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Advances in the Synthesis and Biological Applications of Enoxacin Based Compounds

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01 October 2024

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02 October 2024

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Abstract
A comprehensive review of advances in the synthesis and biological applications of enoxacin (ENX) based compounds is presented. ENX, a second-generation fluoroquinolone (FQ) is a prominent 1,8-naphthyridine containing compounds studied in medicinal chemistry. Quinolones, a class of synthetic antibiotics, are crucial building blocks for designing multi-biological libraries due to their inhibitory properties against DNA replication. Chemical modifications at positions 3 and 7 of the quinolone structure can transform antibacterial FQs into anticancer analogs. ENX and its derivatives have been examined for various therapeutic applications, including anticancer, antiviral, and potential treatment against COVID-19. Several synthetic methodologies have been devised for the efficient and versatile synthesis of ENX and its derivatives. This review emphasizes all-inclusive developments in the synthesis of ENX derivatives, focusing on modifications at the C3 (carboxylic acid, Part A), C7 (piperazinyl, Part B), and other positions (Part C). The reactions considered were chosen based on their reproducibility, ease of execution, accessibility, and availability of the methodology reported in the literature. The review provides valuable insights into the medicinal properties of these compounds, highlighting their potential as therapeutic agents in various fields.
Keywords: 
Subject: Chemistry and Materials Science  -   Medicinal Chemistry

1. Introduction

Quinolones, a class of synthetic antibiotics, are widely recognized as crucial building blocks for designing multi-biological libraries [1,2]. Their inhibitory properties against DNA replication make them effective against various pathogens, including mycoplasma, bacteria, and protozoa [3,4,5]. These synthetic antibacterial drugs belong to the broader class of fluoroquinolones (FQs) and act by targeting DNA gyrase, topoisomerase enzymes, and topoisomerase IV involved in DNA replication and repair processes in bacteria [6,7,8,9,10,11,12,13].
The discovery of nalidixic acid in 1962 marked the beginning of quinolone derivatives' use as antibacterial agents worldwide [13,14]. The subsequent development of FQs in the 1970s and the 1980s significantly expanded their coverage [15,16]. FQs exhibit diverse biological activities, including anti-infectious diseases like malaria, parasitic, bacterial, and fungal [3,17,18,19] as well as viral infections like hepatitis, human immunodeficiency virus (HIV), and herpes [20]. They are highly effective against Gram-negative Pseudomonas infections and have been employed in treating pneumonia and intra-abdominal infections [21]. Additionally, they show promise in treating autoimmune diseases, organ transplantation, and rheumatoid arthritis with low toxicity [2,22,23,24]. FQs can impede tumor growth by inducing damage to type II human DNA topoisomerases, similar to specific chemotherapy drugs like etoposide [25,26] , making them noteworthy agents in infectious disease management and potential adjuncts in certain cancer treatment strategies.
The critical structural attributes of quinolones have been identified, with 4-oxo-quinolone-3-carboxylic acid being a significant substructure in numerous quinolone derivatives with outstanding biological activities [27,28]. Chemical modifications at position 7 transform antibacterial FQs into anticancer analogs, while the carboxylic group at position 3 plays a vital role in enzyme binding and functional group transformation, enhancing anticancer potential [27,29,30]. FQs like levofloxacin and moxifloxacin are designated by the WHO as second-line drugs for treating tuberculosis due to their broad and potent spectrum of activities as well as oral administration [31,32,33]. The versatility of quinolones and FQs makes them valuable tools in medicinal research and therapeutic applications across different disciplines.
FQs with a 1,8-naphthyridine core are a specific subset of the fluoroquinolone class, where the quinolone nucleus is replaced by a naphthyridine structure. In the case of FQs with a 1,8-naphthyridine core, the compounds primarily differ at two key positions: N1 and C7, with modifications often occurring at C3 and C7. Figure 1 depicts the 1,8-naphthyridine core, clearly labeling N1 through N8 to emphasize these distinctions within the structure. To illustrate, enoxacin (ENX) is known for having a piperazinyl group at C7 and an ethyl group at N1. In contrast, gemifloxacin, while also featuring the 1,8-naphthyridine core, has an aminopyrrolidinyl group at C7 and a cyclopropyl group at N1. Other FQs with this core typically have a different group at C7 as well as N1 positions as illustrated in Figure 2.
In 1980, ENX, a 1,8-naphthyridine derivative of nalidixic acid was discovered [34]. Although six distinct isomeric forms of naphthyridine exist, 1,8-naphthyridine derivatives have been extensively researched [35,36,37]. This unique skeleton has led to various bioactive compounds derived from natural sources, demonstrating significant biological applications [38,39,40]. ENX, a fluorinated antibacterial drug, and voreloxin, a non-fluorinated potential anticancer agent, are prominent 1,8-naphthyridines studied in medicinal chemistry [26,41]. Other important 1,8-naphthyridine containing molecules with demonstrated biological activity include nalidixic acid, trovafloxacin, tosufloxacin, voreloxin, and gemifloxacin (Figure 2).
ENX, a second-generation fluoroquinolone, is known for its wide-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. [42,43,44]. Structurally, ENX comprises of two fused six-membered rings with 1,8-naphthyridine core as the parental structure (Figure 3) [45,46]. This drug is often well tolerated and has a low frequency of side effects. It is typically delivered orally in the form of tablets. However, due to the development of resistance by many strains of bacteria, including Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa), it is no longer considered a first-line treatment for bacterial infections [47]. Over the past few decades, scientists have examined the potential usage of ENX and its derivatives for several therapeutic applications [48,49,50]. In vitro tests have revealed that ENX exerts significant cytotoxicity in human cancer cells [48,51]. Moreover, it has also been reported to enhance the anticancer effects of other chemotherapeutic medications, including paclitaxel [51,52,53]. In addition, ENX possesses antiviral properties, making it effective against many different infections including HIV and hepatitis C virus (HCV) [48,52].
A recent study on repositioning FQs demonstrated the potential of repurposing ENX for its use as a potential treatment against COVID-19 (SARS-CoV-2) [54,55,56]. Although there are many motives for reviewing the chemical synthesis of ENX and its derivatives, some of the critical reasons are selectivity [57], repositionability [51], oral bioavailability [58], better safety profile, prooxidative activity, and regulation of microRNA biogenesis [59]. ENX 's unique microRNA-interfering activity sets it apart from other FQs and topoisomerase II drugs [45].
Several synthetic methodologies have been devised and implemented and are known for their efficiency, versatility, and convenience [1,60,61]. However, no exhaustive review has exclusively presented the synthesis of ENX and its derivatives based on current literature and understanding [62]. In this review, we highlight key developments in the synthesis of 4-quinolone-3-carboxylic acid derivatives with a 1,8-naphthyridine core, specifically focusing on ENX, and discuss its medicinal properties where relevant. Recent publications have discussed the expanded therapeutic potential of diverse heterocyclic molecules beyond their conventional applications [63,64,65,66].
The present analysis is structured into three distinct segments: part A focuses on the modification of the carboxylic acid at the C3 position, part B addresses the modification of the piperazinyl group at the C7 position, and part C explores combined modifications involving both parts A and B. The reactions considered in this review were chosen based on their capacity for reproducibility, relative ease of execution, accessibility, and availability of the methodology, as reported in the literature. Below is the structural representation of ENX with labeled atom positions comprising the C3-carboxylic part, C7-piperazinyl part and the fluoroquinolone core (Figure 1).

