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Anti-Infective Agents, 2020, 18, 207-223 MINI-REVIEW ARTICLE

ISSN: 2211-3525 eISSN: 2211-3533

Synthetic Methods and Antimicrobial Perspective of Pyrazole Derivatives: An Insight

Harish Kumar1, Kushal Kumar Bansal1 and Anju Goyal2,*

1Govt. College of Pharmacy, Rohru, Shimla, Himachal Pradesh, India; 2Chitkara College of Pharmacy, Chitkara University, Punjab, Rajpura 140407, India

Abstract: Background: Due to newly emerging microbial infections and the development of re- sistance against cutting-edge therapeutics, innovative and robust medicinal agents are required. Small ring heterocycles, such as pyrazole and its derivatives have been acknowledged to possess myriad biological properties and the presence of pyrazole in clinics like celecoxib, phenylbutazone (anti-inflammatory), CDPPB (antipsychotic), rimonabant (anti-obesity), antipyrine, difenamizole (analgesic), fipronil (broad-spectrum insecticidal), betazole (H2-receptor agonist) and fezolamide (antidepressant) drugs has proven the pharmacological perspective of pyrazole nucleus. Objectives: The current review paper aimed at a recent update made on novel methodologies adopted in the synthesis of pyrazole derivatives with the emphasis on antibacterial (DNA gyrase inhibition) and antifungal activities. A R T I C L E H I S T O R Y Methods: Pyrazole is one of the major tools to be investigated in drug design and discovery. Many

studies have been reported by researchers that have claimed the significant biological potential of Received: July 18, 2019 Revised: September 05, 2019 these derivatives. However, numerous studies on pyrazoles compounds shown to exhibit potential Accepted: September 21, 2019 antifungal and antibacterial activities, the focus has also been made on DNA gyrase inhibition.

Additionally, some important patents granted to this heterocyclic nucleus related to antimicrobial DOI: potential are also addressed appropriately. 10.2174/2211352517666191022103831 Results: DNA gyrase is a promising biotarget yet to be explored against a number of medicinal agents. The present work provides valuable insight into synthetic methods and antibacterials/antifungal signifi- cance of pyrazoles in general as well as new inhibitors of DNA gyrase in particular. Conclusion: The manuscript constitutes a valuable reference which advocates candidature of pyra- zoles as a potential therapeutic alternative as antibacterial and antifungal agent.

Keywords: Pyrazoles, DNA gyrase, antimicrobial activity, patents, anti-inflammatory, antipsychotic.

1. INTRODUCTION in the synthesis of novel medicinal agents with remarkable biological activities. Pyrazole is one such moiety that has Life threatening infectious diseases pose grave concern to widely been investigated and shown promising scope in the human lives for long time. The antibiotics, antimicrobials development of valuable therapeutics [4]. This heterocyclic and anti-infective cover a variety of pharmaceutical com- pharmacophore has five membered, aromatic rings and has pounds that are regimens for treatment against dreaded infec- structural features with two nitrogen atoms at adjacent posi- tions [1]. The rapid development of antimicrobial resistance tions and three carbon atoms. Ludwig Knorr (1883) has been [2], the continuous evolvement of microbes, and mutations known for his pioneering work on pyrazole (1) scaffold. Af- has aggravated the problem thus, discovery of potent and terward, the chemistry of pyrazoles has been extensively affordable antimicrobial agents represents a resilient chal- investigated by numerous researchers and many papers have lenge [3]. The design and robust scientific exploration of been published in this regard [5]. heterocyclic agents with novel modes of actions might lead the solution to this problem in hand. Nitrogen-containing heterocyclic compounds and their derivatives offer ease N N H (1) *Address correspondence to this author at the Chitkara College of Pharma- cy, Chitkara University, Punjab, Rajpura 140407, India; Tel: 9646499252; In pyrazole, nitrogen atom (N1) resembles pyrrole, while E-mail: [email protected] the second nitrogen (N2) is pyridine-like. The unshared elec-

2211-3533/20 $65.00+.00 2020 Bentham Science Publishers Anti-Infective Agents 208 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

