A review on the chemistry and pharmacological properties of benzodiazepine motifs in drug design

Abstract Benzodiazepines are an important class of heterocyclic compounds in organic chemistry. They are known for their diverse physicochemical and biological properties. Some benzodiazepine derivates are well-known drugs with diverse and strong pharmacophoric moiety. An immense number of pharmacological research on benzodiazepine heterocycles and their derivatives have recently been conducted to explore its numerous pharmacological potentials as better therapeutic candidates for the treatment of various disorders, benzodiazepines, however, are one of the main sources of interest for many medicinal chemists. Researchers are drawn to the benzodiazepine nucleus for the synthesis of new drugs because of its potent pharmacophoric moiety and ring shape. Due to the emergence of new pathogenic strains’ resistance to the presently available drugs, there has been a constant demand for more effective and selective drugs. Benzodiazepine moiety has all the desired qualities for selective drug candidates used as useful therapeutic agents. Given the importance of benzodiazepine moiety, the current review aims to assess benzodiazepine syntheses as well as their pharmacological properties for potential molecular targets in therapeutic development.


Introduction
Heterocyclic compounds are essential group of medicinal compounds with more than half of the wellknown organic medications contained this template (Ajani et al., 2019). Because of its significance in the study of pharmacological variety in medicinal chemistry and organic synthesis, it may be claimed that the world is currently in the phase of heterocyclic chemistry (Ajani et al., 2019). The foundation of planetary and human existence is heterocyclic chemistry which is a large subset of organic compounds with a diversity of biological functions (Balaban, Oniciu, & Katritzky, 2004). For the quantification and confirmation of biologically active heterocyclic based medicines, spectrophotometric analysis has been recognized as the essential toolbox (Azmi et al., 2013;Azmi, Al-Fazari, Al-Badael, & Al-Mahrazi, 2015;Azmi, Al-Hadhrami, Al-Marhoubi, Al-Sulaimi, & Al-Shamoosi, 2017). For instance, imipramine hydrochloride, a benzodiazepine bioisostere, has just been validated in tablet as solid material by the use of spectrophotometric determination (Azmi et al., 2022). Additionally, the detection of doxepin hydrochloride in commercial dosage forms as well as the identification of piroxicam in commercial dosage forms have both been effectively accomplished using the spectrofluorimetric approach (Azmi, Iqbal, Jaboob, Al Shahari, & Rahman, 2009;Rahman, Siddiqui, & Azmi, 2009). In order to conclude all investigations and acquire a suitable specification to ensure the level of purity of drug substances and drug products, a proposed method of profiling drug impurity has been made (Rahman, Azmi, & Wu, 2006).
Benzodiazepine, a potent pharmacophore of crucial biodiversity for drug discovery, is the heterocyclic molecule of focus in this study. The psychoactive substance benzodiazepine, 1 and its derivatives are bicyclic heterocyclic compounds having a benzene ring fused to a seven-membered ring. The diazepine ring has two nitrogen atoms at various places in the ring (Shorter, 2005). Regardless of where the nitrogen atoms are located, benzodiazepines are numbered from the position next to the carbocyclic ring. Hoffmann-La Roche discovered the first benzodiazepine in 1955, and Librium, its brand name, was introduced to consumers in 1960 (Wicy, 2013). Benzodiazepine motifs are found in trace amount in Carod plants (Ceratonia siliqua) and are used as anxiolytics, hypnotics and as chemo-anticipatory agents (Avallone, Cosenza, Farina, Baraldi, & Baraldi, 2002).