2. Modifications of ENX Based Compounds

2.1. C3 Modification of ENX (Part A)

In 2009, You and colleagues [67] designed and synthesized a novel series of quinolone and naphthyridine derivatives as potential topoisomerase I inhibitors by modifying the scaffold in three steps. The first step involved condensation of ENX with 2 in polyphosphoric acid (PPA) at 170-250 °C to obtain 3a-c or 4 (Table 1). In the subsequent step, intermediate 3a-c was nitrated in a mixture of concentrated sulfuric acid (H2SO4) and nitric acid (HNO3) in an approximately equal ratio at 5 °C, followed by heating at 40-45 °C for 1-2 h, yielding 5a-c. In the final step, the nitro-containing compound 5c was subjected to hydrogenation over Pd/C in 1N hydrochloric acid (HCl) solution to produce 6 (Scheme 1). All derivatives containing three kinds of heterocycles, benzoxazole, benzimidazole, and benzothiazole, at the C3 position were screened in vitro for their antiproliferative effects against oral epidermal carcinoma (KB), ovarian carcinoma (A270), and hepatocellular carcinoma cells (Bel-7402) using a 1-N-methyl-5-thiotetrazole (MTT)-based assay (Table 1). In summary, the 3-benzothiazolenaphthyridine skeleton 3c showed the highest antiproliferative activity (IC50= 2.4-2.7 μM) against three tumor cell lines. Conversely, nitro-containing 3-benzoxazolenaphthyridine scaffold 5b displayed even better cytotoxic activity (IC50=31.8-3.0 μM). Surprisingly, reducing the nitro group in 5a to 6 resulted in significantly diminished cytotoxicity. This reinforces the hypothesis that an electron-withdrawing group is essential for cytotoxic activity.
Few years later, Yang and coworkers [68] synthesized 1,8-naphthyridin-3-yl-1H-benzo-6-carbonitrile derivatives of ENX by replacing the carboxyl group at C3 with a 2,3-dihydro-1H-benzimidazole-5-carbonitrile system in a single step employing same procedure as described in Scheme 1 [67]. The target compound was realized by condensing ENX with 7 at 170-250 °C in PPA to yield product 8. Their studies were primarily centered around investigating the potential molecular mechanism by which it exhibits its antitumor activity against non-small cell lung cancer (NSCLC). The results revealed that compound 8 exhibited significantly stronger inhibitory effects against NSCLC compared to its leading compound ENX, both in cultured cells and in a xenograft mice model. It also increases Reactive Oxygen Species (ROS) generation and DNA Damage Response (DDR) dose-dependently. The ROS scavenger N-acetyl-cysteine (NAC) reduced DDR and apoptosis triggered by 8, confirming its antitumor actions are due to oxidative stress. Thus, 8 promotes oxidative stress and cell death by activating the mitochondrial and endoplasmic reticulum (ER) stress pathways [68].
Preprints 119943 sch002
Scheme 2. Synthesis of 1,8-naphthyridin-3-yl-1H-benzo[d]imidazole-6-carbonitrile 8.
Scheme 2. Synthesis of 1,8-naphthyridin-3-yl-1H-benzo[d]imidazole-6-carbonitrile 8.
Preprints 119943 sch002
In a study conducted by Arayne et al. [69], the synthesis of various ENX carboxamide and carbohydrazide derivatives as antibacterial agents was reported. This synthesis involved the amidation of 3-carboxylic acid group of ENX using aromatic amines and phenyl hydrazine. Initially, ENX ester, 9 was prepared via Fischer esterification, in methanol with a catalytic amount of H2SO4 at reflux for 7-8 h. The resulting ester was further reacted with different aromatic amines under reflux for 2-3 h to yield the desired carboxamides 10a-d and carbohydrazide 10e with moderate to good yields (Scheme 3). Compounds 10a-e were tested against various bacteria, revealing remarkably improved antimicrobial effectiveness against Gram-negative strains. Furthermore, their potential to influence the immune response was assessed in a separate study [70]. To evaluate their immunomodulatory activity, the impact on the oxidative burst activity of phagocytes in whole blood, as well as macrophages and neutrophils, was investigated. Among the synthesized derivatives, compounds 10c and 10d exhibited the highest level of inhibition in whole blood (IC50= 2.6 and 1.4 µg/mL), macrophages (IC50= 3.2 and 1.4 µg/mL), and isolated neutrophils (IC50= 0.8 and 1.4 µg/mL), respectively (Table 2).