N N N N H N N

R R R R R

N HN N N N N N N N N H Fig. (1). Tautomeric forms of un-substituted and substituted pyrazole. trons of nitrogen (N1) are in conjugation with the aromatic methods. One of the best strategies for synthesizing pyrazole system and the unshared electron of the latter is not negotiat- rings are annulations commenced by the condensation of a ed with resonance. This property or the difference in the ni- monosubstituted hydrazine with a carbonyl for example, trogen atoms of pyrazoles offers many reactions with rea- cyclocondensation of α,β-unsaturated carbonyl or 1, 3- di- gents including acids and bases. Another important aspect is carbonyl compounds with hydrazines. Subsequently, a num- the tautomerism in pyrazole since there are three possible ber of researchers elaborated pharmacologically active pyra- tautomers for un-substituted pyrazoles, while five tautomers zole derivatives synthesized through conventional and non- are possible for mono-substituted pyrazoles (Fig. 1) [6-8]. conventional means [23]. In this section of the article, we tried to compile some important methods on the synthesis of Numerous compounds possessing pyrazole moiety have pyrazole derivatives. diverse applications in the pharmaceutical and agrochemical industries. Pyrazole derivatives have emerged as potential Heller et al. proposed one pot synthesis of pyrazole- therapeutics with a broad spectrum of pharmacological and containing compounds by using simple starting material ke- biological activities comprising anti-histaminic [9], antimi- tones and acid chlorides to give 1,3-diketones. The interme- crobial [10], anti-depressant [11], antiviral [12], antitumor diate thus obtained was reacted with hydrazines to give ex- [13] and fungicides [14]. Owing to the diverse biological cellent yields of pyrazoles [24]. Deng et al. suggested a regi- characteristics, various well-understood synthetic methods oselective reaction between nitro-olefins and N- monosubsti- have widely been observed by the medicinal chemists over tuted hydrazones formed nitropyrazolidine in significant the last few decades. The importance of pyrazole derivatives yields [25]. Jiang et al. reported One-pot synthesis of 4- can be revealed by the fact that several drugs, such as, beta- substituted 1,5-diaryl-1Hpyrazole-3-carboxylic acids by ® ® zole (histamine H2 receptor agonist) [15], fipronil (broad- MeONa/LiCl-catalyzed Claisen condensation. The enolated spectrum insecticide) [16], mepirizole® (nonsteroidal anti- lithium salts of diketo ester were made to react with arylhy- inflammatory drug) [17], lonazolac® (nonsteroidal anti- drazine hydrochloride, trifluoroacetic in ethanol followed by inflammatory drug) [18], sildenafil® (treatment of erectile the hydrolysis to furnish pyrazole derivatives in excellent dysfunction and pulmonary arterial hypertension) [19], ri- quantity [26]. Hu et al. introduced an intramolecular oxida- monabant® (anorectic, antiobesity drug) [20], celecoxib® tive carbon-nitrogen coupling using ruthenium (II)catalyst (nonsteroidal anti-inflammatory drug) [21] and fomipizole® and dioxygen gas in the formation of pyrazole derivatives. (treat methanol and ethylene glycol poisoning) [22] have the Ruthenium (II) is a highly proficient catalyst used for the pyrazole pharmacophore and have met tremendous success development of tri- and tetra-substituted pyrazole deriva- in the market. Microbial enzymes are the alternative ap- tives with the wide acceptance of functional groups [27]. proaches that have been developed over the last few decades. Wu et al. designed a series of 3,5-disubstituted pyrazoles Among these, DNA gyrase is an ATP dependent enzyme, from condensations of various tosyl hydrazine, aldehydes which is the ultimate target of novel pyrazole derivatives and and terminal alkynes in toluene and sodium ethoxide at am- has diverse action on microbes. The inhibition of DNA gy- bient temperature [28]. Zhang et al. executed a one-pot syn- rase results in the disruption of DNA synthesis and, subse- thesis of 3,4,5-trisubstituted 1-H-pyrazole derivatives from quently, cell death, thereby showing the killing effect on aromatic aldehyde, vinyl azide and tosyl hydrazine in the microbes. Hence, keeping in view, the significance of pyra- basic medium (Fig. 2) [29]. zole pharmacophore, the present work has been carried out Sha et al. designed a new method for the synthesis of 3,5- to provide a brief overview of recent developments of pyra- diaryl-4-bromopyrazole derivatives. The reaction was pro- zole containing compounds and their antimicrobial activities ceeded via 1,3-dipolar cycloaddition reaction between to- reported in the recent scientific literature. sylhydrazones and gem-dibromoalkenes in the presence of sodium hydroxide to give 3,5-diaryl-4-bromo-3H-pyrazoles. 2. GENERAL METHODS OF PREPARATION OF PY- The product thus formed undergoes the isomerization of 3,5- RAZOLE diaryl-4-bromo-3H-pyrazoles by using the aldehyde hydra- Pyrazole nucleus is an important chemical entity found in zones to obtain 3,5-diaryl-4-bromo-1H-pyrazoles [30]. Hari- numerous pharmacologically potent drugs. The significance gae et al. proposed a procedure for the synthesis of 3,5- of pyrazole is attributed to its ease of preparation for spec- disubstituted pyrazoles and isoxazole derivatives utilizing tacular activities. Ludwig Knorr 1883, pioneered in the de- the reaction intermediates like, n-Buli, aldehydes. Subse- velopment of pyrazole and their derivatives through various quently, the reaction mixture was followed by the addition of Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 209

