The Impact of Incorporation Piperazine on Biological Activities of Benzazoles

Abstract

Heterocycles are widely distributed compounds in natural products and are involved in many biological processes. Its uses have been extended to different fields, including industry, medicine, and agriculture sectors. Benzazole is one of the popular heterocycle scaffolds known as a privilege structure which is commonly found in many pharmaceutical agents. Another outstanding scaffold is piperazine that is known as a distinguishable motif in drug design with a wide range of biological activities. One of the fruitful approaches in the drug design is a hybridization of privilege structures in one skeleton which are believed to grant a characteristic feature with improved or more selective biological activities than the two scaffolds. The effect that piperazine imparted while introduced into a benzazole has drawn attention since first used in the nineteenth century. Numerous research has been performed discussing the synthesis and biological activities of benzazoles containing piperazine. In this chapter, we will highlight a general introduction about chemistry and structure of piperazine, and its importance in medicinal chemistry and benzazole as well. Next, several studies will be discussed that highlight the importance of incorporating piperazine in benzazole skeletons, benzimidazole, benzothiazole, and benzoxazole, and biological activity inherited from this combination.

1. Introduction

Heterocycles are paramount scaffolds that are extremely involved in various biochemical reactions. The ability of many heterocycles to produce stable complexes with metal ions has great biochemical significance. The heterocycle containing nitrogen could behave as acid and base depending on the type of nitrogen. Due to the presence of lone pairs, heterocycles can coordinate with practically all metal ions. Hydrophobic properties of heterocycles affect various biological and chemical processes, including the behavior of heterocyclic compounds. It can enhance the binding to specific targets. The hydrophobic interaction of the heterocycle can be exploited which favors its interaction with the hydrophobic active site and affects its solubility in water. Hydrophobic interaction can be engaged in hydrogen bonding or π-π stacking, depending on their specific structures. These interactions contribute to the overall stability and properties of the compounds [1].

In this chapter, we will be focusing on two magnificent heterocycles, piperazine and benzazole scaffold, and their importance in medicinal chemistry.

1.1 Chemistry of piperazine

Piperazine is a non-aromatic six-membered nitrogen heterocycle called hexahydropyrazine containing two opposed primary nitrogen atoms at positions 1 and 4 with a chemical formula C₄H₁₀N₂ as shown in Figure 1. Piperazine has cyclohexane-like structure that adopts spatial conformation, chair, and boat conformation [2].

Figure 1.

Piperazine structure.

The piperazine moiety is found in a wide range of natural products [3] which make it a remarkable scaffold in different aspects of our life. That is because it has fascinating properties and one of these properties is the presence of two basic nitrogen atoms and two pKa values. Generally, piperazine is a weak base in which the first acid dissociation constant (pKa₁) of piperazine is 5.333 larger than the second acid dissociation (pKa₂) 9.731 at 25°C [4].

The presence of two nitrogen atoms provides a larger polar surface where the first nitrogen atom acts as hydrogen bond donors/acceptors, and this increases the ability to form hydrogen bonding. As a result of that, these hydrogen bonds enhance the water solubility and binding with biomolecules structure, compared to the other six-membered rings e.g., piperidine and morphine, the additional nitrogen in piperazine allows for adjusting 3D geometry at the distal position of the six-membered rings [5].

About 30% of drug candidates failed because of pharmacokinetic properties reasons [6]. Thus, understanding the pKa of piperazine and its derivatives is critical in the medicinal field, especially in drug design, as the protonation influences the ligand-receptor interaction, and this sequence affects its bioavailability and pharmacokinetics properties. Thus, we can conclude that pKa of a drug influences lipophilicity, solubility, protein binding and permeability. As a sequence, this will in turn directly affect pharmacokinetic (PK) characteristics such as absorption, distribution, metabolism, and excretion (ADME) [7].