2.2. C7 Modification of ENX (Part B)

According to the literature, C7 piperazinyl quinolone modifications are effective not only against Gram-positive and Gram-negative pathogens [71] but also have numerous biological applications against cancer [72,73], inflammation [74], osteoclasts [75], viral infections [76], and other diseases [77,78]. As prospective osteo-adsorptive drugs, Herczegh and coworkers [79] developed a series of bisphosphonate FQ derivatives. The piperazinyl group of ENX was transformed with tetraethyl ethene-1,1-diylbis(phosphonate) 11. In the first step, ENX was combined with 11 in the presence of triethylamine (Et3N) in dichloromethane (DCM), under stirring at room temperature (rt), for 3 h. Afterwards, an aqueous work-up and recrystallization from toluene produced the bis-(diethoxy-phosphoryl)-ethyl ester 12. The ester was then hydrolyzed with bromotrimethylsilane (CH3)3SiBr in DCM at rt for 72 h, yielding 13 as hydrobromide salt. Treatment of the salt with water (H2O) at rt for 6 h, followed by agitation in DCM and subsequent ether washing resulted in an average yield of the desired compound, bis-phosphonic-ENX derivative 13 (Scheme 4).
In another study, Vracar and colleagues [80] discovered that ENX and bis-phosphonic -ENX, 13 have been found to induce the release of extracellular vesicles from 4T1 murine breast cancer cells, which possess inhibitory effects on osteoclastogenesis. Surprisingly, adding a bisphosphonate moiety boosted bone binding affinity. Moreover, bis-phosphonic-ENX, similar to ENX, displayed inhibitory effects on the binding of V-ATPase to microfilaments, as well as on bone resorption in vitro. In summary, bis-phosphonic-ENX, offers multiple benefits beyond preventing bone mineral loss. It does not only modify the composition of bone glycoproteins, making them more resistant to fractures but also completely suppresses osteoclast differentiation. Both ENX and bis-phosphonic-ENX demonstrate similar potency, with IC50 values around 10 µM, indicating their strong inhibitory effects on osteoclasts.
Darekhordi and colleagues [81] established a one-pot approach for the synthesis of antibacterial N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone 15 under moderate conditions. N-aryl trifluoroacetimidoyl chloride 14 was nucleophilically substituted by ENX using potassium carbonate (K2CO3) in dimethylformamide (DMF) at reflux for 24 h to give 15 in moderate to good yields (Scheme 5). In addition, the synthesized conjugate was tested via the agar diffusion method and exhibited a concentration-dependent improved antibacterial activity against E. coli, Klebsiella pneumoniae (K. pneumoniae) and Staphylococcus aureus (S. aureus).
In their study, Xiao et al. [82] described the synthesis of FQ-flavonoid hybrids using a well-designed pharmacophore system, aiming to develop a multi-target bacterial topoisomerase inhibitor with potential as efflux pump inhibitors. The synthesis involved the reaction of FQs with different flavonoids, such as apigenin and naringenin, while including an ethylene linker in the process (Scheme 6). In the initial step, the flavonoids 16 was o-selectively alkylated with 1,2-dibromoethane in the presence of K2CO3 in DMSO at 70 °C for 15 h yielding compound 17a-c. Treating the intermediates 17a-c with ENX in DMSO using DMAP as base at 60 °C for 40-50 h produced new antibacterial hybrids 18a-c in moderate yields (55–75%). The antibacterial efficacy of FQ-flavonoid hybrids was tested against different microorganisms including Tetracycline-resistant Bacillus subtilis ATCC 6633 (B. subtilis), amphotericin B-resistant Candida albicans (C. albicans), multiple drug-resistant E. coli ATCC 35218, and methicillin-resistant S. aureus ATCC 25923. Some of these compounds displayed impressive antibacterial properties, particularly against drug-resistant strains. Remarkably, derivative 18a exhibited outstanding activity against B. subtilis and C. albicans with minimum inhibitory concentration (MIC) of 0.45 µg/mL and 2.60 µg/mL in comparison to the standard drug ciprofloxacin (CPX), with MIC values of 2.70 µg/mL and 32.4 µg/mL for the respective microorganisms (Table 3).
A methylene-bridged nitrofuran N-substituted piperazinylquinolone was designed and synthesized by Emami and colleagues [83]. ENX mixed with 2-(bromomethyl)-5-nitrofuran 19 in DMF in the presence of sodium hydrogen carbonate (NaHCO3) as a base at rt for 120 h resulting in the formation of the desired compound 20 (Scheme 7), in good yield (81%). The antibacterial assessment demonstrated that the efficacy of 7-piperazinylquinolones with (5-nitrofuran-2-yl) derivative against diverse bacterial strains is contingent upon the nature of the substituents located at the N1 and C7 sites. Overall, the compound displayed noteworthy antibacterial efficacy against Staphylococci in a manner that was dependent on their concentration. 20 showed the best inhibitory activity against S. aureus with MIC of 0.39 μg/mL.
In another report [84], four novel ENX derivatives were synthesized by introducing 2-(5-chlorothiophen-2-yl)ethyl into the piperazine ring. The synthesis was performed by reacting ENX with either α-bromoketone or α-bromooxime 21 in DMF at rt, in the presence of NaHCO3 yielding 22a-d in 62-73% yields (Scheme 8). The introduction of 2-(5-chlorothiophen-2-yl)ethyl into the piperazine ring of ENX resulted in an enhanced cytotoxicity against various cancer cell lines compared to the unmodified ENX [85]. 22 exhibit varying modifications to the ethyl spacer structures. Regarding their cytotoxicity against cancer cell lines, including melanoma (SKMEL-3), breast (MCF-7), epidermoid (A431), bladder (EJ), colon (SW480) and KB cell line. Compounds 22b and 22c demonstrated the most significant impact. Specifically, 22b displayed an IC50 range of 3 to 10 μM, while 22c showed an IC50 range of 3 to 20 μM (Table 4). On the other hand, 22d exhibited IC50 values of 2 to 14 μM for melanoma, epidermoid, cervical, and bladder cell lines, respectively. In summary, incorporating the 2-(5-chlorothio-phen-2-yl)ethyl group into the piperazinyl portion of ENX enhanced its cytotoxic properties compared to the parent ENX. Though the extent of improvement depended on the structure of the spacer. By introducing an additional functionality, the antitumor effectiveness rose considerably (Table 4).
Chadha and Agarwal [86] conducted synthesis and preformulation studies on a prodrug of ENX , resulting in the synthesis of N-hydroxymethylenoxacin 25. The synthesis involved condensing ENX with formaldehyde (CH2O) as solution in a mixture of methanol and dichloromethane (1:1) at rt for 3h. The resulting compound was obtained in 89% yield (Scheme 9). The antimicrobial effectiveness of the prodrug was evaluated in comparison to ENX using the agar diffusion method, specifically targeting E. coli, P. aureginosa and S. aureus. The most noteworthy outcome was observed against E. coli, where the MIC was determined to be 0.2 μg/mL.
N-substituted piperazinyl quinolone 26 was synthesized and examined for in vitro antibacterial activity against various strains of bacteria [87,88]. Through the reaction of ENX with 25 and NaHCO3 in DMF at 85-90 °C for 12 h, 26 was obtained in satisfactory yield (Scheme 10). The antibacterial evaluation demonstrated that 26 exhibited potent and superior activity against the tested Gram-positive bacteria compared to reference FQs like ENX. Compound 26 exhibited the highest activity against B. subtilis, with a MIC value of 0.008 μg/mL, surpassing the ENX value of 0.125 μg/mL.
Foroumadi et al. [89] reported a series of N-substituted piperazinyl quinolones via nucleophilic substitution reaction using thiadiazole derivatives 27 with ENX and NaHCO3 in DMF at 85-90 °C for 12 h (Scheme 11). This method successfully synthesized bioactive derivatives of N-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolones 28a-d in moderate yields (62-67%). To evaluate the efficacy of the synthesized compounds, the agar dilution method was employed against a panel of bacteria including S. aureus, Staphylococcus epidermidis (S. epidermidis), B. subtilis, E. coli, K. pneumoniae, and P. aeruginosa. The results indicate that the obtained derivatives exhibited moderate antibacterial activity against the tested microorganisms (Table 5).