O O O Zhang et al. [35] Zhang et al. [34] R2 Yuan Li et al. [33] BocO COOR2 R1 R3 R3 R R NH 1 + 2 HN + + Ar N N Ts R4-NHNH2.HCl OLi nBU R3

R 3 P (20 mol %) R3 R 1 R1 CH + R2 N 2 Cl ] 2 N Ts 2 +

2

, EtOH , 2

R4 -NHNH2 O I * RhCl H R2 R3 Heller et al. [24] [Cp Kong et al. [32] Cl NaOAC, MeCN Pyridine

H NO2 KOt-Bu, 18-crown-6

R3 R4 R1/R2/R3/R4 i) n-Buli MeOH/H2O R1 H + ii) R2-CHO N + R1 N R2 N N H iii) I K CO R-NHNH2 H 2 2 3 Harigae et al. [31] Deng et al. [25] ,HCl 2 NaOH, THF O Ar'-NHNH R2 MeONa/LiCl 2 R1 R3 Br THF, EtOH Ru(II), O CHO Br + CH O OEt + NNNH-Ts

C R R4 R3 5 3

H H N 6 R1 R2 EtO O C R1 H N R2 Sha et al. [30] iii) Jiang et al. [26] i) Toluene, NaOEt R1 R2 O + N3 + Ph-NHNH ,HCl 2 Ts-NHNH2 R1 H Jiantao Hu et al. [27] + Zhang et al. [29] Ts-NHNH2 Lei-Lei Wu et al. [28]

Fig. (2). Important methods for synthesis of pyrazole derivatives. iodine and hydrazines in the reaction [31]. Kong et al. pre- tives. The reactions carried out smoothly under suitable mild pared 1,3,5-trisubstituted pyrazole compounds from N- temperature conditions to produce corresponding annulations alkylated tosyl hydrazones and alkynes in pyridine and t- products in excellent yields [35]. BuOK at 0°C [32]. Li et al established a method for the syn- thesis of a series of highly substituted pyrazole derivatives 2.1. Pyrazole Derivatives Endowed with Antimicrobial by reacting phenylacetohydrazide with dialkyl but-2- Activities ynedioate in rhodium catalysts and AgOAc in MeCN [33]. In another study, Zhang et al prepared di, tri, and tetrasubsti- Presently, many of the clinically available antimicrobial tuted pyrazole compounds by reacting α, β-unsaturated car- drugs are toxic and create a repetition of infection because bonyl compounds such as aldehydes and ketones and hydra- they are inhibiting the growth of bacteria rather than killing zine in the presence of ethanol. The reaction was I2-mediated them. Consequently, they may also lead to the spreading out metal-free that occurs through the oxidative formation of of resistance due to the extended periods of administration C−N bond. Experimentally, the reaction was efficient, regi- [36]. Hence, novel antimicrobial agents with new modes of oselective, one-pot synthesis which formed the product in action are in extreme demand. Heterocyclic scaffold like excellent yields by transition-metal-catalyst aerobic oxida- pyrazole are attractive options to medicinal and synthetic tion [34]. In continuation, Zhang et al. proposed a simple, chemists for the development of new antimicrobial drugs facile and rapid efficient nBu3P-catalyzed de-sulfonylative [37, 38]. This section of the paper comprises pyrazole con- [3+2] cyclo-additions for the production of pyrazole deriva- taining derivatives with potent antimicrobial activity. 210 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

H Cl N N H N N H R3 = N H H3COOC N H3COOC R3

O CH3 N CH CH3 3 CH3 (2) (3)

Cl H Cl N N N N Cl O HN Cl HN N CH3 (4) (5)

O O S N H N N O N N N H H N N N O N N H S (6) (7)