Piperazine has such characteristic features which make a popular skeleton in the industrial field as well. It can be used as an inexpensive, environmentally organo-catalyst [8, 9, 10] in synthesis of some heterocycles and synthesis of polymer [11, 12]. Besides that, it required short reaction time, simple procedure, available, highly yielded, and easy in separation without chromatographic separation.

Piperazine moiety provides a versatile platform for further functionalization of the two nitrogen atoms. The amine group can undergo several reactions, amine coupling reactions, acylation, alkylation, and other transformations. Piperazine can be easily replaced by another amine heterocyclic, as bioisostere, to maintain or improve biological activity.

Despite the wide usage of piperazine-containing compounds in marketed drugs, its structure is limited to substituent in nitrogen site. The limitation can be summarized in the hindrance of nitrogen, limited availability of starting material, and long procedure synthesis. As such, the piperazine’s structure has a limitation in functionality and thus diversity. Thus, further functionalization of the C–H bond adjacent to nitrogen has become a topic of interest that was discussed lately [5].

1.2 The importance of piperazine in medicinal chemistry

In general, nitrogen heterocycles have become indispensable constituents that are widely sound in many biomolecules and other sectors in our life. In drug design, nitrogen heterocycles are considered as a privileged structure that is commonly available in many commercial drugs. Among the commercially approved drugs by US FDA, the vast majority are nitrogen heterocycles that account for about 75% of marketed drugs. Piperazine is considered the third most common nitrogen heterocycles that found in 59 marketed drugs [13].

In the 1950s piperazine was first introduced as an anthelmintic agent in medicinal field. Over time, the piperazine derivatives have been expanded with different moieties for various medical purposes. The N-arylpiperazine-containing compounds are available in more than 50 commercial medicinal drugs which are exhibiting diverse medicinal uses [14].

Aryl piperazine skeletons are found in many therapeutic agents that target CNS receptors such as various subtypes of serotoninergic, adrenergic, and dopaminergic receptors such as natural agonists, e.g. 5HT6-serotonin, dopamine, and adrenaline, respectively. In the nervous system, it can mimic the interactions and the conformational features of several bio-targets.

Regardless of the progress done in the pharmacological properties of arylpiperazine containing compounds, the ionization constant of arylpiperazine is not getting much attention. In pursuance of their research, Lacivita et al. have reported a novel series of 1-(substitutedphenyl)-4 propylpiperazines (1) to study the effect of manipulation of the substituent on the phenyl ring on the basicity of the N-propyl-substituted nitrogen [15]. Based on the compiled data, the electronic properties of the substituent on the phenyl ring are not the only feature that modulates the basicity of the N-4 nitrogen of the piperazine. The substituent at the ortho position has increased the basicity of the compound. This result can be related to steric and conformational effects not to its electronic properties. On the other hand, the meta and para positions show a slight decrease in the pKa and that was qualitatively related to electronic properties of the substituent.

As mentioned above, the availability of two ionizable sites on piperazine contributes to affect the acid dissociation constant (pKa) which is very crucial in absorption and distribution processes as it influences the physicochemical properties, lipophilicity, and solubility in water.

Hydrophobic interactions and π-π stacking of piperazine are important, hydrogen bonding, electrostatic interactions, and steric effects also play roles in determining the overall binding affinity and specificity of ligands for their target enzymes [16].

Many studies proved the binding affinity of N-phenylpiperazine derivatives to certain enzymes such as monoamine oxidase (MAO) A and B and receptors of dopamine and serotonin receptors. Thus, N-phenylpiperazine is utilized in drug design in order to improve the pharmacokinetic (selectivity) properties [17].

An example of such modification of arylpiperazine was done by Chen et al. where a new series of arylpiperazine derivatives is combined with saccharin motif and tested for anti-prostate cancer. This combination with piperazine shows high potential cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC₅₀) < 2 μM). Interestingly, the position on arylpiperazine plays a role in activity and selectivity in which position-4 with fluoro group (2) exhibited potent cytotoxic activity and excellent selectivity compared to the other derivatives [18].