In a similar study, a variety of N-substituted piperazinyl quinolones 30a-g were synthesized and tested for antibacterial activity in vitro combining the ENX with α-bromo ketones or oximes 29 as precursors [90]. Zahoor and their colleagues recently reported the synthesis of these compounds [62]. The target derivatives were obtained through the condensation of ENX with properly substituted precursors 29 in the presence of NaHCO3 in DMF as an appropriate solvent in good yields (76-79%) (Scheme 12). The in vitro antibacterial activity of 30a-g against various bacterial strains revealed that compounds 30a-c, and 30g demonstrate antibacterial activity similar to ENX against certain bacterial strains, particularly Gram-positive bacteria like Staphylococci and Gram-negative bacteria like E. coli and Enterobacter cloacae (E. cloacae). However, none of the derivatives consistently outperformed ENX across all the tested strains (Table 6).
Foroumadi et al. [91] synthesized novel ENX analogs from diverse α- chloro methyl oxime precursors 31. By reacting 31 with ENX using NaHCO3 in DMF at rt, they successfully generated ENX analogs 32a-d in 45-72% yields (Scheme 13). The synthesized derivatives were evaluated against a variety of bacterial strains. All the tested derivatives show appreciable antibacterial activity against B. subtilis with inhibitory concentration ranging from 1.56 to 6.25 μg/mL. Although 32b has consistently shown moderate activity across the tested strains, none of the compounds 32a-d demonstrated potent antibacterial effects that were comparable to the reference drug ENX (Table 7).
The same group [92] synthesized novel antibacterial ENX derivatives via nucleophilic substitution of furan-based α-bromoketone or oximes 33. N-[2-(furan-3-yl)-2-oxoethyl] or N-[2-(furan-3-yl)-2-oxyiminoethyl] 34a-d were produced by treating ENX with α-bromoketone or α-bromooxime 33 in the presence of NaHCO3 at rt in moderate yields (41-59%) (Scheme 14). Evaluation of 34 against various bacterial strains revealed that 34a-c exhibit comparable antibacterial activity to ciprofloxacin (CPX) against S. aureus, methicillin-resistant S. aureus (MRSA I and II), S. epidermidis, and B. subtilis. Specifically, compound 34a has an MIC range of 0.39 to 0.78 μg/mL against these strains, which is similar to the MIC range of 0.19 to 0.39 μg/mL observed for CPX. Compound 34b demonstrates a potency of 0.39 μM against S. aureus, MRSA, and S. epidermidis, closely matching the efficacy of CPX. Likewise, compound 34c shows an MIC of 0.78 μg/mL against the same strains, again aligning with the antibacterial potency of CPX (Table 8).
Emami et al. [93] synthesized ENX-coumarin structural hybrids 36a-d with strong antibacterial activities. The synthesis of the analogs required the reaction of piperazinyl quinolones with a coumarin-based oximes 35 through nucleophilic substitution reaction (Scheme 15). This reaction took place in DMF in the presence of NaHCO3 at rt for 6-72 h, resulting in the desired compounds 36a-d in good yields (88-91%). The antimicrobial efficacy of the synthesized derivatives was assessed using the agar diffusion method. Compound 36a, exhibits the most potent antibacterial activity across all tested bacteria, including S. aureus, MRSA I, MRSA II, S. epidermidis, B. subtilis, E. coli, and K. pneumoniae, with MIC values ranging from 0.049 to 3.13 μg/mL. Notably, 36a shows comparable or superior activity to the reference compound ENX against S. aureus, MRSA I, MRSA II, S. epidermidis, B. subtilis, and E. coli. Compound 36b, also demonstrates significant antibacterial activity, with MIC values between 0.39 μg/mL and 12.5 μg/mL. However, 36b is generally less potent compared to ENX. On the other hand, compounds 36c and 36d exhibit weaker antibacterial potency compared to both 36a and 36b, with MIC values that are generally higher than those of ENX (Table 9).
Shafiee et al. [94] documented the synthesis and antibacterial activity of N-[2-(2-naphthyl)ethyl]piperazinyl quinolones. The desired compounds 38a-d were successfully synthesized using a versatile and efficient synthetic pathway (Scheme 16). This approach involved reacting ENX with suitable α-bromooxime or α-bromo ketone derivatives 37 in the presence of NaHCO3 in DMF at rt for 72 h. The resulting products were obtained in good to excellent yields (51-83%). The antibacterial evaluation of these derivatives demonstrated promising activity for certain N-[2-(2-naphthyl)ethyl]piperazinyl quinolones. Compound 38a displays comparable or superior antibacterial activity to ENX across all tested strains, with IC50 values ranging from 0.049 to 0.780 μg/mL. Similarly, 38b shows superior activity compared to ENX, particularly against B. subtilis and E. coli, with IC50 values of 0.190 and 0.390 μg/mL, respectively. In contrast, compounds 38c and 38d generally exhibit weaker antibacterial activity compared to 38a and 38b, as well as the reference compound ENX (Table 10).
Ahmed and colleagues [95] conducted a groundbreaking study where they skillfully synthesized and screened new alternative molecules of ENX derivatives as potential antibacterial as well as antibiofilm agents (Scheme 17). ENX was acylated with acid chlorides 39 using Et3N as base in refluxing tetrahydrofuran (THF). The desired products 40a-e were obtained with a moderate yield (49-64%). Evaluation of the antimicrobial potential of 40 against a panel of pathogens via micro broth dilution method revealed that all the synthesized derivatives were found to be active at low concentrations against MRSA, K. pneumoniae, and Proteus mirabilis (P. mirabilis) with MIC in the range of 12.5 to 25 μg/mL compared to the parent molecule, ENX. Specifically, compounds 40b, 40c, and 40e inhibited the growth of MRSA at a 1 μg/mL concentration better than the parent drug ENX. The antibiofilm inhibitory properties of the synthesized derivatives revealed that 40b, 40c, and 40e inhibited MRSA biofilm formation in the range of 0.5 to 1 μg/mL concentration (Table 11).
Wang and coworkers [96] generated a library of 3-arylfuran-2(5H)-one-fluoroquinolone hybrids 46a-e. Initially, substituted phenylacetic acids 41a-e were converted to sodium phenylacetates 42a-e in dilute NaOH solution. Subsequent treatment of the intermediate salt with ethyl bromoacetate in DMSO at rt for 4 h resulted in the formation of phenylacetic acid ethyl esters 43a-e in excellent yields (90–95%). Cyclization of 43a-e were accomplished using sodium hydride (NaH) in THF at 0 °C to rt, leading to the formation of 4-hydroxy-3-phenylfuran-2(5H)-ones 44a-e. Introduction of an ethyl linker was achieved by dissolving 44a-e in acetone and adding 1,2-dibromoethane and Et3N, followed by refluxing the mixture for 3-5 h, resulting in the formation of compounds 45a-e in good yields. Finally, the target products 46a-e were realized in moderate yields by combining ENX with 45a-e in the presence of KI, and DMAP in DMSO at 60 °C for 72 h (Scheme 18). The conjugated compounds were evaluated against a range of bacteria including tetracycline-resistant B. subtilis, E. coli, and S. aureus. Many of these analogs displayed antibacterial activity that was akin to the reference drug, CPX. Specifically, 46b exhibited superior antibacterial efficacy across all the tested bacteria, with MIC50 values ranging from 1.6 to 2.6 μg/mL, significantly better than CPX, with MIC50 values between 2.7 and 6.82 μg/mL (Table 12).
Shaheen et al. [97] developed and produced a series of novel FQs that exhibit strong inhibitory effects on α-glucosidase (Scheme 19). The analogs were prepared by subjecting ENX to reflux conditions with various substituted benzyl chlorides 47a-g in anhydrous acetone, in the presence of K2CO3, for 4-8 h. This process resulted in the desired monosubstituted compounds 48a-g with satisfactory yields. The synthesized derivatives were then subjected to in vitro screening for α-glucosidase inhibition, along with in silico docking studies. The analogs 48a-g demonstrated strong α-glucosidase inhibitory activity ranging from 48.7 to 74.5 μM, in comparison to the IC50 value of 425.6 μM observed for the reference α-glucosidase standard inhibitor drug, 1-deoxynojirimycin (Table 13). Docking studies of 48a-g reveal that the molecular interactions of mono benzylated derivatives align well with their inhibitory activity. These compounds were observed to form polar contacts with the active site of proteins, mainly involving residues such as Glu771, Asp392, Trp391 and Arg428.