2.1.1. Pyrazole Derivatives Endowed with Anti-DNA Gy- 8 times more potent inhibitory activity against DNA gyrase rase Activity due to less lipophilic characteristics. The 43 kDa fragment of DNA gyrase B of ATP active binding site was found to show DNA gyrase is an ATP-dependent enzyme that has been the interaction with compound (3) [43]. found in bacteria and categorized into topoisomerases I and II. Bacterial DNA gyrase plays a crucial role in DNA tran- In continuation, Tanitame et al. have described DNA gy- scription, replication, chromosome segregation, supercoiling, rase and topoisomerase IV activity of 5-[(E)-2-arylvinyl] catenation, decatenation and unknotting of DNA. DNA gy- pyrazoles through the inhibition of cell wall synthesis. All rase inhibitors have a vast potential in chemo- the synthesized compounds were evaluated antibacterial ac- pharmacotherapeutics and are obtained from natural and tivity against bacterial strains like, E. coli and S. aureus. The synthetic sources. A series of compounds have been de- tested compounds (4) and (5) showed the most active anti- signed that targets DNA gyrase and have also shown inhibi- bacterial activity against quinolone resistant Gram-positive tory action against resistant bacterial strains. Fluoroquin- bacteria with MIC ranges (1-2 µg/mL) equivalent to against olones and Nalidixic acid drugs are commonly effective an- susceptible bacterial strains. Compound (4) and (5) showed tibacterial agents that target DNA gyrase [39-41]. Unfortu- moderate inhibitory action against both the enzymes DNA nately, many of the clinically available DNA gyrase inhibi- gyrase and topoisomerase IV (IC = 13.9-27.8 µg/mL) [44]. tors have proved to be toxic and have created repetition of 50 infection as they are bacteriostatic rather than bactericidal A series of recemic pyrazole derivatives were introduced [42]. Hence, novel and robust antimicrobial agents with nov- by Gomez et al. the in vitro antimicrobial activity was per- el mechanism of action are in extreme demand. Heterocyclic formed against Escherichia coli (Gram-negative) and S. au- scaffold like pyrazole is attractive options to medicinal and reus and S. pneumoniae (Gram-positive) bacterial strains. synthetic chemists for the development of new antimicrobial Out of the tested compounds, compounds (6 & 7) were drugs [37, 38]. This section of the paper comprises pyrazole found to be the most potent against the bacterial strains with containing derivatives with potent DNA gyrase inhibition MIC value of 1 µg/mL, 0.25 µg/mL and 0.5-2 µg/mL, re- and resultant antimicrobial potential. spectively. Furthermore, these compounds were found to target the parC subunit of topoisomerase IV in S. pneumoni- Tanitame et al. reported a novel series of 5-vinylpyrazole ae. Compound (6) possessing tetrahydroindazole core struc- derivatives and evaluated for their antibacterial and DNA tures have emerged as the most potent against DNA gy- gyrase inhibitory activities against Enterococcus faecalis and rase/Topo IV with IC50 values of 0.25 and 0.016 µg/mL. It Staphylococcus aureus. The tested compound (2) showed has been found that the relative orientation of both the right promising antibacterial activity against bacterial strains like and left-hand side of the linker (pyrazole) affects the antibac- Enterococcus faecalis, Staphylococcus aureus and exhibiting Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 211 terial activity of the compounds and does not interact with Bansal et al. analyzed in vitro antibacterial antimicrobial ac- the linker itself and enzyme topoisomerases [45]. tivity of novel series of substituted 3-[(1,3-diphenyl-1H- Sun et al. designed N’-benzoyl-3-(4-bromophenyl)-1H- pyrazol-4-yl)methylene] indolin-2-one derivatives. The synthe- pyrazole-5-carbohydrazide derivatives as potent DNA gyrase sized derivatives were screened against bacterial strains such as, inhibitors. The newly synthesized compounds were screened for B. subtilis, S. aureus, K. pneumonia and E. coli and compared with the standard drug ampicillin. Among the tested com- their antibacterial activity against different bacterial strains like, pounds, compound (9) depicted excellent MIC value against B. E. coli (ATCC 35218), B. subtilis (ATCC 6633), S. aureus subtilis (19.6 μg/mL) and S. aureus (22.5 μg/mL). While com- (ATCC 6538) and P. aeruginosa (ATCC 27853) and inhibitory pounds (10) and (11) showed moderate activity against B. sub- action against B. subtilis (DNA gyrase) and S. aureus (DNA tilis and S. aureus due to the electronic factors. Docking simula- gyrase). Out of the tested compounds, compound (8) displayed tion studies against DNA gyrase showed that lead compound good antibacterial activity against B. subtilis (MIC 3.12 µg/mL) (9) interacted with various amino acid residues of the targeted and S. aureus (MIC 0.78 µg/mL) and excellent DNA gyrase protein through hydrogen bonding, hydrophobic and Vander inhibitory activity against S. aureus (with IC50 value 0.15 Walls interaction [47]. µg/mL) and B. subtilis (with IC50 value 0.25 µg/mL). A docking study revealed that compound (8) interacted with the active site Liu et al developed 4,5-dihydro-1H-pyrazole derivatives of DNA gyrase that showed the tested compound (8) to interact as DNA gyrase inhibitors. Antibacterial activity was carried with ARG 144, GLY 85, and ARG 84. Compound (8) showed out against different bacterial strains such as S. aureus, B. good interactions with GLY 85, amino hydrogen (O-H: 2.44 Å, subtilis, P. aeruginosa and E. coli. The biological data re- vealed that compound (14) showed excellent antibacterial 119.96°), hydrogen atom on pyrazole ring (O-H: 2.12 Å, ° ° activity against all the bacterial strains with (MIC 0.39– 127.68 ) and carbonyl oxygen (N…H-O: 2.24 Å, 120.69 ). 3.125 μg/mL) in comparison to penicillin (MIC 0.39–3.125 Thus, compound (8) holds the significance to be used as a po- μg/mL) and kanamycin B (MIC 1.562 μg/mL), potent inhibi- tential inhibitor of DNA gyrase in the future [46]. tory activity against S. aureus DNA gyrase (IC50 0.125 Br μg/mL) and B. subtilis DNA gyrase (IC50 0.25 μg/mL). While compound (12) exhibited excellent antibacterial inhib- O itory action against S. aureus DNA gyrase (IC50 of 0.125 μg/mL) and B. subtilis DNA gyrase (IC of 0.125 μg/mL as H 50 N compared to novobiocin (IC50 of 0.25-0.5 μg/mL). The ex- N N N cellent activity of the compound (12) was attributed due to H H para-methyl (p-CH3) group on phenyl ring (A) and chloro O (Cl) group on phenyl ring (B). On the other hand, com- H C O pounds (13) and (14) showed antibacterial activity due to the 3 presence of p-methoxy (p-OCH3) and bromo (Br) group, (8) respectively [48].

