derivative detection limit of aqueous solubilized Cu (II) at 34.8 nM [69]). (r) Imidazole-based iron chemosensors (fluorescence “on–off” aniline-derived imidazole probe demonstrated high selectivity and sensitivity for ferric ions Fe (III) with a detection limit of 0.72 μM/L at 30 min) [70].
Several imidazole-based medicines have been widely employed in clinical trials to treat various disorders with significant therapeutic promise. Imidazole-containing drug research and development is becoming a more active and appealing issue in medicinal chemistry due to its substantial therapeutic usefulness. 

2. Etiology of Depression, Structural and Mechanistic Insights

According to the World Health Organization, depression is a severe condition affecting millions of people worldwide and is one of the primary causes of disability [71,72][71][72]. Monoamine neurotransmitters like norepinephrine and serotonin (5-hydroxytryptamine, 5-HT) have been used as significant indicators of psychiatric disorders, such as anxiety and depression, for several decades [73,74][73][74]. Serotonin exists in both the CNS and PNS systems, which describe its nature as both an autacoid and a neurotransmitter [75,76][75][76]. It is released by serotonergic neurons. The serotonergic system is linked to the regulation of mood, emotion, and sleep, as well as a variety of behavioral and physiological activities [77]. It is one of the most studied and multifunctional biogenic amines among neurotransmitters. Depending on the physiological action, occurrence, agonist, and antagonist, it is categorized into various classes, among whom 5-HT1 (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B, and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6, and 5-HT7 have been widely reported in the literature [78]. Serotonin is primarily found in three cell types: (a) serotonergic neurons in the central nervous system and the intestinal myenteric plexus [79], (b) enterochromaffin cells in the gastrointestinal tract mucosa, and (c) blood platelets [80].
Serotonin receptors are categorized as G protein-coupled receptors (GPCRs), which orchestrate the signaling mechanism of serotonin. Serotonin binds to its chief receptors (5-HT1 and 5-HT2 subtypes) within the transmembrane region of the receptor. This region comprises transmembrane helices classified as TM1–TM7 [81]. These transmembranes are further connected via intracellular and extracellular loops, forming a binding pocket that facilitates the formation of serotonin and its competitive modulators. These transmembrane domains are further surrounded by cholesterol molecules that, besides contributing to the receptor’s shape, are also contributing factors for receptor stability and proper receptor folding. The cholesterol composition within the cell membrane directly modulates receptor activity.
The essential amino acids that play a critical role in serotonin and ligand are embedded within the binding pocket. Considering the 5-HT1 subtype receptor, the key amino acid is aspartate (ASP), located in TM3 (ASP116). This amino acid mediates serotonin affinity via the formation of a salt bridge with the amine functionality of serotonin, thus stabilizing the ligand-receptor complex. Considering the 5-HT2 subtype, the key amino acid that is involved in stabilizing the ligand affinity is asparagine (ASN), located in TM7. This specific amino acid is known to interact with the carboxyl group of serotonins via the formation of the H-bond. Apart from these vital amino acids, Arginine (ARG) residues present in TM3 (ARG 134) and TM6 are also found to interact with carboxyl groups via H-bonding and electrostatic interactions. Glutamate (GLU), present in TM2 and TM7, is involved as a proton acceptor or donor required during protein interactions, besides participating in H-bonding and electrostatic interactions with ligands. Another amino acid, histidine (HIS), present in TM3 and TM5, is also associated with receptor activation and participates in ligand stability via the formation of an H-bond, a salt bridge, or by acting as a proton donor or acceptor. In addition to this, cysteine (CYS) residues present in TM2 and TM7 are involved in the stability of the receptor protein via the formation of disulfide bridges. They are vital for ligand recognition and receptor activation. The tryptophan (TRP) residues (particularly TRP 358) available at TM6 and TM7 also contribute to receptor activation along with receptor conformational stability and ligand binding primarily via hydrophobic interactions. Apart from amino acids, three water molecules (W1–W3) within the active domains are also vital in maintaining the stability and activation of the receptor. These water molecules interact with 5-HT (apoprotein), where W1 interacts with the hydroxy group and W2 with the indole ring, followed by the interaction of the primary amine with W3. W3 also interacts with ASP116 by forming an H-bond that is conserved in GPCRs (aminergic), whereas W2 is found to toggle the amino acid residue TRP358, which determines receptor activation [82].
Mechanistically, serotonin and norepinephrine are released in the synaptic cleft, where they activate the postsynaptic cleft and some reuptakes through the pump, where MAO breaks them and moves them back to the presynaptic neuron [83]. In the case of depression treatment using SSRIs/SNRIs as per the monoamine hypothesis, the therapeutic benefits are based on increasing low serotonin levels and norepinephrine (Figure 1) [84,85][84][85]. As the name indicates, SSRIs/SNRIs function by preventing serotonin/norepinephrine reuptake and thereby increasing activity. SSRIs block the serotonin transporter (SERT) at the presynaptic axon terminal [86], whereas SNRIs block the norepinephrine reuptake transporter [87]. The information-sending presynaptic cell in the brain releases neurotransmitters into the gap [88]. The neurotransmitters are subsequently identified by receptors on the recipient postsynaptic cell’s surface, which then relay the signal in response to the stimulus. More serotonin (5-hydroxytryptamine, or 5HT) remains in the synaptic cleft when SERT is blocked, which can stimulate postsynaptic receptors for extended periods [89]. Further, SNRIs and SSRIs boost serotonin and norepinephrine levels in the brain. Neurotransmitters, such as serotonin and norepinephrine, are chemical messengers that transfer messages from one region of the body to another. Following the transmission of a signal by neurotransmitters, cells in the brain typically take up these substances and store them for later use. SNRIs and SSRIs block serotonin and norepinephrine reuptake, resulting in higher levels of serotonin and norepinephrine in the synaptic cleft [90].
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Figure 1.
Role of serotonin receptor modulators in depression.