Justification for the review
There have been some recent reviews on benzodiazepine, for instance, da Silva et al. (2021) focussed their review on formation of organometallic complexes, Arora, Dhiman, Kumar, Singh, and Monga (2020) put emphases on recent advances in synthesis and medicinal chemistry, Christodoulou et al. (2020) centered their review on the synthesis of benzodiazepine via palladium-catalyst. Also, Farhid et al. (2021), focused their review on the multicomponent reaction as a vital instrument for the formation of benzodiazepines. Velasco-Rubio, Varela, and Saa (2020) reviewed mainly on the transition metals as catalysts in the production of benzazepines and benzodiazepines. Varvounis (2016) has his review mainly from 2010 to 2015. In addition, Rashid et al. (2019) centered their review on 1,4-diazepines formatiom, reaction and biological usefulness.
Meanwhile, the introduction of long-lasting synthetic techniques that isolate specified compounds in an efficient and environmentally responsible manner is the primary constraint facing the pharmacological business in synthetic organic chemistry. Due to benzodiazepines remarkable biological characteristics and success, the study of this system provides a very fascinating field for exploration in drug research. Therefore, this review includes a variety of plant extracts, a recent synthetic approach, and pharmacological properties to address the ongoing need to find improved medications that will deliver the highest level of clinical benefits. This present review also provides avenue to harness most recent updates after the publications date of those previous reviews so as to bridge necessary gaps.

Chemistry
Benzodiazepine and other heterocyclic-based templates are core components of drug design. They have been extracted in various form using diverse methods. The extraction method and the applications of some of these selected biomolecular entities is as shown in Table 1. For instance, Doxepin hydrochloride which is a tricyclic heterocyclic compound was extracted through fluorescent ion pair complex formation with eosin Y. It was effectively extracted with dichloromethane using buffer solution of pH 4.52 . Piroxicam as a non-steroidal anti-inflammatory drug (NSAID) was spectrophotometrically determined after effective extraction in ethanol-water medium (Table 1). Method was based on the chelation of the drug with Fe(III) in ethanol-water medium to form a pink colored complex which absorbs maximally at 504 nm . The liquid-liquid extraction approach was also used for detection of piroxicam in human plasma and subsequently analyzed with HPLC (Calvo et al., 2016).
Benzodiazepine based drugs have been extracted from diverse medicinal plants and their biomass feed stocks using various methods. However, benzodiazepine derivatives are found in trace amount in Carod plants (Ceatonia siliqua) and are used as anxiolytics, hypnotics and as chemo-anticipatory agent (Avallone et al., 2002;El-Sayyad, Elkholy, & Hamed, 2017) as shown in Table 1. It can also be found in Mimosa pudica (touch me not leaves) and are used in the treatment of insomnia, epilepsy, anxiety, agitation and depression (Mbomo et al., 2015;Patro, Bhattamisra, & Mohanty, 2016). In addition, benzodiazepines can also be extracted from biological fluid (Westland & Dorman, 2013), and Erythrina velutina Willd (Fabaceae plant) (Danta et al., 2004;Ribeiro et al., 2006;Teixeira-Silva et al., 2008). However, benzodiazepine was first established in mammalian tissues in 1986 (Sand et al., 2000). The first chlordiazepoxide (benzodiazepine) was first revealed by Leo Stern Bach and his team in 1957 while reviewing the action of quinazoline oxide (Wicy, 2013).

Synthesis via H-MCM-22 catalyzed approach
According to Majid et al. (2012), the reaction of a calculated amount of o-phenylenediamine, the matching ketones, and H-MCM-22 catalyst produced eight examples of 1,5-benzodiazepines derivatives (Scheme 1). Compound 14a-h was produced from acetone and used to demonstrate the catalyst's recyclable nature. Its initial yield was 87%, while the yields obtained from its synthesis using H-three MCM-22's time's recyclable effort were 85%, 81%, and 75%, respectively. This demonstrated the great efficiency of recovery and reuse for this catalyst. In order to obtain 1,5-benzodiazepines with a very good yield, the combination was employed and reacted in the CH 3 CN at normal temperature and pressure. It was reported that H-MCM-22 catalyst was highly expeditious and efficient for both cyclic and acyclic ketones. Some shortcoming like corrosiveness, toxic nature, waste products generation, and expensiveness evident in homogenous catalysts, were cheaply overcame by the use of H-MCM-22 catalyst. Radatz et al. (2011) synthesized eight trisubstituted benzodiazepines 15a-h by reacting o-phenylenediamine with excess of acetophenone and other aromatic and aliphatic ketones using glycerol as solvent. At 25 C, the yield of 15awas very low but when the temperature was elevated to 90 C for 4 hours, it gave the product in an excellent yield of 96% (Scheme 2). It was validated that the glycerol could be reused for about four times with no loss of potency. Although, seven of these products were obtained in excellent yield (70-96%); however, this solvent-dependent catalyst-free reaction was not well favoured when simplest symmetrical ketone (acetone) was use as it produced the corresponding benzodiazepine, 15b in low yield (45%) despite the efficacy of glycerol in the reaction optimization study.