N N N N N N

N O N O N O H H H

NO Cl 2 (9) (10) (11)

O O CH3 CH3 Cl Cl O N N N CH3 Cl N B B N N B A A O O H CO Br 3 O2N A O2N NO2 O NO2 H3C O2N NO2

CF3 CF3

CF3 (12) (13) (14) 212 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

Ahn et al. described the synthesis of ultra-short pyrazole- pounds 0.25 mg/L, 0.125 mg/L, 0.05 mg/L and 0.125 mg/L, arginine peptidomimetics from N-alkyl/aryl pyrazole amino respectively as compared to ciprofloxacin (MIC 0.25 mg/L) acids. The newly synthesized peptides were assessed for and novobiocin (MIC 0.25 mg/L). Compound (18) specifi- their antimicrobial activity against Escherichia coli, Pseu- cally has more potent inhibitory action against Salmonella domonas aeruginosa, Staphylococcus epidermidis and (MIC 0.05 mg/L) and displayed ten-time higher inhibition Staphylococcus aureus. Out of the test peptidomimetics, action than ciprofloxacin and five-time than novobiocin. analog (15) proved to be a very promising lead compound From the SAR viewpoint, bromine and cyano substitution on having different activities such as, anti-MRSA, anti-VREF, compound (16) enhanced, a nitro group on compound (17) anti-MDRPA, anti-biofilm activities and salt resistance. Fur- decreased antibacterial activity against Salmonella. Further- ther, the mechanism of the lead compound was shown to more, the coumarin-pyrazole nucleus show high inhibitory kills bacterial cells, possibly by disrupting or damaging the action against Topo-II and Topo-IV [50]. cell membrane, leading to the cytosol leakage and eventual Kate et al. designed a novel series of Schiff base 4-{[(Z)-(1,3- cell death without causing cytotoxicity and damage to the diphenyl-1H-pyrazole-4-yl)methylidene]amino}-5-methyl-4 mammalian cells [49]. H-1,2,4-triazole-3-thiols derivatives and evaluated them for NH their antibacterial activity against various bacterial strains 2 like Klebsiella spp., E. coli, Acinetobacter spp., Enterobacter H N 2 NH HN spp. and Proteus spp. Compounds (20) and (21) showed NH NH NH 2 commendable antibacterial activity at 5 μg/mL concentration O against all the tested bacterial species probably due to 4-bromo and 4-fluoro groups substitution on the phenyl ring. Molecular H2N O O H NH docking studies were performed against the active site of N N DNA gyrase B. Active compound (22) and (23) showed bind- ing energy of (-66.52 kcal/ mol and -58.02 kcal/mol ). Com- N H N N O pound (22) showed hydrogen bonding interaction with ASP73 N (2.4 Å ), hydrophobic with ILE94, and Vander Waal’s interac- tions with ASN46, ASP49, GLU50, ALA53, HIS55, GLY77, ILE78, PRO79, ARG136,THR 165. Moreover, active com- pounds (22) and (23) showed the inhibitory action against DNA gyrase B via interaction with different amino acids of the targeted protein through hydrogen bonding, hydrophobic (15) and Vander Wall interactions [51]. Liu et al developed a new series of coumarin-pyrazole Zakeyaha et al. have illustrated in vitro antimicrobial ac- carboxamide compounds and screened them for their in vitro tivity of several pyrazole derivatives. The antimicrobial ac- antibacterial activity against L. monocytogenes, S. aureus, tivity was carried out against four bacterial strains, namely S. Salmonella, and E. coli. The tested compounds (16), (17), aureus, methicillin-resistant S. aureus, B. subtilis and A. (18) and (19) displayed remarkable antibacterial activity baumannii. Among the tested compounds, compounds (24) against bacterial strain Salmonella with MIC value of com- and (25) have emerged as the most potent from the series by

