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New five-membered ring heterocyclic compounds with antibacterial and antifungal activity

M. Pitucha*,1, A. Pachuta-Stec1 and A.A. Kaczor*2,3 1 Medical University of Lublin, Department of Organic Chemistry, Faculty of Pharmacy with Division of Medical

Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland 2 Medical University of Lublin, Department of Synthesis and Chemical Technology of Pharmaceutical Chemistry, Faculty

of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodzki St., PL-20093 Lublin, Poland

3School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland, [email protected], [email protected]

Projects on design and discovery of anti-infective compounds are at present one of the main research lines in academia and pharmaceutical industry. It is caused by the fact that in addition to a growing number of drug-resistant bacterial infections there is also a significant increase in fungal infections. Among heterocyclic compounds five-membered heterocycles constitute a wide and differentiated group with broad spectrum of biological activity. The presented chapter focuses on the medicinal chemistry of novel five-membered ring heterocyclic compounds with antibacterial and antifungal activity. The literature from the years 2007-2013 is covered. The systems with different kind and number of heteroatoms are described. Among each subgroup structure-activity relationships and pharmacophore models are discussed as well as interactions with the molecular target. The chapter constitutes a valuable reference for researchers dealing with drug discovery projects on antibacterial and antifungal compounds.

Keywords azole; pyrazole; imidazole; oxazole; antibacterial activity; antifungal activity; antibacterial targets

1. Introduction

Bacterial and fungal infections have been for many centuries a major cause of death in humans. In the 19th century the main reasons of morbidity among children and adults were pneumonia, tuberculosis, diarrhea and diphtheria [1]. It was found in late 19th century that many common diseases are caused by microscopic pathogens which led to introduction of antiseptic procedures in order to diminish mortality related to postsurgical infections. Furthermore, sanitation and hygiene also contributed to reduction of the mortality caused by bacterial infections. Finally, the discovery of the first compounds with antimicrobial activity made it possible to conquer multiple infectious diseases, including the first compound with antimicrobial activity elaborated against syphylis in 1911 by Erlich. The discovery of penicyllin and later streptomycin revolutionized treatment of many diseases, including pneumonia and tuberculosis. The next breakthrough was the development of cephalosporins with broad activity against gram-positive and also some gram-negative bacteria [1]. Despite the relevance of infectious disease as main causes of human morbidity and mortality, the development of new antibacterials is not among the highest priorities for pharmaceutical companies. New antibacterial compounds are necessary to replace those that have become less effective as a result of the emergence of a high level of resistance amongst target bacteria. One of most serious problems of contemporary medicine is drug-resistant tuberculosis, occurring not only in developing countries (where it often accompanies AIDS) but also in some well-developed countries [2]. Most drugs present nowadays at the market are diverse heterocyclic compounds, i.e. compounds which possess a ring structure with one or more atoms different than carbon atom inside the ring. Among heterocyclic compounds five-membered heterocycles constitute a wide and differentiated group with broad spectrum of biological activity [3-6]. Compounds from this class are present in nature as constituents of nucleic acids, some important amino acids, alkaloids and hormones. The members of this group such as pyrazole, imidazole, oxazole, triazole, thiadiazole, oxadiazole, thiazole are particularly important antibacterial and antifungal agents [7-10] including Tazobactam, Cefatrizine, Rufinamide, Fluconazole, Itraconazole, Voriconazole, Posaconazole and Ketoconazole. The presented chapter focuses on the medicinal chemistry of novel five-membered ring heterocyclic compounds with antibacterial and antifungal activity. The literature from the years 2007-2013 is covered. The systems with different kind and number of heteroatoms are described. Among each subgroup structure-activity relationships and pharmacophore models are discussed as well as interactions with the molecular target (if known).

Microbial pathogens and strategies for combating them: science, technology and education (A. Méndez-Vilas, Ed.)

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2. Five-membered heterocycles

2.1. Pyrazole derivatives

Pyrazoles, the well-known five-membered heterocycles having two adjacent nitrogen atoms within the ring, have received considerable interests in the fields of medicinal chemistry. These derivatives are the subject of many research studies due to their widespread potential antimicrobial activities. Changes in their structure have offered a high degree of diversity that has been proven useful for the development of new therapeutic agents having improved potency and lesser toxicity. Novel 3,5-disubstituted 1-(1-chlorophenyl)pyrazole derivatives 1 were synthesized by Tanitame et al. (Fig.1) [11]. All compounds were tested in vitro against two Gram-positive bacteria, that is a drug susceptible strain, Staphylococcus aureus FDA 209P and a multidrug resistant strain, S. aureus KMP9 (MRSA), and against two Gram-negative bacteria that is a susceptible strain, Eschericha coli NIHJ JC-2 and a multidrug efflux pump mutant, Escehrichia coli W3110 DacrA. For comparison, the in vitro antibacterial activity of Sparfloxacin and Novobiocin has also been evaluated. The obtained results show that (3-chlorophenyl)-5-(4-phenoxyphenyl)-3-(3-piperidyl) pyrazole hydrochloride and 1-(3-chlorophenyl)-3-[3-(N-methyl)aminopropyl]-5-(4-phenoxyphenyl) pyrazole hydrochloride exhibits comparatively strong antibacterial activity against tested Staphylococcus. aureus and Escherichia coli W3110 DacrA with MIC 2‒4 µg/mL [11].