Furthermore, Clark et al. have reported a novel series of α7 neuronal nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)methyl) piperazine derivatives. Some previous studies propose that these receptors are ligand-gated ion channels that are involved in disorders of the central nervous system. The structure of these modulators is designed by a combination of different potential scaffold that are potent in Alzheimer’s disease and schizophrenia treatment and piperazine moiety that serves as a hydrogen bond acceptor. Among these modulators, compounds (3 and 4) have the potential for α7 nAChR with good selectivity and good oral bioavailability (Figure 2) [19].

Figure 2.

Arylpiperazine derivatives.

Numerous studies revealed that the incorporation of piperazine with heterocycles improves biological activities where the potency was attributed to the presence of piperazine moiety. Scanning throughout literature, piperazine has a wide range of activities such as anticancer [20, 21, 22, 23], anti-inflammatory [24, 25, 26], anticonvulsant [27, 28, 29], anti-HIV [30, 31], antidepressant [32, 33, 34], antitubercular [35, 36, 37], antifungal [38, 39, 40], anti-obesity [41, 42], and antimalarial [43, 44, 45].

2. Benzazole scaffold

Benzazole skeleton is a class of aromatic heterocyclic compounds that are composed of benzene fused with azole ring structure. There are several types of benzazole, benzimidazole, benzothiazole, benzoxazole, and benzotriazole in which azole structure varied to be imidazole, thiazole, and oxazole, respectively (Figure 3).

Figure 3.

Benzazole structures.

There is no doubt that benzazole unit has granted significant attention in various sectors, medicine, industrial, and agricultural fields. It is a popular scaffold in material science and that is because of its high quantum yield, ease synthesis, and thermal stability. Thus, it can be incorporated in polymers as additives to enhance its thermal stability [46, 47, 48]. Due to its aromaticity, tends to be stable so it can be utilized in the synthesis of liquid crystal and conducting polymer with specific features. Moreover, it is used as chromophores in dyes and pigments in fluorescent agents, luminescent material, and photovoltaic Devices [49, 50, 51].

During the past years, benzazole scaffold has been utilized with different strategies in drug design. To start with, benzazole scaffold known as privileged structure that is commonly utilize as core structure in drug design. That’s because the former is a structural bioisosteres of biomolecules, nucleotide macromolecules, e.g., adenine and guanine and this structural similarity allows benzazole-containing compounds to interact with biomolecules in biological system. The employment of the privilege structure concept can be alone or combined with another molecular strategy like bioisosterism which is another fruitful strategy of molecular modification in drug discovery [52, 53]. The structure-activity relationship (SAR) stands as an exceptional strategy that has been exploited in drug design in which the strategic modification of different type substituents can lead to significant alteration of molecules’ biological activity. These approaches are used alone or combined in drug design based on the hypothesis that similar molecules tend to behave similarly and hence obtain similar biological activities.

As the azole structure is modified to be imidazole, thiazole, and oxazole, that can provide variety in structure and hence in their physicochemical properties which subsequently affect its biological action. For example, benzimidazole scaffold is considered acidic due to the NH group and weakly basic in nature with the ionization constant (pK_a) 12.8, and its conjugate acid is 5.6. In the other scaffolds, benzoxazole has pK_a = 24.4 and the benzothiazole is the more basic with pK_a = 27.0.

Herein, compiled literature regarding the importance of incorporation piperazine with benzazole derivatives will be discussed individually in the following sections.

2.1 Benzothiazole containing piperazine

To start with, a new set of 36 new benzothiazole derivatives were synthesized by Xie’s et al. and subjected for antitumor activity. Antitumor SAR analysis was obtained using various substituents at 2-,5-, and 6- positions and the results revealed that the presence of two phenyl rings at positions 2 and 5 along with N-methylpiperazine moiety at position-6 in benzothiazole derivative (5) (GI₅₀ = 0.87 μM) is crucial for antitumor activity [54]. The results of this study provide a starting point for future lead compound optimization and finding new antitumor agents.