Synthesis via CdCl 2 mediated approach
The synthesis of a series of ten imino-based benzodiazepines, 16a-j was carried out via condensative reaction of 1,2-phenylenediamine with acetoacetanilide using CdCl 2 as catalyst under heat and microwave irradiation techniques (Scheme 3). The products were obtained in good yields (52-68%) within 2 mins under microwave irradiation. Although, none of them was obtained in excellent yield but the presence of catalyst improved the yields when compared with reaction in the absence of CdCl 2 as catalyst. Effort was made to compare this with reaction under convention heating method under reflux and it was noted that all reaction were Treatment of central nervous system disorder (Danta et al., 2004;Teixeira-Silva et al., 2008, Ribeiro et al., 2006, 5. Erythrina mulungu Extracted from stem back of willd plant via cold maceration method Insommia, anti-convulsion, nervous coughs, Anxiety, epilepsy and sedative at high dose (Ribeiro et al., 2006)
also completed at < 1 h under reflux heating. It occurred using the blending of tetrahydrofuran and acetic acid combined solvent system (Scheme 3). The microwave reaction occurred in short reaction times (Ilango, Remya, & Ponnuswamy, 2013).

Synthesis via one-pot three-component reaction approach
An array of twenty new benzodiazepine derivatives, 17a-t were synthesized via a special multi-component reaction involving one-pot three-component reaction with the three components being diaminobenzene-3-carboxamide, meldrum's acid and isocyanomethylbenzene (Scheme 4). This multicomponent reaction safes time, but its limitation in this present design was that the 17a-t products were obtained in low yields (25-45%). This compound 17a having R ¼ isopropyl, was obtained in 45% which was the highest yield among the series. Hence, there may be need to improve on the solvent through the use of deep eutectic solvent in order to enhance the product yields. These compounds were screening for anticancer potential and they displayed good antitumor activities against human notable carcinoma (Chen et al., 2014).
Benzodiazepine 18 was accessed in 92% yield. Other aliphatic and cyclic ketones were also utilized to obtain other seven benzodiazepine derivatives in varying yields (70-92%) and reaction time of not more than 20 min (Pasha & Jayashankara, 2006). The research effort here which used p-toluenesulfonic acid catalyzed condition to produce the benzodiazepine, occurred within 20 min while a similar reaction in glycerol by Radatz et al. (2011) furnished the benzodiazepine product after 4 hours. Hence, role of p-toluenesulfonic acid in lowering the activation energy for a better kinetic is well commendable.

Synthesis via gold(I)-catalyzed approach
The formation of an array of twenty-four derivatives of 1,5-benzodiazepine 19 was successfully reported from the reaction of 1,2-phenylenediamine with alkynes at 60 C in chloroform for 6 hours under the influence of a catalytic amount of Gold (I) (Scheme 6). Efficacy of diverse gold-based catalysts were investigated. Also, (2-Scheme 1. Synthesis via catalytic performance of H-MCM-22 Scheme 2. Synthesis of benzodiazepines using glycerol as solvent. biphenyl)Cy 2 PAuNTf 2 featured as the most efficient catalytic substrate that resulted in highest yield within 6 h. Interestingly, 5 mol% catalytic amount was used for the product to be accessed in good yield (Qian et al., 2012). Out of these twenty-four benzodiazepines, the first fourteen 19a-n were obtained in 46-97% yields by starting from un-substituted o-phenylenediamine precursor while the remaining ten 19o-x were accessed in 62-99% yields using substituted o-phenylenediamine. Although, this reaction was high atom economical in accessing the 24 derivatives, but when prop-1-yn-1-ylbenzene was used as the alkyne synthon the reaction failed woefully.