N N

R2

Cl

R1

1

N NR

NHAr

2

N N

OH3C

R2

R1

3

Fig. 1

Similar research was performed for the series of 5-[(E)-2-arylvinyl]pyrazoles 2 (Fig.1). These compounds were tested in vitro against quinolone-resistant Gram-positive bacteria (Staphylococcus aureus FDA 209P, Staphylococcus aureus KMP9 and E. coli NIHJ JC-2, E. coli W3110 DacrA). Compounds with 5-chloro-1-methyl-1H-indole and 3,4-dichlorophenylphenoxyphenyl substituent (Ar) exhibited the most potent antibacterial activity against susceptible and resistant Gram-positive bacteria with across-the-board MIC values of 1–2 µ/mL [12]. The 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives 3 were synthesized by Lu et al. as a substance with potential antibacterial activity (Fig.1) [13]. All the synthesized compounds were screened for antibacterial activity against three Gram positive bacterial strains and three Gram negative bacterial strains by MTT method [13]. The electivity of tested compounds were MIC (minimal inhibitory concentrations). Studies were performed by modification of the rings of the parent compounds to determine how the substituents of the subunits affected the antibacterial activities. Compounds possessing 4-metoxyphenyl substituent (R1) and 4-fluoro- or 4-chlorophenyl substituent (R2) displayed potent activity with MIC values of 0.39 μg/mL and 0.78 μg/mL against E. coli ATCC 35218, which were superior to the positive control Kanamycin B, whereas compound with R2 4-bromophenyl group exhibited significant activity with MIC values of 1.562 μg/mL against E. coli ATCC 35218, which was comparable to the positive control Kanamycin B [13]. Rahimizadeh et al. synthesized 5-amino-1-(2,4-dinitrophenyl)-1H-4-pyrazolecarbonitryle derivatives and screened them for antibacterial activity against Escherichia coli, Staphylococcus aueus pathogenes (MRSA, MSSA), Pseudomonas aeruginosa and Bacillus subtilis [14]. Compounds which have 4-cyanophenyl and 4-nitrophenyl substituent showed the best inhibitory effects against methicillin resistant S. aureus (MRSA) and methicillin susceptible S. aureus (MSSA) with MIC from 25.1 µg/ml to 29.4 µg/ml. Compound possesing 4-nitrophenyl substituent shows the higher inhibitory activity against methicillin susceptible than Cephalexin, Cloxacillin and Erythromycin [14]. New 3-[3-(substituted phenyl)-1-isonicotionyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives were obtained by Aradage et al. for their antibacterial profile [15]. These compounds were tested in vitro for their activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa using agar-dilution method. The investigation of the structure activity relationship revealed that the compounds with 2,4-dichloro, 4-fluoro and 4-hydroxy substituents at the phenyl ring were the most active [15]. 3-[3-(2,4-Dichlorophenyl)-1-isonicotionyl-1H-pyrazol-5-yl]-2H-chromen-2-one exhibit the most potent antibacterial activity against all evaluated microorganism with MIC from 0.5 µg/mL (S. aureus, B. subtilis, E. coli) to 2 µg/mL (P. aeruginosa). Compound with 4-fluorophenyl substituent show MIC 0.25 µg/mL for S. aureus and E. coli. The most effective was 3-[3-(4-hydroxyphenyl)-1-isonicotionyl-1H-pyrazol-5-yl]-2H-chromen-2-one which inhibits the growth of bacteria with MIC 0.25 µg/mL (for S.


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aureus and B. subtilis) to 1 µg/mL for E. coli and P. aeruginosa. As a reference standard Ampicillin was used (MIC = 0.5 µg/mL) [15]. Mostafa et al. prepared a series of 4-[(3,5-diamino-1H-pyrazol-4-ylidene)methylamino]-N-(substituted)-benzenesulfonamide derivatives and evaluated them for antimicrobial activity. Antimicrobial investigation of synthesized compounds was done by microdilution method against both Gram-positive bacteria: Staphylococcus aureus and Gram-negative bacteria: Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Antifungal activities were determined against Asperigillus fumigates, Asperigillus flavus, Pencillium chrysogenum and Candida albicans by broth microdilution method. Among the synthesized compounds, compound possessing 1,3-thiazol substituent showed the most favorable antimicrobial activity [16]. A series of N-substituted 3-benzyl-5-phenylpyrazole derivatives (Fig.2) were synthesized by Gupta et al. [174]. All the compounds were screened in vitro for their antimicrobial activity against varieties of bacterial strains such as Bacillus subtilis, Bacillus aureus, Escherichia coli and Micrococcus luteus. From the activity data (3-benzyl-5-methyl-1H-pyrazol-1-yl)(4-bromophenyl)methanone and (3-benzyl-5-methyl-1H-pyrazol-1-yl)(2-nitrophenyl) methanone show significant activity against Bacillus subtilis, Bacillus aureus, whereas compounds possesing 4-bromphenyl, 4-chlorophenyl or 3-nitrophenyl substituent showed significant activity against Escherichia coli [17].