Another study to be mentioned was reported by Gurdal et al. in which a new series of benzothiazole-piperazine analogs were screened against three different cancer cell lines. Among the whole of synthesized compounds, compound (6) showed the highest cytotoxicity against the tested cancer cell lines and causes apoptosis by cell cycle arrest at subG1 phase [14]. The data analysis to understand the mechanism of cytotoxicity, fluorescence-activated cell sorting analysis (FACS), shows an increase in subG1 phased cells indicating the subG1 cell cycle arrest compared to control cells. This result is an indication that the presence of cells arrested at the subG1 phase supports the induction of apoptotic cell death in those cells treated with compound (6).

Analysis of SAR by Nagarapu et al. identified that both nucleus benzothiazole and substituent methyl-piperazine moieties are essential for enhancing the cytotoxic activity [55]. Compound (7) exhibited a promising cytotoxicity specifically against human breast adenocarcinoma cell lines MDA-MB-231 and MCF-7. Compared with to the secondary amines, the methyl piperazine moiety shows more potential inhibitory activity against human-tested cancer cell lines.

As mentioned above, arylpiperazine is a good choice template for various biological targets. One attempt in piperazine modification to find cytotoxic agents for better treatment of cancer, a combination of more than one pharmacophore, with different mode of action could lead to potent drugs. For instance, Murty et al. have combined arylpiperazines, benzothiazoles/benzoxazoles, and substituted 1,3,4-oxadiazol-2-thiol scaffold. Some compounds show interesting cytotoxicity while the benzothiazole (8) with N-phenylacetamide displayed the highest cytotoxicity against five cancer cell lines [56].

The importance of bearing N-methylpiperaizne is discussed in the study done by Abdelgawad et al. who prepared a new derivative of benzazoles that targets epidermal growth factor receptor (EGFR) represents for cancer treatment. Their finding showed that the derivatives containing N-methylpiprazine-1-yl-acetamide derivative for both benzoxazole (9) and benzothiazole (10) were the most potent cytotoxic against breast cancer cell lines with IC50 values 12 nM and 10 nM, respectively [57].

Karaca et al. have designed a new series of enzyme inhibitors against Alzheimer’s disease. They have utilized the dual acetylcholinesterase (AChE)–monoamine oxidase B (MAO-B) inhibitors which are known as a new approach in the treatment of Alzheimer disease (AD) [58]. The amine motif e.g. piperazine or piperidine in the structure of donepezil is essential for the interaction with the AChE enzyme binding site called catalytic active site (CAS) region of the enzyme. This chemical structure provides flexibility which enables the proper binding to gorge of the enzyme active site. Among the synthesized inhibitors, compound (11) displayed inhibitory activity against AChE and MAO-B enzymes with IC₅₀ values of 23.4 + 1.1 nM and 40.3 + 1.7 nM, respectively.

It is worth mentioning the study done by Ktadna et al. in which they combined pyrimidine/benzothiazole piperazinyl moieties with flavones to enhance the antiradical and antioxidant activity of flavones as both piperazine and benzothiazole are known for their antioxidant activity [59]. Several sets of 2(2-hydroxyphenyl) pyrimidine/benzothiazole piperazinyl-substituted flavones were prepared and evaluated the antioxidant activity. Among the synthesized molecules, (12–14) containing benzothiazole and piperazine moieties show a higher antioxidant activity compared to pyrimidine analogous and 3BTA in particular the most potent one. These results can serve as an opening for preparing new compounds containing flavonoid—piperazine moieties with more effective and less toxic potential candidates for anti-inflammatory and anticancer drugs.