NC NC O O N N O2N Br N N N N H H O O O O

Cl Cl (16) (17) HOOC C H OOC 2 5 O O N N N N N N H H C2H5 N O O C2H5 N O O C2H5 C2H5 Cl Cl (18) (19) Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 213

Br F H3C N N H3C N N N N SH N N SH N N N N

(20) (21) HO N H C N H3C 3 N N O2N N N N N SH SH N N N N

(22) (23) Cl CF3

Cl HN N HN OH N O N O N N OH N

F F F F (24) (25) exhibiting MIC value of 0.73-12.5 µg/mL than the standard idazole and pyrazole pharmacophore in both the series en- drugs ciprofloxacin, colistin and vancomycin (MIC range hanced biological activity [53]. 0.39-12.5 µg/mL). The results of antimicrobial activity con- In another study, Vijesh et al. contributed three different cluded that halogen groups substituted on the phenyl group series of new 1,2,4-triazole and benzoxazole clubbed pyra- of the hydrazone showed excellent activity than that of zole derivatives. The antimicrobial activity was performed strong electron-attracting groups (e.g. NO , CF ) [52]. 2 3 against S. aureus, B. subtilis, E. coli, P. aeruginosa and C. Two novel series of imidazole clubbed pyrazole nucleus albicans while ceftriaxone and fluconazole were used to were developed by Vijesh et al. The newly synthesized com- compare the results. Among the tested compounds, com- pounds were screened for their in vitro antimicrobial effect pound (27) has demonstrated commendable activity. It was against different bacterial and fungal species. Out of the test- anticipated that compound (27) contains 2, 5-dichloro- ed compounds, compound (26) depicted the excellent activi- thiophene group on a pyrazole ring accounted for the in- ty against P. aeruginosa (1 and 0.5 mg/mL) than streptomy- creased activity [54]. cin. The compound (26) has also shown equal potency with Bekhit et al. developed four series of pyrazolyl benzene- the standard drug against C. profingens at same concentra- sulfonamide derivatives in order to screen their antimicrobial tions. On the other hand, compound (26) has also shown and anti-inflammatory activities. To our interest, the antimi- potent antifungal activity against fungal strain T. rubrum crobial activity was evaluated against S. aureus (Gram- than the standard drug fluconazole. The structure activity positive bacteria), E. coli (Gram-negative bacteria) and C. relationship revealed that thio-anisyl moiety along with im- 214 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

H C S H 3 H N S N N O Cl N N N S O N N O Cl HS N N O CH3 N H (26) (27)

Br

O S S N N N N N N

CH3 CH3 CH N 3 N N N N N CH3 N CH3 N S S O O O O (28) (29)