N N

H3C

ROC 4

N

S

R

Ar N NH

R1

5

N NCOCH3

R2

R1

6

Fig. 2

Next compounds with pyrazole system were also synthesized by Ronkin et al. [Fig.2]. Novel, substituted 5-(1H-pyrazol-3-yl)thiazole compounds 5 were tested for influence on enzymes of selected bacteria. Antibacterial activity was not observed against wild type strains of E. coli, S. aureus, or S. pneumoniae at MIC concentration of 64 µ/mL. Compounds which possess 3-pirydyl (Ar), carboethoxy (R1) and cyclopropyl or phenyl group (R3) had moderate activity against the hypersensitive S. aureus Smith strain (MIC = 4 g/mL and 1.3 g/mL, respectively). Compound possessing 3-pirydyl substituent (Ar) shows a 5–10 fold improvement in potency over compounds which have thiophen or phenyl group with a Ki of 0.33 µM. It was found that this position of the scaffold preferred lipophilic substituents, such as cyclohexyl (Ki of 0.12 µM) which was more potent than cyclopropyl (Ki of 0.24 µM), and 2.5-fold more potent than methyl (Ki of 0.33 µM) [18]. The derivatives of pyrazolopyrimidinedione 6 synthesized by Basarab et al. are shown in Fig. 2. These compounds were tested against Helicobacter pylori. The most active compounds were obtained by incorporating an imidazole ring at the 7-position of the scaffold. The basicity of the imidazole may contribute to increased aqueous solubility at lower pH allowing for improved oral bioavailability. The lipophilicity of the scaffold series proved important for expression of antibacterial activity. Clearances in vitro and in vivo were monitored to identify compounds with improved plasma stability [19]. New pyrazole derivatives were also obtained by Pitucha et al. [20,21]. N-substituted 3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide/carboxamide were tested for their antimicrobial activity. It was found that N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide inhibited the growth of 10 clinical isolates of S. aureus with MIC values 15.63 µg/ml [20]. This compound appears to be precursor of agents against pathogenic (Staphylococcus species) and opportunistic (Micrococcus luteus) bacteria. The antibacterial activities of the N-substituted 3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carboxamide were tested in vitro against reference Staphylococcus aureus, Staphylococcus epidermidls, Bacillus subtilis, Bacillus cereus, Micrococcus luteus and Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa. Beside this clinical isolates of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA) and MRSA reference strains S. aureus were used. The obtained results showed that the most active N-(1-naphtyl)-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carboxamide was effective against the reference strains of pathogenic S. aureus and opportunistic S. epidermidis with MIC value of 7.81 µg/ml and against the other Gram-positive species with MIC values l5.63–31.25 µg/ml [21]. N-cyclohexyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carboxamide had activity against three tested reference strains of staphylococci with MIC values ranging from 7.81 to 15.63 µg/ml and against the remaining reference strains of Gram-positive bacteria with MIC values from 7.81 to 31.25 µg/ml. According to the obtained data these compounds showed better activity against opportunistic B. cereus species, compared to both ampicillin and cefuroxime. Antistaphylococcal activity of N-(1-naphtyl)-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carboxamide showed that this agent inhibited the growth of 12 clinical isolates of methicillin-sensitive S.


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aureus (MSSA) with MIC values from 0.96 to 25 µg/ml and clinical isolates of methicillin-resistant S. aureus (MRSA) with MIC 1.96 –7.8l µg/ml. The MIC of the antibiotic used for treatment of MRSA infections (Linezolid) ranged from 0.24 to 0.98 µg/ml for the tested MRSA strains.

NH

N

NH2

O X

NHR

X = O or S

Fig. 3

2.2. Imidazole derivatives

Imidazole is a planar five-member heterocyclic ring with two nitrogen atoms in ring at the 1st and 3rd positions. The imidazole ring is a constituent of several important natural products, including purine, histamine, histidine and nucleic acid. The high therapeutic properties of the imidazole related drugs have encouraged the medicinal chemists to synthesize a large number of novel chemotherapeutic agents [22]. Sharma et al. synthesized 2-(substituted phenyl)-1H-imidazole and (substituted phenyl)-[2-(substituted phenyl)-imidazol-1-yl]-menthanone analogues (Fig. 4) and screened for their in vitro antimicrobial activities against two Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis; Gram-negative bacterium: Escherichia coli and fungal strains: Aspergillus niger and Candida albicans by the tube dilution method using Norfloxacin and Fluconazole as control drugs for antibacterial and antifungal activities, respectively. The results of antibacterial study indicated that 3 compounds shown in Fig. 4 exhibited appreciable antibacterial activity and one compound emerged as the most potential antifungal agent. The results of the study indicated that these compounds might be of interest for the identification of new antimicrobial molecules as their antibacterial activity is equivalent to the standard drug Norfloxacin [23].