In another study of piperazine containing benzothiazole, Al-Harthy et al. introduced a new compound of 2-aminobenzothiazole (15) as intermediate and a library of benzothiazole Schiff bases with piperazine at position-6 and underwent cytotoxicity assays [60]. Al least one compound (16) fluorine at position 4 of phenyl exhibited a selective antitumor activity against DMS-53 human lung cancer cell line in comparison to primary HLMVECs. In addition, a new series from the same intermediate (15) was proposed with the same research team of 5-fluoro-6-(4 methylpiperazin-1-yl)-substitutedphenylbenzo[d]thiazoles and screened against different bacteria and fungi strains. Among, two compounds, (17 and 18) show potent bacterial growth inhibition against Gram-positive bacteria S. aureus with MIC 32 μg/cm³ compared to 10 μg/cm³ for tamoxifen used as a positive cytotoxicity standard (Figure 4) [61].

Figure 4.

Benzothiazole derivatives incorporating piperazine.

2.2 Benzimidazoles containing piperazine

To begin with, Hu et al. disclosed a series of 1-cyano-2-amino-benzimidazole derivatives which was investigated against cancer cell lines. Several compounds showed certain cytotoxicity, and compound (19) was the most promising analogues. Based on extensive SAR studies, the presence of methyl piperazine was crucial in enhancing the potency against A549, K562, and PC-3 cell cancer cell lines with IC₅₀ values of 6.48, 2.69, and 18.51 μmol L-1, respectively [62]. In addition, they have examined the influence of compound (19) on the growth and division of K562 cells by measuring the DNA content of eukaryotic cells. The results show an arrest of the cells in the G2/M phase of the cell cycle by the examined compound.

It is well-known that Hoechst 33342 and 33,258 are adenine-thymine-specific dyes that stain DNA by binding to its minor groove. In Hoechst 33342, the ethoxy group has a role in inducing apoptosis and causing cell death in HL-60 cells unlike in Hoechst 33258. To mimic their biological activity, Alp et al. reported a synthesis and biological evaluation of 5-(4-methylpiperazin-1-yl)-2-phenyl-1H-benzimidazoles. At least four compounds (20–23) exhibited significant antiproliferative activities against the cancer cell lines with IC50 values 1.86 ± 0.09, 1.86 ± 0.20, 1.70 ± 0.11, and 1.56 ± 0.09 μM, respectively [63].

As part of their efforts in synthesizing benzimidazole and alkoxyamine derivatives for antifungal activities, Jin et al. and his team have investigated the effect of appendage piperazine moiety on a series of α-alkoxyimino-(1H-benzoimidazol-2-yl) acetonitriles. The derivatives (24 and 25) showed high antifungal activities against B. cinerea with EC50 7.14 and 13.99 μg/mL respectively, which is more potent than the standard used in their investigation [64].

Nimesh et al. prepared a potential topoisomerase IA inhibitors of bisbenzimidazoles. The in vivo antimicrobial testing data shows that 5-(4-propylpiperazin-1-yl)-2-[2′-(4-ethoxyphenyl)-5′-benzimidazolyl]benzimidazole (26) is an efficient candidate as antibacterial agent [65].

Recently, Zhang et al. have designed a new series of benzimidazole quinolones as potential antibacterial agents to improve the quinolone’s resistance against bacteria by utilizing the benzimidazole ring at the 7-position of quinolone core. The quinolone derivative (27) shows significant antibacterial potency which was more effective than norfloxacin, ciprofloxacin, and clinafloxacin [66].

Basavaraja et al. have proposed unique piperazine-linked benzimidazole analogs and evaluated for their antibacterial, anthelmintic, and anticancer properties [67]. Regarding the antibacterial activity, compound (28) exhibits the most potent activity that similar to procaine penicillin and Streptomycin which is referred to as the piperazine attached to the methoxy group. While compounds (29 and 30) show a potential antifungal activity which can be attributed to the resonance phenyl and nitro groups connected to benzimidazole through the piperazine motif. For the anthelmintic activity, compound (31) showed excellent activity compared to the standard drug Albendazole. Compound (32) with methyl piperazine, exhibited excellent activity against only the MCF7 cell lines, with an IC₅₀ value of 9.32 μg/mL. Interestingly, compound (30) with a phenyl ring attached with piperazine, showed excellent activity against human liver (HUH7) and breast cancer (MCF7) cell lines, with IC₅₀ values of 6.41 and 9.70 μg/mL, respectively.