2.3. Other Modifications (Part C)

This category encompasses modifications performed on both the C3 and C7 sites of the 1,8-naphthyridine core of ENX derivatives.
In the same report, Shaheen and colleagues [97] developed and produced a novel di substituted benzyl FQ derivatives with an excellent α-glucosidase inhibitory effect (Scheme 20). The analogs were prepared as demonstrated in scheme 19. However, in this case the ENX was refluxed with various substituted benzyl bromide 49a-c in the presence of K2CO3, for 4-8 h resulting in the formation of disubstituted derivatives 50a-c. The in vitro α-glucosidase inhibition screening showed that compound 50a had the highest potency among all tested analogs, with an IC₅₀ value of 45.8 μM. Other analogs in this series, 50b and 50c, also exhibited notable inhibitory activity, with IC₅₀ values of 67.8 μM and 59.8 μM, respectively. These values are significantly lower than the IC₅₀ of 425.6 μM for the reference α-glucosidase inhibitor. Interestingly, 50a is not only more potent than the reference drug but also surpasses the parent compound, ENX, which has an IC₅₀ of 58.9 μM. Specifically, 50a is about 9.3-fold more potent than the reference drug, stressing its strong potential as a lead candidate for further development. Docking studies of compounds 50a-c indicate that their molecular interactions are consistent with their observed inhibitory activity. These studies show that the di-benzylated derivatives form polar contacts with the active site of the enzyme, primarily interacting with residues such as Gly566, Glu771, Trp391, Asp508, Arg428 and Asp392 (Table 14).