N

N

O

R1

R2

R3

R4

R5

X1: R

1=Cl, R

2=H, R

3=H, R

4=H, R

5=H, X=NO2

2: R1=COOH, R

2=H, R

3=H, R

4=H, R

5=H, X=NO2

3: R1H, R

2=H, R

3=Cl, R

4=H, R

5=H, X=2-Br

Fig. 4

Khabnadideh et al. synthesized a series of imidazole derivatives and investigated their antibacterial activity against different species of Gram-positive and Gram-negative microorganisms. Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Bacillus subtilis, Escherichia coli, Salmonella typhi, Shigella sonnei, Pseudomonas aeroginosa and Proteus vulgaris [24]. Among tested compounds 2-(1H-1-imidazolyl)-1-cyclohexanol was the most active compound against all microorganisms at the MIC form 3.125 µg/mL to 25 µg/mL. Good activity against Staphylococcus epidermidis, Staphylococcus haemolyticus, Bacillus subtilis, Shigella sonnei, Escherichia coli and Proteus vulgaris show 1-dodecyl-2-methyl-1H-imidazole (MIC=1.06–12.5 µg/mL). 2-(2-Methyl-4-nitro-1H-1-imidazolyl)-1-cyclohexanol was found to be active against Staphylococcus epidermidis, Bacillus subtilis, Salmonella typhi and Proteus vulgariswith MIC 6.25 µg/mL. The obtained results indicated that analogues with alkyl chain at N1

position and a methyl substitution at 2 position of the azole ring, showed the optimum activity with 12 carbon atoms in the alkyl chain. A variety of 1,2,4-trisubastuted imidazole-4-one derivatives (Fig. 5) were synthesized and tested for their antimicrobial effects against Escherichia coli, Bacillus subtilis, Shigellla flexnari, Staphylococcus aureus, Pseudomonas aeurinosa, Salmonella typhi, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, Candida glabrata. Activity was determined by measuring the diameter of zones showing complete inhibition (mm) [25]. The most active antibacterial agent against S. typhi was found to be 5-[(E)-(3-chloro-5-nitrophenyl)methylidene]-3-(2-methoxyphenyl)-2-phenyl-3,5-dihydro-4H-imidazole-4-one.


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N

N

R

O

R2

R1

Fig. 5 Some 1-substituted 3-[4-(1H-imidazol-1-yl)phenyl]prop-2-en-1-one derivatives were tested in vitro against strains of fungi: Asergillus fumigates, Trichoderma viride, Candida lipolytica and Aspergillus niger. Compounds possessing phenyl, chlorophenyl, fluorophenyl, dichlorophenyl and difluorophenyl show strong activity against A. fumigates. Their inhibition zone were from 17 to 20 mm and were compared with standard drug (Nystatin) [26]. Zampieri et al. synthesized bis-imidazole derivatives and screened them for antimicrobial activity [27]. All compounds showed moderate to good activity against Candida albicans and Candida glabrata. The derivative 1-arylo-3-(1H-imidazol-1-yl)-2-[(1H-imidazol-1-yl)methyl]-propan-1-one, in which the biphenylyl moiety is present, exhibited a good inhibitory activity against the clinical strain of C. albicans, with MIC values of 2 and 4 µg/mL after 24 h and 48 h, respectively. The activity was higher than that of the reference drug Miconazole and similar to the activity of Amphotericin B.

2.2. Thiazole derivatives

Thiazole is five-member heterocyclic compound having two heterocyclic atoms nitrogen and sulphur in the position 1 and 3 (Fig. 6). Thiazole derivatives are one of the most important classes of heterocycles in medicinal chemistry due to its wide range of biological activities. These derivatives showed antibacterial, antifungal, anti-HIV, anti-inflammatory, anticonvulsant and antitumor activities [28,29]. Furthermore, there are some important drugs containing thiazole moiety too, e.g. Sulfathiazole - antimicrobial drug, Ritonavir – anti-HIV drug, Abafungin and Ravuconazole – antifungal drugs and antibiotics (penicillin, cephalosporin and micrococcin) [30].

N

S

R2

R1

Fig. 6

New interesting 2,4-disubstituted thiazoles with potential antibacterial and antifungal activity contain 2,3,5-trichlorophenyl group and various aryl ring attached to C2 and C4 position of thiazole nucleus, respectively. Some of these derivatives had 2,3,5-trichlorophenyl group attached to thiazole ring by -C=N-NH- linker [28]. All compounds presented moderate to good antibacterial activity. The most active against all tested bacteria strains (E. coli, S. aureus, P. aeruginosa, B., subtilis) were thiazoles containing 4-(methylthio)phenyl, salicylamide, N-methylpiperazine and 4,6-dimethyl-2-mercaptopyrimidine substituents. Activity of these derivatives was compared to control ciprofloxacin (MIC=6.25 µg/mL). The highest antifungal activity compared to cicloproxolamine against Aspergillus flavus, Aspergillus fumigatus, Trichophyton mentagrophytes, Penicillium marneffei exhibited compounds having 3-pyridyl, biphenyl and 4-mercaptopyrazolopyrimidine substituents. Other compounds with potential antifungal and antibacterial activity having thiazole nucleus are 2-bromo-5-methoxy-N’-[4-(aryl)-1,3-thiazol-2-yl]benzohydrazide derivatives [29]. The most active derivative have 3,4-dihydroxyphenyl group attached to 4-position of 1,3-thiazole ring against K. pneumoniae and P. aeruginosa and showed similar activities to the control drug furacin (MIC=12.5 and 6.5 µg/mL respectively). Compounds containing salicylamide and 2-chloropyridinyl group displayed antifungal superior activity against Penicillium marneffe, Aspergillus fumigatus and Trichophyton mentagrophytes as that of Itraconazole. Antifungal activity was also determined for 2-thiazoylhydrazone derivatives with cycloalkyl ring attached to hydrazone group. On the other hand thiazole ring in 4-position is connected with aryl ring having various substituent in different positions [31]. Most of cyclopentyl and 2-methylcyclopentyl derivatives with 4-methyl, 4-methoxy and 4-chloro substituent at phenyl ring had good activity against Candida albicans and Candida glabrata. Three cyclopentyl derivatives having 3-nitro, 4-nitro and 4-cyano group at phenyl ring showed superior activity against one C. glabrata strain compared to control Clotrimazole. The most interesting is 3-methylcyclohexyl derivative with 4-methylphenyl group attached to thiazole ring. Such compound displayed superior activity than Clotrimazole against C. albicans, C. tropicalis, C. krusei, C. parapsilosis and C. sake. Other methyl-cyclohexyl derivatives were active too. Other Schiff bases with 2,4-disubstituted thiazole moiety had 4-methoxy or 4-bromophenyl ring attached to C4 position of thiazole. Some compounds having aryl ring with various substituent in different positions attached to double bond of azomethine group and other derivatives having cyclohexyl or cyclopentyl moiety connected with hydrazone