Synthesis via photo-redox catalyzed radical cascade approach
The formation of fluorinated pyrrolo[1,2-d]benzodiazepine derivatives by means of photo-redox catalyzed radical cascade reaction was made possible in inert condition created by the presence of argon and reaction time of 24 h (Scheme 7). Specifically, when R 1 ¼ R 2 ¼ H; X ¼ C; this led to the formation of five tetracyclic benzodiazepines 20a-e. Single electron transfer (SET) played a crucial role in the initiation of the photochemical reaction reported therein. The reaction environment was basified with triethylamine with dichloromethane being the solvent (Lian et al., 2019). Cyclization was successful, but the yields were low (below 50%), except for 20e which was obtained in 62% yield, which was also the only derivative where substitution took place on the indole ring. Thus, there may be need for further search on yield improvement strategy. The sixth attempt as 20f failed woefully as the cyclization to benzodiazepine was abortive when benzimidazole was used instead of indole which showed that Scheme 3. Synthesis of benzodiazepine using CdCl 2 as catalyst.

Scheme 4. Synthesized of benzodiazepines using three-component reaction in a mixture
Scheme 5. Synthesis of benzodiazepines via catalytic performance of p-toluene sulfonic acid second nitrogen heteroatom of benzimidazole might have played a crucial in this failure.

Synthesis using gold-catalyzed domino reaction
The synthesis of eighteen benzodiazepines21a-r was harnessed from catalytic performance of gold catalyzed hydroamination of 1,2-phenylenediamineand propargylic alcohols having substituents at positions 2 and 4 respectively (Scheme 8). Each of the products formed centered on the activity of R 1 and R 2 . The last compound of this series was a yellow compound 21r (R 1 ¼ Ph, R 2 ¼ H) which was obtained in 77% yield (Cacchi et al., 2016) while other was obtained in 32-72%. This reaction was reported to proceed well at 60 C and was maintained as the refluxing temperature (Cacchi et al., 2016). It was observed that the presence of strong electron donor at the terminal portion of acetylenic bond resulted in benzodiazepine yield enhancement.

Synthesis via Brønsted catalyzed approach
The effective performance of Brønsted catalysts (MIL/ K-SO 3 H and MIL/Ks-CN) were carried out through condensation of 1,2-phenylenediamine and ketones at 50 C in lieu of the formation of substituted 1,5-benzodiazepines (Scheme 9). When nona-5-one is used, the product 22 was obtained in 83%. MIL/Ks-CN indicated better catalytic efficiency and activities when compared with MIL/K-SO 3 H (Isaeva et al., 2019). Indalkar et al. (2017) synthesized 4-substituted 1,4benzodiazepine in an environment friendly one pot system through 3 components reaction which was effectively catalyzed by sulfated polyborate (Scheme 10). Optimization study for 23 productions was investigated using the reaction of o-phenylenediamine, cyclohexa-1,3-dione and un-substituted benzaldehyde. Effect of catalyst loading and temperature showed that the highest yield of 23 (95%) was obtained when 15 mol% of the catalyst was used at 100 C reaction temperature. The reaction time was short with excellent yield when the refluxing temperature was elevated to 100 C (Indalkar et al., 2017).