CH3 Cl

CH O N N CH3 O N N 3 N N CH3 S O CH3 S O

CH CH3 N 3 N N N N N CH CH N 3 N 3 S S O O O O (30) (31) albicans (fungi). Among the tested compounds, compounds derivatives was developed by Gadakh et al. and evaluated (28) and (29) demonstrated comparable antibacterial action for antimicrobial evaluation against bacterial and fungal against E. coli as compared to standard drug ampicillin at strains viz. S. aureus, E. coli, P. aeruginosa, B. subtilis and MIC value of 25 µg/mL. The two compounds (30) and (31) C. albicans. Compound namely 1-(3,4-difluorophenyl)-4-(5- exhibited (MIC; 25 µg/mL) antifungal activity half to that of fluoro-2-hydroxybenzoyl)-1H-pyrazole (35) have emerged clotrimazole (MIC; 12.5 µg/mL) [55]. as promising antibacterial agent by inhibiting the growth of bacterial strains in the range of MIC value 62.5-125 µg/mL, Several new 4-acyl-pyrazoles were developed and as- while against C. albicans, the MIC was found at 500 µg/mL sayed for antimicrobial activity against B. subtilis, S. aureus, as compared to standard drugs [57]. E. coli, P. aeruginosa and K. pneumonia by Cetin et al. gen- erally, all the derivatives displayed antibacterial activity Antimicrobial activity of a novel series of pyrazole against the represented strains. Out of the tested derivatives, clubbed s-triazine derivatives was executed by Sharma et al. compounds (32, 33 and 34) depicted excellent activity Compounds were tested against microbial strains, such as, E. against K. pneumonia than amikacin with MIC value of 100 coli, P. aeruginosa, M. luteus, methicillin-resistant S. aureus µg/mL. The results revealed that substituents comprising (MRSA) and fungi C. albicans. Out of the tested com- pounds, N-benzyl-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-(pipe- different groups, such as Cl, F, CH3, and NO2, contributed to antibacterial activity [56]. ridin-1-yl)-1,3,5-triazin-2-amine (36) was found to possess significant antibacterial activity with a zone diameter 11-22 A new series of fluorine holding 4-(substituted-2- mm at a concentration of 10 mg/mL. All the compounds hydroxybenzoyl) pyrazoles and pyrazolyl benzo[d]oxazole exhibited weak antifungal activity. The results from the cur- Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 215

H3C CH3 H3C O O N N O O2N N Cl N N N CH3 H3C N N NO2

H3C N O N O

CH3 (32) (33) (34)

H3C

N N O CH F F N 3 HN N N F N OH N N

(35) (36) O O N Cu - N N N N N O N N N N N O Cl O [M(NO2)(dbdmp)]ClO4 O N N

dbdmp M = Cu(II), Co(II) (37) rent investigations concluded that compound (36), which antifungal activities at a dose of 100 µg/mL. The SAR study contains pyrazole and other heterocycles demonstrated the revealed that electron-releasing groups (OCH3 > CH3 > F > highest antibacterial activity against all bacterial strains [58]. Br > Cl) enhanced antimicrobial activity. The active moiety Solanki et al. produced complexes of Cu(II) and Co(II) like 1-(2,4-dimethoxy-phenyl)-propenone on phenyl ring was another key factor for the increased antimicrobial activi- viz. [Cu(NCCH3)(dbdmp)](ClO4)2, [M(ONO)(dbdmp)]ClO4, ty [60]. [M(pz) (dbdmp)](ClO4)2, pz = 3,5-dimethylpyrazole and dbdmp = N,N-diethyl-N′,N′-bis((3,5-dimethyl-1H-pyrazol-1- Numerous isoxazole, pyrazole, benzoxazepine, benzodi- yl)methyl)-ethane-1,2-diamine and reported their antimicro- azepine and benzothiazepine derivatives were screened for bial activities. The MIC values were calculated against S. aureus, B. subtilis, E. coli and P. aeruginosa. Out of the their antimicrobial and anti-inflammatory activities by tested complexes, complex (37) has emerged as the most Kendre et al. In vitro antimicrobial activity was performed potent antibacterial agent by exhibiting the MIC range at against the pathogens namely B. subtilis, S. aureus, E. coli, 200-400 µM. The results conferred that electron- P. aeruginosa, F. oxysporium, A. flavus and A. niger while, the results thus obtained were compared with standard drugs withdrawing NO2 ligand has a key role in the contribution of antibacterial activity of this complex [59]. ampicillin and norcadine (100 µg/mL with zone diameter 21- 25 mm). Out of the tested compounds, compound (40) A new series of 1-(2,4-dimethoxy-phenyl)-3-(1,3- against bacteria and compound (41) against the fungal strains diphenyl-1H-pyrazol-4-yl)-propenone were contributed by have demonstrated the potent antimicrobial activity with a Bandgar et al in order to assess its anti-inflammatory, antiox- zone of inhibition range 17-22 mm. The results concluded idant, and antimicrobial activities. The in vitro antimicrobial that enhanced antimicrobial activity might be due to 2- activity was performed against the bacterial and fungal substituted pyrazole ring thiazepine ring and aryl sulfonate strains viz. B. megaterium, B. subtilis, K. pneumoniae, S. nucleus [61]. aureus, P. vulgaris, E. coli, T. viridae, A. flavus and A. niger. Among the tested compounds, compound (38) displayed Sangani et al. synthesized a new novel series of pyrazole potent antibacterial and compound (39) displayed potent linked quinoline-pyridine compounds showing antimicrobial 216 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