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group [30] displayed good to excellent antifungal activity against C. albicans, Cryptococcus neoformans, Aspergillus flavus and Chrysosporium tropicum. Only one compound 2-(2-(4-(4-bromophenyl)thiazol-2-yl)hydrazono-1,2-diphenylethanol showed moderate antibacterial activity against S. aureus and Vibrio cholerae. Interestingly, these compound posses antifungal activity too. New antibacterial and antifungal compounds containing thiazole moiety substituted triazole or benzotriazole derivatives [32,33]. All compounds 2-(4-(4-substitutedphenyl)thiazol-2-yl)-1-(1-(4-sudstitutedphenyl)-2-(1H-1,2,4-triazol-1-yl)etylidene)hydrazine and 1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-(4-substitutedphenyl)ethylidene)-2-(4-(substituted-phenyl)thiazol-2-yl)hydrazine showed good to moderate activity against Gram-positive and Gram-negative pathogens. MICs values were 16–64 µg/mL and 32-256 µg/mL, respectively. The most active compounds against fungi species (A. niger and C. albicans) possessed electron-withdrawing F, Cl and CF3 at the phenyl ring. Activity of these derivatives was similar to Nystatin (MIC=16 µg/mL). Other coumarin-thiazole derivatives containing cycloaliphatic ring linked to thiazole moiety by hydrazone group presented antifungal (Candida) and antibacterial (clinical strains of Helycobacter pylori) activity [34]. Clotrimazole and Metronidazole were used as antifungal and antibacterial control drug, respectively. The most active against isolates C. albicans and C. parapsilopis were derivatives with cyclohexyl and cycloheptyl groups, respectively. The same compounds were active against Metronidazole resistant strains of H. pylori. Derivatives of 2,4,5-trisubstituted thiazole displayed antibacterial activity against Gram-positive clinical S. pneumoniae with MIC values superior than control Ampicillin (MIC=0.168 µM) only. These thiazole ring possessed both carboxylic or ethyl ester groups and benzamide, 4-chlorobenzamide, 4-methoxybenzamide, butyroamide and acryloamide group at 5- and 2-position, respectively. Peng-Cheng et al. [35] obtained three series of Schiff bases 7 containing thiazole moiety and evaluated them for their antibacterial activity against three Gram positive bacterial strains (B. subtili, S. aureus and S. faecalis and three Gram negative bacterial strains (E. coli, P. aeruginosa and E. cloacae) activities by MTT method (Fig. 7). Some antibacterial 4′-methyl-N2-phenyl-[4,5′-bithiazole]-2,2′-diamines 8 were obtained by Brvar et al. (Fig. 7) [36].

N

R3R2

R4

R1

NH

S

N

R6

R5

S

NNH

S

N

R1

NH

R2

R3

7 8

Fig. 7

2.3. Oxazolidone derivatives

Oxazolidinones are a new class of antibacterial agents with activity against a large number of Gram-positive organisms. Drug Linezolid is the first and only member of the oxazolidinone series. Eperezolid and AZD2563 are still potential drug candidates and they have been used as the structural precursors for modification [37].

NO NO

NH CH3

O

F O

a)

NN NO

NH CH3

O

F O

OH

O

b)

Fig. 8 a) structure of Linezolid , b) structure of Eperezolid

In Eperezolid, Linezolid’s morpholine moiety was replaced by piperazine ring with COCH2OH substituent attached to N-4 piperazine position [38]. The first modification of Eperezolid include derivatives having substituted urea group on the piperazine ring at the 4-position [30]. The compound with unsubstituted urea group (NH2) and compound with substituted benzyl urea group (4-CH3OC6H5CH2NH) showed MIC values in the range of 4–2 µg/mL against Staphylococcus aureus, Staphylococcus aureus (methicillin resistant), Staphylococcus aureus (clinical isolate), Enterococcus faecalis (Vancomycin sensitive), Enterococcus faecalis (Vancomycin resistant) and Enterococcus faecium (Vancomycin resistant). These compounds exhibited antibacterial activity equivalent to Linezolid. Compounds having aryl substituted urea group which contain such substituents as fluorine, methoxy and chlorine in aryl ring (3-FC6H4NH, 2-CH3OC6H4NH, 2,4-ClC6H3NH) exhibited antibacterial activity against S. aureus, S. aureus (methicillin