3. Modern Synthetic Methods for Substituted Imidazole Derivatives

Imidazole is reported to exhibit a broad range of applications in pharmaceutical and industrial applications [14]. For example, this organic framework is sought in many drug pharmacophores, such as angiotensin II inhibitors, anti-inflammatory agents [91], anticancer agents, and building blocks of naturally occurring products [13,92][13][92]. The imidazole ring is a well-observed ligand in metalloenzymes, and its imidazolium salts are also well-exploited to serve as excellent precursors of stable carbene ligands in various metal complexes [93,94][93][94]. The application of imidazolium salts to environmentally friendly ionic solvents is another example [95]. Thenrajan and coworkers explored the role of imidazolate-based bimetallic nickel-iron zeolitic fibers as sensors for serotonin neurotransmitters [96]. Various advancements reported in the synthesis of new imidazole derivatives with various bioactivities using different catalytic systems are described in Figure 2.
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Figure 2.
Recently developed synthetic methodologies for imidazole and its derivatives.
The use of metallic catalysts for imidazole synthesis has increased in recent years. This can be attributed to the improved percentage yields, lessening the time required for reaction, and ease of removal from a reaction mixture that make the technique appealing [93,97][93][97]. Because of their nontoxic, affordable, reusable, and eco-friendly properties, zinc (Zn)-based heterogeneous catalysts were well-exploited in a range of multicomponent reactions for synthesizing this organic framework. Marzouk et al. [98] developed a one-pot multicomponent synthesis of 1,2,4,5-tetrasubstituted imidazoles via reacting aromatic aldehydes, benzil, 1-amine-2-propanol, and ammonium acetate in the presence of nanoparticles of ZnFe2O4 catalyst. After 30–50 min, the condensation process with a metal catalyst yielded 87–96% multi-substituted imidazoles. For the production of substituted imidazole, Nejatianfar et al. [99] proposed a magnetically separable nanocatalyst based on copper (II) immobilized on guanidine epibromohydrin-functionalized c-Fe2O3@TiO2 (c-Fe2O3@TiO2-EGCu(II)) with a core–shell structure. Eidi et al. [100] used benzil, substituted aldehydes, and ammonium acetate in a condensation procedure to produce 2,4,5-trisubstituted imidazole conjugates. The best reaction conditions were discovered using 10 mg of catalyst and a 60 percent rate power of ultrasonic irradiation at 40 °C in ethanol. The method’s advantages include recovering the catalyst using an external magnetic field and reusing it for up to five runs without losing activity. Maleki et al. [101] developed a greener synthetic strategy for the formation of 2,4,5-trisubstituted imidazoles via condensation of 1,2-diketone, aromatic aldehydes, and ammonium acetate in the presence of mixed oxide (Fe3O4/SiO2) nanocatalyst, yielding up to 95%. Compared to traditional catalysts such as Fe3O4, the reaction utilizing Fe3O4/SiO2/urea nanoparticles took 50 min and yielded 95% trisubstituted imidazoles. However, designing and synthesizing trisubstituted scaffolds remain of keen interest among researchers [102,103][102][103]. These scaffolds provide a highly functional multitargeting scaffold [104[104][105],105], including dendrimers [106,107][106][107]. Girish et al. [108] used ZrO2-supported b-cyclodextrin as a reusable solid catalyst to synthesize 2,4,5-trisubstituted imidazoles and 1,2-disubstituted benzimidazoles under solvent-free conditions. Using a 40 mol% ZrO2-b-Cyclodextrin catalyst, the reaction was screened with various solvents, including water, DMF, ethanol, and solventless systems. The reaction went off without a hitch in a solvent-free environment, and the product was produced with good yields. Using ZrO2 nanoparticles as a reusable catalyst, Bajpai et al. [109] investigated the one-pot synthesis of multi-substituted imidazoles. The authors used isatin, aromatic aldehydes, and ammonium acetate as reactants in the presence of 15 mol% ZrO2 nanoparticles in a solvent-free environment to create new imidazoles.
Fang et al. [110] described a new method for cyclizing amido-nitriles to produce disubstituted imidazoles. The reaction conditions were moderate enough to include aryl halides, aromatic and saturated heterocycles, and other functional groups. The necessary 2,4-disubstituted NH-imidazoles were obtained by nickel-catalyzed addition to nitrile, followed by proto-demetallation, tautomerization, and dehydrative cyclization. Combining a C2–N3 fragment with an N1–C4–C5 unit has recently been examined as a two-bond disconnection for synthesizing imidazoles. For example, Shi et al. [111] employed this disconnection to make trisubstituted NH-imidazoles in the presence of zinc(II) chloride by reacting benzimidates with 2H-azirines. For the synthesis of 2-aminoimidazoles, Man et al. [112] utilized an approach where vinylazides were transformed in situ into 2H-azirines, which then interacted with cyanamide to create the required 2-aminoimidazoles in moderate to good yields under a range of conditions. Nitriles have also been employed as reagents in metal-free processes to synthesize substituted imidazoles with two bonds. Harisha et al. [113], for example, recently reported the formation of tri-substituted NH-imidazoles by reacting -azidoenones with substituted nitriles. In the absence of a metal catalyst, imidamides can be employed as starting materials for synthesizing imidazoles. In the presence of trifluoroacetic acid, Tian et al. [114] reported the synthesis of substituted imidazole by reacting imidamides with sulphoxonium ylides. At the first, second, and fourth positions, the resulting imidazoles were replaced.

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