Bemonyl, Mecarbinzid, Carbendazim, and Debacarb are one of the most effective fungicide agents in plants that contain benzimidazole derivatives. This benzimidazole with carbamate at position 2 was utilized to prepare a novel series of 2-carbamate benzimidazoles that have been posted by Al-Harthy et al. and evaluated for antifungal activity. Compounds (33 and 34) were the most efficacious, which resulted in a 96% growth inhibition in Pythium at 100 mg L⁻¹ [68]. In pursuit their effort in preparing bioactive, these 2-carbamate benzimidazoles have been investigated for potential α-glucosidase inhibitory behavior. It was found that the most effective inhibitors in this series were (35 and 36) with IC₅₀ values of 118 and 155 μM, respectively. The data collected found out that compound (35) competes with the substrate in binding to the enzyme active site as a competitive inhibitor and the docking results revealed an interesting interaction between these two benzimidazoles and the enzyme active site (Figure 5) [69].

Figure 5.

Benzimidazole derivatives incorporating piperazine.

2.3 Benzoxazoles containing piperazine

For benzoxazole’s derivatives, Erol et al. have synthesized new derivatives of benzoxazoles, 2-(p-substitutedphenyl)-5-(2-substitutedacetamido) benzoxazole and evaluated for their antimicrobial activities on 10 different microorganisms. In general, the benzoxazole derivatives revealed a weak activity against S. aureus and MRSA with MIC: 256 μg/m while the antifungal activities of the compounds against C. albicans and C. albicans ranged between 64 and 128 μg/mL. The cytotoxic activities were investigated on (breast cancer cell line) MCF-7 and (lung cancer cell line) A549 cell lines by the MTT method. From the series, compound (37) exhibits the best cytotoxicity on MCF-7 and A549 cell lines, with a reduction of 70% and 71.29% viability. An excellent predictive ADME profile was shown for all compounds within the series which is a promising candidate for further and extensive study [70].

Moheson et al. have proposed a new series of 2-substituted benzoxazole derivatives and their anticancer activities were evaluated in vitro against two human breast cancer cell lines based on their previous work, that substituent at 4-position of the 2-phenyl ring with alter functionality has a role in enhancing the anticancer activity. Thus, the 2-phenylbenzoazole derivatives were designed to be attached with dithiocarbamate and flexible amide NHCOCH₂ spacer. Their findings revealed that when amide was introduced, the 4-(2-ethoxyphenyl)piperazinyl moiety at position-4 grant molecule (38) a moderate to weak activity against both cell lines (IC₅₀ = 132.619 and 62.081 μM against MCF-7 and MDB-MB-231 cell lines, respectively. For dithiocarbamate, compound (39) substituted with 2-phenyl piperazinyl moiety exhibits high selectivity compared to other analogous, where it is highly potent against MDA-MB-231 cells and it is inactive against MCF-7 cells [71].

Extensive effort was performed by Liu et al. to find potential candidates for the treatment of prion diseases. They found that the presence of hydrogen bond acceptor (HBA) is critical for anti-prion potency so benzoxazole has been introduced where oxygen and nitrogen can act as hydrogen bond acceptors and benzene fused structure adds additional binding affinity. They reported SAR study on different arylpiperazines and their findings showed that compounds (40 and 41) have enhanced anti-prion activity, PK profile, and good central nervous system (CNS) penetration [72]. They have concluded that the HBA effect mainly from nitrogen atom as benzazole was replaced with a more hydrophobic moiety, benzothiazole, it has little impact on anti-prion activity. The nitrogen on pyridine attached to piperazine has a role in forming hydrogen bonds with putative target compared with other analogous.