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resistant), S. aureus (clinical isolate), E. faecium (Vancomycin sensitive), E. faecalis (Vancomycin resistant) and E faecium (Vancomycin resistant). The MIC values ranging 1–4 µg/mL Activity of this derivatives is the same as that of Linezolid. The heterocycle substituted urea compound (2-tiazole-NH, 2-pirydyl-NH) exhibited better activity against E. faecalis and E. faecium compared to Linezolid. The MIC values for these compounds were 1 µg/mL but for Linezolid was 2 µg/mL. Next analogues with modification group have different heteroaryls substituted alkenones, alkenes and N-oxide attached to the 4-position of piperazinylaryloxazolidinones [38]. Derivatives with the thiophene and furan moiety (2-tiophen-CH=CH, 3-tiophen-CH=CH, 2-furan-CH=CH, 3-furan-CH=CH) exhibited activity the same as that of Linezolid against references species: Bacillus pumilus, Bacillus cereus, Streptococcus pyogenes, Staphylococcus epidermidis, E. faecalis, S. aureus. The MIC values were 0.5–2 µg/mL. Compound containing pyrrole group (2-pyrrole-CH=CH) showed MIC values ranging 1–2 µg/mL against the same Gram-positive strains. The 3-indolyl derivatives (3-indolyl-CH=CH) revealed slightly better activity against B. cereus and S. pyogenes (MIC=0.12-0.5 µg/mL). Activity of the compounds with different substituents on the furan ring e.g. 5-methyl derivative of furan (5-CH3-furan-CH=CH) exhibited activity compared to Linezolid but 5-formyl (5-OHC-furan-CH=CH), 5-hydroxymethyl (5-OHCH2-furan-CH=CH), and acetoxymethyl (5-AcCH2- furan-CH=CH) derivatives of furan showed lower activity than Linezolid. In the case of derivatives with an electron withdrawing nitro group introduced in position 5 in furan and in tiophene ring activity was far superior than that of Linezolid. Compound with nitro group in furan is the most active. Such derivatives are 4–16 times more active than Linezolid. MIC values were ≤0.12 µg/mL against B. pumilus, B. cereus, S. pyogenes, S. epidermidis. Last two compounds which containing nitro group in furan and in tiophene ring exhibited antibacterial activity against panel of Gram-positive susceptible strains such as E. faecalis and S. aureus and against methicillin resistant S. aureus, Vancomycin resistant E. faecalis, penicillin resistant Streptococcus pneumoniae and Linezolid resistant S. aureus. Derivatives showed MIC values in the range of 0.125–1 µg/mL and their activity was superior to Linezolid. Bioavailability of compound with 5-nitrofuran attached to the C=O group was improved and compound was converted into N-oxide derivative of piperazine ring at the 1-position. These derivative was 2-4 times more active than Linezolid against S. pyogenes, S. epidermidis, and multi-resistant S. pneumoniae. MIC values were in the range of 0.12–0.25 µg/mL. Compound in which group C=O linked to piperazine ring was replace by -CH2- group with attached furan and 5-nitro furan showed similar activity to that of Linezolid. MIC values were 0.12–2 µg/mL against panel of Gram-positive strains. The next antibacterial oxazolidiniones are hybrid analogues of Eperezolid and isoxazoline [39]. The isoxazoline component is linked at 3-position with various substituents in aryl ring and is attached to the 4-position of piperazinylaryloxazolidinones. Compounds having unsubstituted phenyl ring, 2- and 3-tiophenyl ring at 3-position of isoxazoline showed lower activity against all tested bacterial strains than Linezolid. Substitution of electronegative substituent (chloro group) at 4 position and at 3,4 position of phenyl ring increased antibacterial acivity against Gram-positive strins such as S. aureus (floxacin and Methicilin resistant), S. aureus (Methicilin resistant), B. cereus, E. faecalis, S. pyogenes and against Gram-negative bacteria Klebsiella pneumoniae. Compounds exhibited MIC values in the range of 0.1559–0.3499 µM. In the case of S. aureus (Methicilin and Vancomycin resistant) hybrid showed higher MIC values 2.879 µM and 2.7036 µM respectively. Replacement of the chloro substituent with the fluoro one at 4 and at 3,4-position of phenyl ring create compound less potent that these with chloro substituent. MIC values were 0.3486–0.7400 µM against all panel of bacteria. Such derivatives were more potent than Linezolid. Among two hybrids having 3- and 4-trifluoromethylphenyl group attached to 3-position of isoxazoline ring, derivatives with 4-trifluoromethylphenyl substituent are more active against all resistant strains. The MIC values for these compound were 0.3292–0.6759 µM. Both derivatives were more active than standard drug. The most active compound against E. faecalis MTCC 439 showed MIC of 0.0866 µM. Another active hybrid contain 3-nitrophenyl group. Among heterocyclic analogues 2-furanyl and 2-pyridyl substituents the most potent was compound with pyridyl group showing MIC of 0.3725-1.5294 µM. The most active compounds against resistant S. aureus strains were hybrids with p-chlorophenyl and 3,4-methylene dioxyphenyl showing MIC 0.1657 and 0.1627 µM, respectively. All hybrid analogues of Eperezolid and isoxazoline expect for compounds having lower activity against all tested bacterial strains than Linezolid were more active than Vancomycin against Methicilin resistant S. aureus. The final compounds were also active against Gram-negative K. pneumoniae with MIC of 0.1627–2.7036 µg/mL. In the family of oxazolidinones are compounds in which the piperazine ring of Eperezolid is connected to different linkers or directly bond with five member heterocycles ring (furan and tiophen) [40]. As the linkers used -CH2-, -CO-, -CH2=CH2CO-, and –CH(CH3)- groups are used. Among the thienyl analogues the most active compounds have direct bond and C=O group between the piperazine ring and 5-nitro-thiophene. These derivatives showed MIC values in the range of 0.125-0.25 µg/mL and of 0.06-0.5 µg/mL respectively against S. aureus, Methicilin resistant S. aureus, Methicilin resistant S. aureus, Vancomycin resistant E. faecium, E. faecalis, S. pyogenes, S. pneumoniae. Derivatives with -CH2=CH2CO- and –CH(CH3)- groups as linkers have similar activity (MIC 0.5–2 µg/mL). Compound with direct bond in which the other side of piperazine ring is attached to 2,6-difluorophenyl have similar activity too (MIC 0.25–0.5 µg/mL). Among the furan series compounds most of them have the same activity MIC 0.06-2 µg/mL as the thienyl analogues. The most active is compound which has –CH2=CH2CO- linker between the piperazine ring and 5-nitro-furan. All derivatives are more active than Linezolid.