Synthesis via copper catalyzed thermal cyclization
Chen et al. (2020) produced 1,4-benzodiazepines-5one, 24(when Scheme 6. Synthetic pathway to trisubstituted-1,5-benzodiazepines using Gold (1)-catalyst Scheme 7. Synthesis of benzodiazepine using photo-redox catalyzed radical cascade reaction copper catalyzed thermal cyclization of alkenylated anthranilamide derivatives (Scheme 11). This was mechanistically described to have occurred through copper-catalyzed rearrangement cascade allyl-amination and C ¼ C rearrangement with good yield of not less than 90%. The reaction was completed in 12 h when the heating was done at 110 C using toluene as solvent. Shaikh et al. (2020) stated that microwave assisted preparation of thiophenyl-1,5-benzo diazepines were made possible by utilizing various clay backing catalyst and clay backing transition metals support (Scheme 12). Microwave assisted reaction of o-PDA with 3-acetyl thiophene using Cu(II)-clay nano catalyst afforded benzodiazepine 25 in 98% yield. Among all the metal clay catalysts, copper (II) on clay nano catalyst adsorbent was the most viable and exhibited excellent action with high yield based on the reported optimization study (Shaikh et al., 2020).

Synthesis via clay backing supported microwave approach
2.1.13. Synthesis from chalcones and 1,2phenylenediamine Taha and Rasheed (2022) reported the microwave assisted preparation of 1,5-benzodiazepine 26 via the condensation of 1,2-phenylenediamineon chalcone in absolute ethanol and NaOH (10% w/v). The chalcone utilized was prepared from the condensation reaction of acetylacetone with cinnamaldehyde in a basified environment (Scheme 13). This reaction proceeded smoothly in the microwave at 400-Watt power modulation (Taha & Rasheed, 2022).
2.1.14. Synthesis from AlKIT-5 catalysts at room Shobha et al. (2010) stated that ambient temperature synthesis of 1,5-benzodiazepineswas achieved by the use of various clay backing catalyst and cage type mesoporous aluminosilicate catalysts. When cyclopentanone was treated with o-phenylenediamine, 27 were obtained in 92% within 1 h reaction time (Scheme 14). It was reported that the high catalytic activity was due its high acidity and excellent textural parameters (Shobha et al., 2010).

Pharmacological properties
The undeniable roles of benzodiazepine-based drug in the treatment of diversities of infections cannot be over-emphasized as many commercially marketed drugs possess benzodiazepine as their core templates as shown in Table 2. Some of these drugs are chlordiazepoxide with sedative and anxiolytic properties (Prommer, 2020); diazepam with inhibitory properties which facilitate the action of gamma aminobutyric acid (GABA) (Chakraborty, Sharmin, Rony, Ahmad, & Sohrab, 2018); clonazepam with anti-epileptic properties (Panahi et al., 2014); alprazolam with antidepressant activities (Rao, Ahmad, Madni, Ahmad, & Shahzad, 2020); lorazepam with anti-anxiety efficacy (Mercier et al., 2022); midazolam (marketed under the brand name versed) possessed amnesic properties (Taghizadeh, malakpouri, & Javidan, 2019); delorazepam with muscle relaxant endowment (Magalhães et al., 2012) and oxazepam with anxiolytic and anticonvulsant properties (Chan, 2019;Varenne et al., 2022). The structures and therapeutic applications of the benzodiazepine-based drugs are as presented in Table 2. Benzodiazepines are used by Psychiatrists to treat nervousness, sleeping syndromes and liquor withdrawal and this afford relief at low doses when likened with barbiturates. They show fewer negative effects when likened with pyrimidinetrione motifs and dicarbamates (Pagel & Parnes, 2001;Shaikh et al., 2020). The long-term uses of benzodiazepines are prohibited by Food and Drug Administration but are rather permitted for shortrange use base on the conditions (Casher, Botswick, & Yasugi, 2012).

Anxiolytics activity
Benzodiazepines are used by Psychiatrists to treat numerous anxieties for short-term administrations and provide relief at low doses. They are safer than Scheme 11. Synthesis involving copper-catalyzed rearrangement cascade allyl-amination.