3. Future Perspectives

The recent developments discussed in this review shed light on the synthesis of 4-quinolone-3-carboxylic acid derivatives, with a particular focus on scaffolds containing a 1,8-naphthyridine core reminiscent of ENX. These advancements pave the way for future exploration and innovation in this field. One promising avenue for future research is the further exploration of C3 modifications, as they have shown potential for generating diverse analogs with improved medicinal properties. By employing strategic modifications at the C3 position, researchers can fine-tune the pharmacological profile of these compounds, enhancing their efficacy and reducing potential side effects. Additionally, the C7 modification segment warrants further investigation, as it offers opportunities to optimize the physicochemical properties and biological activities of 4-quinolone-3-carboxylic acid derivatives. By carefully manipulating the C7 position, researchers can potentially enhance the bioavailability, target specificity, and overall therapeutic potential of these compounds. Lastly, the approach that combines modifications from both A and B presents a promising direction for the design and synthesis of novel enoxacin derivatives with diverse pharmacological applications. Within this framework, researchers can explore a wide range of structural modifications in order to produce analogs with specialized features and unique biological activities. Overall, these prospects for the future emphasize the intriguing possibility for further breakthroughs in the synthesis and research of 4-quinolone-3-carboxylic acid derivatives.

4. Conclusions

In conclusion, this review provides a comprehensive analysis of developments in the synthesis of 4-quinolone-3-carboxylic acid derivatives, focusing on scaffolds containing a 1,8-naphthyridine core akin to ENX. The reviewed literature showcases various modifications at the C3 and C7, and combination of C3 and C7 positions, demonstrating their impact on the structural diversity, medicinal properties, and potential pharmacological applications of these compounds. The chosen reactions were selected based on their reproducibility, ease of execution, and the accessibility of the described methodologies. Researchers seeking to design and synthesize novel ENX derivatives with diverse pharmacological activities will find the insights presented in this review both valuable and insightful. This comprehensive analysis sets the stage for future investigations, where researchers can explore the untapped potential of 4-quinolone-3-carboxylic acid specifically ENX derivatives, thereby opening new avenues for drug discovery and therapeutic interventions.