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The other compounds of these series are oxazolidinones having cyclic sulfonamide system instead of piperazine [41]. Derivatives having thiadiazolidine, thiadiazinane and [1,2,5]-oxathiazolidine moiety are the most active against Gram-positive, Methicilin and Vancomycin resistant strains. Such compounds showed superior or similar activities to the control drug Linezolid. Next modification of Eperezolid is replacement piperazinyl group by methylamino piperidinyl moiety [42]. These compounds did not display significant antibacterial activity MIC 4–16 µg/mL. Among these series only compound having methylamino piperidinyl system linked with alkenones attached to 5-nitrofuryl moiety exhibited antibacterial activity against B. subtilis, multi-resistant S. pneumoniae, S. epidermidis strains. MIC values were comparable to Linezolid. Different interesting analogues of these group are spiro[2,4]heptane substituted oxazolidinones [43]. Such derivatives did not exhibit significant antibacterial activity against both Gram-positive and Gram-negative strains. Only one compound having fluoro substituted spiro[2,4]heptane system reveled antibacterial activity superior or similar as that of lizenoild against Methicilin and Vancomycin resistant strains. The MIC values were 0.78-1.56 µg/mL. Structure of Eperezolid has been changed on the C-5 position e.g. acylamino group of the oxazolidinones. Acylamino substituent was replaced by different O-linked carbamates and tiocarbamates, O-linked heterocycles, and S-linked alkyl and aryl derivatives [44]. On the other side, the piperazine ring at the 4-position has been connected to 5-nitro-thiopfene moiety. In these series only two compounds are more potent than the standard Linezolid. The first compound has hydroxyl group instead of acylamino moiety but the second is its acetate derivatives. The MIC for such derivatives values of 0.5–1 µg/mL against S. aureus, Methicilin resistant S. aureus, Methicilin resistant S. aureus, E. faecalis, Vancomycin resistant E. faecium, S. pyogenes, S. pneumoniae. Interestingly, these compounds exhibited antibacterial activity against Gram-negative bacteria Haemophilus influenzae and Moraxella catarrhalis, too. Other modified compounds have 5-nitro-furan attached to the piperazine ring at the 4-position but acetamido methyl group is replaced by haloalkyl, formamide, carbamate, thioamide, thiocyanide, thioester, thioketone, thiourea, mathoxymethylacetamide and cinnamoyl substitutes [45]. Among these compounds only thioamide, thiourea and difluoromethyl derivatives exhibited comparable or superior activity to Linezolid against panel of Gram-positive bacteria. Such derivatives showed the best activity against S. pyogenes, S. pneumoniae, too. Next, novel class of oxazolidinones are derivatives in which N-4 position of piperazine is connected to substituted arylcarbonyl-, heteroarylcarbonyl- and arylsulfonyl-, heteroarylsulfonyl- moiety with various substituents in different positions at aryl ring [46]. On the other hand 5-acetamidomethyl group was replaced by N-linked triazolylmethyl substituent. All compounds are active against a panel of standard and clinical isolates of Gram-positive and Gram-negative bacterial strains and showed superior or similar activities to the control drug. Similar compounds have N-linked 5-triazolylmethyl group too, but the piperazine ring at the 4-position is connected to methylheteroaryl- and methylaryl- moiety with various substituent in different positions [47]. Most of these derivatives displayed antibacterial activity against resistant and Gram-positive organisms (MIC range 0.008–4 µg/mL) and showed superior activities than Linezolid and Vancomycin. Especially compound with 5-nitro-furan group attached to the piperazine ring is promising as a drug candidate. The MIC for such derivative values of 0.06–0.5 µg/mL against S. aureus, Methicilin susceptible and resistant S. aureus, S. pneumoniae and E. faecalis. The other compounds of these series are 5-(4-methyl-1,2,3-triazole) oxazolidinones with various alkylcarbonyl and arylcarbonyl substituent at the piperazine N-4 position [48]. In these series only one compound with isopropylcarbonyl substituent appended to piperazine ring at the 4-position is active against all Gram-positive organisms tested. MIC value range of 0.5–1 µg/mL. The other compounds displayed good to moderate antibacterial activity against Gram-positive strains and were inactive against Gram-negative clinical isolates. Next modified compounds have larger homomorpholine structure instead of six-member Linezolid’s morpholine ring but acetamide group of the oxazolidinones was replaced by ethyl amides, methyl carbamate and triazole moiety [49]. Similar derivatives have carboxyamide group attached direct to oxazolidinones system. Phenyl ring of these analogs contain mono-, di- and tri-fluoro substituents. Most of these derivatives did not display significant antibacterial activity. Only compounds with mono- and difluorophenyl ring showed comparable activity to Linezolid against a panel of Gram-positive bacteria. MIC values of 1–4 µg/mL. Different interesting analogues of Linezolid were oxazolidinone attached to benzenocykloheptane fused pyrazole ring containing a fluorine or without fluorine atom at phenyl ring [50]. In addition, the pyrazole structure on the 3-position had alkyl, aryl and heteroaryl substituents. Derivatives with unsubstituted pyrazole showed superior activity to Linezolid against Gram-positive pathogens S. aureus and S. pneumoniae and against Gram-negative bacteria H. influenzae and M. catarrhalis too. Interestingly, compound with isoxazol-5-yl substituent attached to pyrazole ring is promising as a drug candidate. Such derivative exhibited 8-, 16- and 33-fold increase in activity against S. aureus, S. pneumoniae and S. pyogenes, respectively. In addition, these compound showed superior activity than Linezolid, against H. influenzae and M. catarrhalis too (MIC values of 1–2 µg/mL). Similar analogues of Linezolid have oxazolidinone attached to benzenocykloheptane fused pyrazole ring with amino and amino-substituted group in the 3-position of the pyrazole [51]. The most active were compounds with amino, small alkyloamino, and phenylamino substituents at the pyrazole ring against S. pneumoniae. These compounds showed activity against Gram-negative bacteria H. influenzae and M. catarrhalis too.