The solubility of some anticancer agents causes difficulty for in vivo studies. For this reason, some functional groups can be introduced to enhance the solubility e.g., piperazine or its derivatives. Based on their previous study, Xiang and his team are trying to overcome the poor solubility in which, N-methyl-piperazine moiety has been introduced at the 2-position and 6-position to a promising lead compound to enhance its solubility. Impressive results have been obtained from this modification shown in compounds (42–44), the placement of N-methyl-piperazine at position 6 has decreased the potency. On the other hand, where it was placed at position 2 enhanced solubility (and hence drug delivery) and antitumor activity. As the benzothiazole scaffold was replaced by benzoxazole and benzimidazole, it retained its anticancer activity. A new phenomenon was observed for the first time, that is, cytosolic vacuolization after treatment compared to their previous work which is worth further study [73].

In pursue with their ongoing work on synthesis of benzazole scaffolds, Al-Harty et al. have synthesized novel benzoxazoles appendaged with different aryl-piperazine moieties at position 6. Generally, cytotoxicity assay was performed at 50 μM since almost all tested compounds above 50 μM precipitated in cell-culture media. In other words, 43 and 42% of hepatocytes and cancer cells, respectively. The CT₅₀ value of ~50 μM could only be obtained for (45), and it shows no selectivity in killing health and cancer cells. At low concentration, 10 μM, compounds (46–49) were highly toxic to lung cancer cells, killing 30–40% of all cancer cells at this low concentration. Concentrations below 10 μM were not toxic for both [74].

Siracusa and his research team have proposed a new series of different benzazole analogues that are linked with arylpiperazine by different thioalkyl chains and evaluated for their radioligand binding affinities [75]. Many compounds show an interesting binding profile for the 5-HT_1AR and good selectivity over 5-HT_2A, α1, D1, and D₂ receptors. Out of the synthesized benzazole and benzothiazole scaffold being potent ligands than benzimidazole and the compound (50) displayed higher affinity at D₁, D₂ dopaminergic, and 5-HT_2A serotonergic receptors and selectivity at 5-HT_1A receptor over all the tested receptors. This high-affinity binding can be referred to as the remarkable π-π stacking in compared to other teste analogs.

In addition, another work was done by Liu et al. to identify potent and selective ligands as effective treatments for central nervous system diseases (CNS) such as Alzheimer’s disease (AD) and schizophrenia. Their focus was on the synthesis of a novel series of benzoxazole derivatives as 5-HT₆ ligands. The former derivatives (51) have demonstrated full antagonism as determined by blockage of 5-HT-induced cyclic AMP (cAMP) formation [76].

Moreover, another study targeting Acetylcholinesterase (Ach), Butyrylcholinesterase (BCh) and Tyrosinase, which play an important role in the development of Alzheimer disease (AD), was reported by Celik et al. The in vitro enzyme inhibition activity revealed that the inhibitor effect of against ACh and tyrosinase enzyme was very low and compound (52) with ethyl piperazine moiety inhibited the BCh enzyme at a concentration of 50 mM by 54 ± 0.75%. The calculated data collected found that the compound (52) highest BChE inhibitory activity, has the ability to form hydrogen bonding and has more electronic structure stability compared to standard drug, galantamine (Figure 6) [77].

Figure 6.

Benzoxazole derivatives incorporating piperazine.

3. Conclusions

In summary in this work, we emphasis the significance added to biological activity of benzazole when piperazine is within the structures. The strategic choice of heterocycle, and substituent around plays a vital role in modifying by increasing, decreasing, or maintaining the biological activity. In terms of future regard, structural modification at strategic position is becoming a promising direction in drug discovery. Bioisosterism is utilized as well in drug design to maintain or enhance the biological activity of a molecule while improving other properties such as toxicity, metabolic stability, or pharmacokinetics. From the literature discussed, we can value the importance of piperazine and benzazole when they are engaged in one scaffold. Hence, this will be a useful tool in predicting the biological activity of the compound which in sequence minimizes the cost and time for the designing step. In the above discussed studies, till date, piperazine still owing the top priority in the drug design when incorporated with other heterocycles.

Conflict of interest

The authors declare that there is no conflict of interest.