Author Contributions

Conceptualization, G.S., N.E.B., G.G. and S.E.K.; resources, N.E.B., G.G. and S.E.K.; writing—original draft preparation, G.S.; writing—Review and editing, G.S., N.E.B., G.G. and S.E.K.; supervision, N.E.B. and S.E.K.; project administration, N.E.B., G.G. and S.E.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to express our sincere gratitude to Euromed University of Fes (UEMF), Morocco, and the African Scientific, Research and Innovation Council (ASRIC) for their unwavering support and resources provided during the course of this project.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Preprints 119943 g001
Figure 1. Labeled structural representation of FQs containing 1,8-naphthyridine core. There are two important distinct positions, C7 and N1 (R1 and R2) with diverse substituents.
Figure 1. Labeled structural representation of FQs containing 1,8-naphthyridine core. There are two important distinct positions, C7 and N1 (R1 and R2) with diverse substituents.
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Figure 2. Fluorinated & non-fluorinated 1,8-naphthyridine containing molecules.
Figure 2. Fluorinated & non-fluorinated 1,8-naphthyridine containing molecules.
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Figure 3. Main sites for structural modification of ENX. .
Figure 3. Main sites for structural modification of ENX. .
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Scheme 1. Synthesis of 1,8-naphthyridin-3-yl-1H-benzo derivatives 3a-c, 4, 5a-c, and 6.
Scheme 1. Synthesis of 1,8-naphthyridin-3-yl-1H-benzo derivatives 3a-c, 4, 5a-c, and 6.
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Preprints 119943 sch003
Scheme 3. Synthesis of aryl substituted ENX carboxamides 10a-d and carbohydrazide 10e.
Scheme 3. Synthesis of aryl substituted ENX carboxamides 10a-d and carbohydrazide 10e.
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Preprints 119943 sch004
Scheme 4. Synthesis of bis-phosphonic-ENX 13.
Scheme 4. Synthesis of bis-phosphonic-ENX 13.
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Preprints 119943 sch005
Scheme 5. Synthesis of N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone 15.
Scheme 5. Synthesis of N-aryl-2,2,2-trifluoroacetimidoyl piperazinylquinolone 15.
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Preprints 119943 sch006
Scheme 6. Synthesis of ENX flavonoids-based analogs 18a-c.
Scheme 6. Synthesis of ENX flavonoids-based analogs 18a-c.
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Preprints 119943 sch007
Scheme 7. Methylene-bridged nitrofuran N-substituted quinolone synthesis 20.
Scheme 7. Methylene-bridged nitrofuran N-substituted quinolone synthesis 20.
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Preprints 119943 sch008
Scheme 8. Synthesis of chlorothiophene ENX derivatives 22a-d.
Scheme 8. Synthesis of chlorothiophene ENX derivatives 22a-d.
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Preprints 119943 sch009
Scheme 9. Synthesis of N-hydroxymethylenoxacin 24.
Scheme 9. Synthesis of N-hydroxymethylenoxacin 24.
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Preprints 119943 sch010
Scheme 10. Synthesis of N-substituted piperazinyl quinolone 26.
Scheme 10. Synthesis of N-substituted piperazinyl quinolone 26.
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Preprints 119943 sch011
Scheme 11. Synthesis of N-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] quinolones 28a-d.
Scheme 11. Synthesis of N-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] quinolones 28a-d.
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Preprints 119943 sch012
Scheme 12. Synthesis of ENX substituted ketone or oxime derivatives 30a-g.
Scheme 12. Synthesis of ENX substituted ketone or oxime derivatives 30a-g.
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Preprints 119943 sch013
Scheme 13. Synthesis of ENX derivatives 32a-d from α- chloro methyl oxime precursors.
Scheme 13. Synthesis of ENX derivatives 32a-d from α- chloro methyl oxime precursors.
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Preprints 119943 sch014
Scheme 14. Synthesis of ENX derivatives 34a-d from α-bromo ketone or oximes.
Scheme 14. Synthesis of ENX derivatives 34a-d from α-bromo ketone or oximes.
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Preprints 119943 sch015
Scheme 15. Synthesis of enoxacin-coumarin hybrid 36a-d.
Scheme 15. Synthesis of enoxacin-coumarin hybrid 36a-d.
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Preprints 119943 sch016
Scheme 16. Synthesis of N-[2-(2-naphthyl) ethyl] piperazinyl quinolones 38a-d.
Scheme 16. Synthesis of N-[2-(2-naphthyl) ethyl] piperazinyl quinolones 38a-d.
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Preprints 119943 sch017
Scheme 17. Synthesis of acyl substituted ENX derivatives 40a-e.
Scheme 17. Synthesis of acyl substituted ENX derivatives 40a-e.
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Preprints 119943 sch018
Scheme 18. Synthesis of 3-arylfuran-2(5H)-one-ENX hybrids 46a-e.
Scheme 18. Synthesis of 3-arylfuran-2(5H)-one-ENX hybrids 46a-e.
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Preprints 119943 sch019
Scheme 19. Synthesis of piperazinyl mono benzylated ENX derivatives 48a-g.
Scheme 19. Synthesis of piperazinyl mono benzylated ENX derivatives 48a-g.
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Preprints 119943 sch020
Scheme 20. Synthesis of piperazinyl di- benzylated ENX derivatives 50a-c.
Scheme 20. Synthesis of piperazinyl di- benzylated ENX derivatives 50a-c.
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Table 1. In vitro antiproliferative activity of compounds 3a-c, 4, 5a-c, and 6.
Table 1. In vitro antiproliferative activity of compounds 3a-c, 4, 5a-c, and 6.
1. Compound 2. R 3. X 4. Antiproliferative activity (IC50, μM)
5. KB 6. A2780 7. Bel7402
8.  3a 9. H 10. NH 11. 2.0 12. 4.8 13. 4.1
14.  3b 15. H 16. O 17. 11.7 18. 15.3 19. 16.8
20.  3c 21. H 22. S 23. 2.4 24. 2.7 25. 2.4
26.  4 27. Cl 28. NH 29. 10.3 30. 6.3 31. 21.5
32.  5a 33. NO2 34. NH 35. 22.4 36. 12.4 37. 10.8
38.  5b 39. NO2 40. O 41. 1.8 42. ND 43. 3.0
44.  5c 45. NO2 46. S 47. 179.3 48. 200.2 49. 24.6
50.  6 51. - 52. - 53. 30.1 54. 42.3 55. 93.3
ND: not determined.
Table 2. Immunomodulatory effect of ENX carboxamides 10a-d and carbohydrazide 10e (Comparable effects of 10a-d and 10e on the oxidative burst activity of whole blood phagocytes, neutrophils and macrophages).