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3. Molecular targets

The presented compounds exhibit their activity through a few molecular targets, including protein targets (DNA gyrase, fatty acid synthase, FAS and glutamate racemase) and nucleic acid target (RNA). Most compounds for which molecular targets are known, inhibit bacterial DNA gyrase (1, 2, 5, 8). It is a well-known antibacterial target for the fluoroquinoloness [52]. This enzyme catalyses the breakage of a DNA duplex (the G segment), the passage of another segment (the T segment) through the break, and then the reunification of the break [53]. This involves the opening and dosing of a series of molecular 'gates' which is coupled to ATP hydrolysis [53].

Fig. 9 Crystal structure of the breakage-reunion domain of DNA gyrase (PDB ID: 1AB4) [53]

It is well known that the pyrazole derivatives are potent and selective inhibitor against DNA gyrase capable of causing bacterial cell death. It may be noticed that all selective inhibitors of DNA gyrase contain the characteristic arylpyrazole template. Some of 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime strongly exhibit Staphylococcus aureus DNA gyrase and Escherichia coli DNA gyrase [54]. 2-Phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC, MurD enzymes in vitro [55]. Compounds 3 and 8 are fatty acid synthase inhibitors. Fatty acid biosynthesis is an essential metabolic process for prokaryotic organisms. β-Ketoacyl-acyl carrier protein(ACP) synthase III, also known as FabH or KAS III, plays an essential and regulatory role in bacterial FAB [13]. Beta-ketoacyl-acyl carrier protein synthase III (FabH), the most divergent member of the family of condensing enzymes, is a key catalyst in bacterial fatty acid biosynthesis and a promising target for novel antibiotics [56]. These structures display a fold that is common for condensing enzymes (Fig. 10).

Fig. 10 Crystal structure of beta-ketoacyl-ACP synthase III (PDB ID: 1H9N) [56].


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A series of pyrazolopyrimidinediones 6 that inhibits the growth of Helicobacter pylori by targeting glutamate racemase, an enzyme that provides D-glutamate for the construction of N-acetylglucosamine-N-acetylmuramic acid peptidoglycan subunits assimilated into the bacterial cell wall [19]. Ketoconazole is a potent inhibitor of CYP3A4 hepatic metabolism. Ketoconazole is a strong inhibitor of CYP3A4, a moderate inhibitor of CYP1A2, 2A6, and 2E1, and a substrate and inhibitor of p-glycoprotein [57,58]. The oxazolidinone antibacterials target the 50S subunit of prokaryotic ribosomes [59]. In conclusions, the increasing development of bacterial resistance to traditional antibiotics has created an important need to elaborate new antimicrobial agents. The developed drugs should possess novel modes of action and/or different cellular targets. As a result, new classes of compounds, including the presented five-membered ring heterocycles designed to avoid defined resistance mechanisms are undergoing pre-clinical and clinical studies.

Acknowledgements The paper was developed using the equipment purchased within the project “The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases” within the Operational Program Development of Eastern Poland 2007-2013, Priority Axis Imodern Economy, operations I.3 Innovation promotion. The research was partially performed during the postdoctoral fellowship of Agnieszka A. Kaczor at University of Eastern Finland, Kuopio, Finland under Marie Curie fellowship.

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