Hypnotic activity
Benzodiazepines alter the rate of sleeping due to its ability to increase sleeping period by reducing the interval to fall asleep and the rate of arousals (Roehrs & Roth, 2010). Benzodiazepines reduce the deep sleep stages and increase the light-sleep phases. This decreases the most vital phase of sleep and affects sleep worth (Roehrs & Roth, 2010). Examples of commercially available benzodiazepines hypnotic drugs are temazepam,12, quazepam, 13, flurazepam, 28 and estazolam, 29 (Figure 4).

Muscle relaxant activity
Benzodiazepines such as alprazolam 8, diazepam 10, and lorazepam 11 can be used as body relaxants decreasing the manner of muscle spasm and prevent increased muscle tone. The relaxant features are facilitated via a2-comprising receptors in the central nervous system. They could also inhibit the ache of the cerebral palsy caused by other central nervous system pathologies (Griffin et al., 2013). Recently, administration of vehicle of diazepam, 10 indicated that the unilateral exodontia (AO group) promoted an increase of oxidative fibers in the contralateral side (Nascimento et al., 2020) (Figure 5).

Antiproliferative activity
According to Sharp et al. (2017), benzodiazepine motif 30 exhibited viable antiproliferative action in number of definite leukemia and down regulation of gene that has the potential to cause cancer. The mixes showed production of major osteosarcoma cell varieties, indicating the viability of 1,2,3-triazolobenzodiazepine products in tumor studies (Sharp et al., 2017). Benzodiazepine motif 31 exhibited excellent antiproliferative activity with highly potent anticancer activity against five cancer cell lines at nanomolar concentration ranging from 5.83-12.60 nM (Pang et al., 2019). In addition, compound 32 showed very good antiproliferative activity with IC 50 of 2.50 mM (Lisowski et al., 2002) (Figure 6). Shao et al. (2018) reported that compound 33 exhibited very good anticonvulsant activity via maximal electroshock test and enhanced antiepileptic activity with pentylenetetrazol test (ED 50 value of 36.5 mg/kg, ED 50 of 68.2 mg/kg) (Shao et al., 2018). Compounds 34 and 35 possessed methylated lactamic group which might have brought about higher efficacy which was even better than that diazepam, 10 which was the standard drug used (Gaponov et al., 2016) (Figure 7). Verma et al. (2019) reported the design and formation of novel polyfunctionalized benzodiazepine derivatives. The in vitro activities of the formed compounds were carried out and compounds 36 and 37 showed excellent antibacterial activities against S. aureus and B. subtilis at MIC of 1.70 and 2.30 mM respectively. Whereas, compound 38 also showed good activity against E. coli at MIC of 1.98 mM (Verma et al., 2019). A series of pyrazole bearing benzodiazepine designed by simple and cheap precursor were investigated for their binding potential against critical microbial target DNA gyrase. The experimental validation showed 38 to have good activities against bacterial strain used (Desai, Joshi, & Khedkar, 2020) (Figure 8).

Antibacterial activity
Scheme 14. Synthetic pathway to spiro-based benzodiazepines with the aid of AIKIT-5(10) catalyst Decreases abnormal electrical activity in the brain, treatment of anxiety, alcohol withdrawal use (Prommer, 2020).
2 An inhibitory activity in neurotransmitter in the central nervous system.
Facilitate the action of gamma aminobutyric acid (GABA). Treatment of anxiety, sedative, muscle-relaxant, treatment of convulsion and amnestic (Chakraborty et al., 2018, Iwao, Inoue, Hayashi, Yuasa, & Watanabe, 2004. 3 Anti-epileptic, anti-depressant Facilitate GABAergic transmission in the brain, treatment of panic disorders (Panahi et al., 2014;Mercier et al., 2022) 4 Tranquilizer; antidepressant It acts on the brain and nerves by enhancing the effects of certain natural chemical in the body (Rao et al., 2020) 5 Anti-anxiety, Anticonvulsant It acts on the brain and nerves by enhancing the effects of certain natural chemical in the body (Mercier et al., 2022) (continued) 3.7. Anticancer activity Chen et al. (2014) described the establishment of benzodiazepines derivatives as new possible chemotherapeutic agents. Benzodiazepine bearing carboxamide, 39 exhibited worthy chemotherapeutic activities against human (lung, breast, colon, cervical and lewis lung) carcinoma (Chen et al., 2014).
Compound 40 also exhibited very good antiproliferative activity with excellent inhibitory features (Misra et al., 2020). Midazolam, 41 inhibited cancer cell proliferation both in epithelial and mesenchymal types at IC 50 of 5 lM (Lu et al., 2021) (Figure 9).