Table 2. Immunomodulatory effect of ENX carboxamides 10a-d and carbohydrazide 10e (Comparable effects of 10a-d and 10e on the oxidative burst activity of whole blood phagocytes, neutrophils and macrophages).
Oxidative burst effects (IC50, µg/mL)
Compound R Oxidative burst of whole blood using Oxidative burst of PMNs using Oxidative burst of Macrophages using
Luminol Luminol Lucigenin Luminol
10a Preprints 119943 i001 8.5 7.6 17.5 8.7
10b Preprints 119943 i002 2.6 0.8 1.0 3.2
10c Preprints 119943 i003 13.3 9.1 22.3 9.5
10d Preprints 119943 i004 >25 >25 >25 >25
10e - 1.4 1.4 2.6 1.4
ENX - >25 >25 >25 >25
PMNs: Polymorphoneutrophils.
Table 3. In vitro antibacterial activity of 18a-c against selected microbes.
Table 3. In vitro antibacterial activity of 18a-c against selected microbes.
Antibacterial activity (MIC, µg/mL)
Compound R1 R2 E. Coli B. subtilis S. aureus C. albicans
18a H H 46.3 0.45 21.5 2.60
18b H Preprints 119943 i005 >50 16.1 33.6 17.5
18c Preprints 119943 i006 H >50 >50 >50 >50
CPX - - 5.65 2.70 6.82 32.4
Table 4. In vitro cytotoxic evaluation of compounds 22a-d against a panel of cell lines.
Table 4. In vitro cytotoxic evaluation of compounds 22a-d against a panel of cell lines.
Compound R Anticancer activity (IC50, μM)
SKMEL-3 MCF-7 A431 EJ SW480 KB
22a O 106 106 131 66 100 117
22b NOH 10.3 3.6 5.6 5.0 3.2 4.8
22c NOMe 13 19 2.9 5.9 6.7 4.7
22d NOBn 13.6 125 2.2 8.0 42 12
ENX - 196 193 175 178 159 137
Table 5. In vitro antibacterial activity of 28a-d against different bacterial strain.
Table 5. In vitro antibacterial activity of 28a-d against different bacterial strain.
Compound R Antibacterial activity (MIC, μg/mL)
S. aureus S. epidermidis B. subtilis E. coli K. pneumoniae P. aeruginosa
28a 2-Cl 1 2 4 >4 >4 >4
28b 3-Cl >4 >4 >4 >4 >4 >4
28c 4-Cl >4 >4 >4 >4 >4 >4
28d 2,4-diCl 4 4 >4 >4 >4 >4
ENX - 1 0.5 0.125 0.25 0.25 4
Table 6. In vitro antibacterial activity of 30a-g against various bacterial strains.
Table 6. In vitro antibacterial activity of 30a-g against various bacterial strains.
Compound R Antibacterial activity (MIC, μg/mL)
R1 S. aureus S. epidermis E. coli K. pneumoniae E. cloacae P. aeruginosa
30a - H 2 2 0-25 0-5 0-5 4
30b - F 4 2 0-5 2 1 8
30c OH H 0-5 0-5 16 0-5 16 >64
30d OH F 1 0-5 16 0-25 16 >64
30e Preprints 119943 i007 H 16 16 4 16 16 >64
30f Preprints 119943 i008 F 64 64 16 64 16 >64
30g Preprints 119943 i009 F 0-5 0-5 8 0-5 8 >64
ENX - - 1 0.5 0.13 0.5 0.13 4
Table 7. In vitro antibacterial activity of 32a-d against various bacterial strains.
Table 7. In vitro antibacterial activity of 32a-d against various bacterial strains.
Compound R1 R2 Antibacterial activity (MIC, μg/mL)
S. aureus S. epidermis B. Subtilis E. coli K. pneumoniae P. aeruginosa
32a H H 25 25 6.25 12.5 12.5 >100
32b F H 12.5 6.25 6.25 6.25 1.56 100
32c H F 25 25 1.56 50 25 >100
32d Cl Cl 25 25 3.13 12.5 6.25 50
ENX - - 15.6 0.78 0.098 0.098 0.098 6.25
Table 8. In vitro antibacterial activity results of compounds 34a-d.
Table 8. In vitro antibacterial activity results of compounds 34a-d.
Compound R Antibacterial activity (MIC, μg/mL)
S. aureus MRSA I MRSA II S. epidermis B. Subtilis E. coli K. pneumoniae P. aeruginosa
34a O 0.78 0.78 0.78 0.78 0.39 0.39 0.19 12.5
34b NOH 0.39 0.39 0.39 0.39 1.56 1.56 0.39 50
34c NOMe 0.78 0.78 0.78 0.78 1.56 156 0.78 >100
34d NOBn 25 12.5 12.5 12.5 3.13 3.13 1.56 >100
NOR - 0.39 0.78 0.78 0.39 0.025 0.049 0.025 3.13
CPX - 0.19 0.39 0.39 0.19 0.012 0.012 0.012 0.39
Table 9. In vitro antibacterial activity of 36a-d against various bacterial strains.
Table 9. In vitro antibacterial activity of 36a-d against various bacterial strains.
Compound R Antibacterial activity (MIC, μg/mL)
S. aureus MRSA I MRSA II S. epidermis B. Subtilis E. coli K. pneumoniae P. aeruginosa
36a O 0.78 0.78 0.78 0.39 0.39 0.049 0.049 3.13
36b NO 3.13 3.13 3.13 1.56 0.78 0.78 0.39 12.5
36c NOMe 3.13 3.13 3.13 6.25 0.78 6.25 1.56 >100
36d NOBn 50 >100 >100 100 100 100 12.5 >100
ENX - 0.39 0.78 0.78 0.098 0.19 0.098 0.049 1.56
Table 10. In vitro antibacterial activity of 38a-d against a panel of bacteria.
Table 10. In vitro antibacterial activity of 38a-d against a panel of bacteria.
Compound R Antibacterial activity (MIC, μg/mL)
S. aureus MRSA I MRSA II S. epidermis B. Subtilis E. coli K. pneumoniae P. aeruginosa
38a O 0.780 0.780 0.780 0.780 0.390 0.098 0.049 0.780
38b NOH 0.780 0.780 0.780 0.780 0.190 3.130 0.390 >100
38c NOMe 3.130 3.130 3.130 3.130 0.780 1.560 0.780 100
38d NOBn >100 >100 >100 100 100 100 25 >100
ENX - 0.78 0.78 0.78 1.26 0.78 0.098 0.098 1.56
Table 11. In vitro antimicrobial/antibiofilm activity evaluation of 40a-e.
Table 11. In vitro antimicrobial/antibiofilm activity evaluation of 40a-e.
Antimicrobial/antibiofilm activity (μg/mL)
Compound R K. pneumoniae Proteus mirabilis MRSA
MIC MBC MBIC MIC MBC MBIC MIC MBC MBIC
40a Preprints 119943 i010 25 25 6.25 12.5 50.0 25.0 6.4 12.1 4.0
40b Preprints 119943 i011 8.0 16.0 8.0 32.5 65.0 16.0 1.0 2.0 0.5
40c Preprints 119943 i012 25.0 50.0 6.25 25.0 50.0 25.0 1.0 2.0 1.0
40d Preprints 119943 i013 12.5 25.0 6.25 12.5 50.0 25.0 12.5 30.0 2.0
40e Preprints 119943 i014 12.5 25 6.25 25.0 50.0 12.5 1.0 2.5 0.5
MBC: minimum bactericidal concentration; MBIC: minimum biofilm inhibitory concentration; MIC: minimum inhibitory concentration.
Table 12. In vitro antibacterial activity of compounds 46a-e.
Table 12. In vitro antibacterial activity of compounds 46a-e.
Compound R1 R2 R3 Antibacterial activity (MIC (μg/mL)
E. coli S. aureus aB. subtilis
46a H H H 5.6 6.8 12.6
46b F H H 2.6 2.6 1.6
46c H Cl H 2.9 8.7 15.3
46d H H Cl 9.6 24.9 13.2
46e H Br H 12.2 13.1 4.7
CPX - - - 5.65 6.82 2.70
aB. subtilis: tetracycline-resistant Bacillus subtilis.
Table 13. In vitro α-glucosidase inhibitory activity of compounds 48a-g.
Table 13. In vitro α-glucosidase inhibitory activity of compounds 48a-g.
Compound R α-glucosidase inhibitory effect (GIC, μM)
48a - 57.8
48b 4-Me 69.8
48c 4-Cl 74.5
48d 2,4-diCl 63.8
48e 3,4-diCl 52.7
48f 2,6-diCl 74.2
48g 2,6-diF 48.7
DNJ - 425.6
DNJ: 1-deoxynojirimycin (standard inhibitor α- glucosidase); GIC: α-glucosidase inhibitory concentration.
Table 14. In vitro α-glucosidase inhibitory activity of compounds 50a-c.
Table 14. In vitro α-glucosidase inhibitory activity of compounds 50a-c.
Compound R α-glucosidase inhibitory effect (GIC, μM)
50a 2-Br 45.8
50b 2-Cl,4-F 67.8
50c 4-NO2 59.8
ENX - 58.9
DNJ - 425.6
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