Antidepressant activity
Benzodiazepines play a significant role towards the central nervous system by virtue of their selective binding in selective protein regions known as GABA-A receptors which are found in the brain (Anderson, 2022). In the treatment of depression, benzodiazepine  is added to the antidepressant treatment to ease the anxiety and sleeplessness which go in tandem with depression (Bushnell, St€ urmer, Gaynes, Pate, & Miller, 2017). Sharma et al. (2017) reported phenolic linked compound 42 and chlorophenyl-linked compound 43 as viable antidepressant when evaluated via behavioral despair test in mice. Clorazepate, 44 is an extensive-stand-in antidepressant benzodiazepine drug with eradication half-life greater than 24 h (Batile, Lizano, Viñas, & Pujol, 2018). However, it is potentially risky to elderly people or patients with metabolism diseases (Figure 10).       Bhat and Kumar (2016) showed 50 as a good anti-inflammatory agent ( Figure 11).       Aricescu, 2014). Benzodiazepine is one of the most important drugs in the market and under clinical trial phase with laudable efficacy for the allosteric modulation of GABA A receptor (Sieghart, 2015). It was statistically established in 2008 that above 5% of adult population in United State used benzodiazepine drugs for the treatment of insomnia, anxiety and presurgical preparatory condition (Olfson, King, & Schoenbaum, 2015). There are also several isoforms of each subunit exploiting a process called alternative splicing: six alpha subtypes (a1,2,3,4,5,6), four-beta (b1,2,3,4), three gammas (c1,2,3), and one delta (d). The binding affinity of (R)-and (S)-forms of three chemotypes (diazepam, imidazobenzodiazepine, and triazolam) against GABA A receptors was investigated using radioligand displacement as well as electrophysiology (Elgarf et al., 2018). There are two GABA binding sites in the receptor and a single binding site for the BDZs which is located in the coupling (interphase) between an a subunit and a b subunit (Soyka, 2017) ( Figure 13).

Conclusion
In summary, benzodiazepine is a highly endowed heterocyclic scaffold with essential features for excellent performance in therapeutic medicine. This review unveiled and garnered valuable information on chemistry and pharmacological properties of benzodiazepine motifs in therapeutic medicine. Their commonest synthetic approach is the one that involved the utilization of o-phenylenediamine as excellent precursor that undergoes cyclo-condensation reaction with diverse ketones under the influence of catalysis, glycerol recyclable solvent approach, conventional thermal cyclisation, microwave-assisted approach in solvent-free condition, environmentally friendly approach etc. In the last decade, interest on benzodiazepines has increased sporadically due to their fast-growing research applications in the design of drugs for the treatment of diverse infectious diseases. Hence, there is need for continuous studies to pinpoint targeted compounds of this class as hit-to-lead biomolecules and their lucrative privilege in fighting diseases. Therefore, the explorative study of diversities of scientific efforts on chemistry and pharmacological propensity of benzodiazepines derivatives highlighted herein might pave ways for the discovery of novel biomolecules with potential for human utilization through drug commercialization.

Authors' contributions
OOA designed the work and partook in the original draft. OOT wrote the chemistry and part of pharmacological aspect, OSS supervised the work and partook in the conceptualization, APP wrote the pharmacological aspect. The original draft and the entire review were written through contributions of all authors. All authors have given approval to the final version of the review.

Disclosure statement
No potential conflict of interest was reported by the authors.