O2N

O N O S CH S O N 3 O O S CH O2N O 3 N O O

(38) (39)

O2N

O N O S CH S O N 3 O O S CH O2N O 3 N O O

(40) (41) and anticancer activities. Most of the screened derivatives Sowmya et al. screened some pyrazolinylsulfonyl thio- have shown potency against the strains. Out of the tested phene carboxamides and isoxazolinyl sulfonyl thiophene compounds, compound (42) has emerged as the most potent carboxamides derivatives for their antimicrobial activity antibacterial agent against Gram -ve bacteria viz. E. coli by against bacterial strains viz. S. aureus, B. subtilis (Gram- exhibiting MIC value at 1.56 µg/mL, which was in turn positive), P. aeruginosa, K. pneumonia (Gram-negative), much potent than penicillin G (MIC value of 3.13 µg/mL) and fungi A. niger, P. chrysogenum. Out of the tested pyra- than kanamycin B (MIC value of 1.56 µg/mL). From the zole derivatives, derivative (45) and (46) were observed as SAR viewpoint, it has been anticipated that not only bicyclic the most potent against the bacterial strains at different doses heteroaromatic pharmacophore but various substituents have of 50, 75 and 100 µg/well as compared to chloramphenicol also played a significant role in enhanced antimicrobial and (ZOI range 27-42 mm). On the other hand, the pyrazole de- anticancer activity. Thus, the class of pyrazole derivatives rivatives displayed good antifungal activity [64]. holds the significance of novel antimicrobial and anticancer Boschi et al executed antimicrobial activity of new (cy- agents in the future [62]. ano-NNO-azoxy) pyrazole derivatives. Among the tested compounds, compound (47) pyrazolylazoxycyanide scaffold N substituted with thiophen-2-yl group was found as the most NH2 N potent antifungal agent against the species tested specifical- ly, C. parapsilosis and C. tropicalis isolates were shown N CH3 higher MIC values in the range of 0.25-16 µg/mL [65]. Sayed et al described synthesis of few pyrazole and pyra- N zolone compounds and their corrosion inhibition and antimi- crobial activities. To our interest, the in vitro antimicrobial O N Cl assay was performed against the strains namely S. aureus, E.coli, P. aeruginosa, B. subtilus, C. albican and A. flavous using ampicillin and colitrimazole as antibacterial and anti- fungal standards drugs, respectively. Out of the tested com- pounds, compound (48) has been emerged as the most potent CH 3 antimicrobial agent by exhibiting a zone of inhibition diameter (42) in the range of 19.3-25.5 mm than the standard (12-18 mm). The results analysis indicated that these compounds have high In another study, Sangani et al. scrutinized the antimi- potency than conventional bactericidal agents [66]. crobial activity of novel pyrano[4,3-b]pyrane derivatives of 1H-pyrazole. The assay was performed against well known Reddy et al. designed a new multi-component method for microbial strains comprising B. subtilis, E. coli, C. tetani, S. the design of antimicrobial pyranopyrazole derivatives. typhi, S. pneumoniae, V. cholerae, A. fumigatus and C. albi- Among the tested compounds, compound (49) has displayed cans by comparing with ampicillin, nystatin and griseofulvin excellent antimicrobial activity against common kinds of standards. Among the tested compounds, compound (43) pathogens, such as S. aureus, B. subtilis, P. vulgaris, E. coli, against the strain B. subtilis and compound (44) against the A. flavus and A. niger. Compound (49) has shown a maxi- strain C. albicans with MIC’s value of 100 µg/mL have been mum zone diameter of 34 mm against E. coli at a dose of found as the most potent in the series [63]. 100 µg/well, while the standard drug ciprofloxacin has 36 mm zone of inhibition diameter at the same dose [67]. Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 217

NH NH2 2 N N O O CH CH3 3

N N H C O O N H3C O O N 3 O O

Cl CH3

CH CH3 3 (43) (44) Cl

S S

O O N O 2 NH O2N NH O O S S O O

N N N N

(45) (46)

NO2

- S OH H2N + NC N H3C N N NH S N N S N N N H3C N H3C N CH3 H2N N N O NH H 2 (47) (48) (49)

N N N N

S S S OH S NO2

N N O O

Cl Cl (50) (51)

Bhatt et al. screened a novel series of pyrazole clubbed 2- against Escherichia coli (MIC value of 62.5 µg/mL) and thioxothiazolidin-4-one derivatives in order to find out anti- compound (51) against C. albicans (MIC value of 200 microbial effect of these derivatives. The in vitro assay was µg/mL) have demonstrated potent antimicrobial activities as performed by taking P. aeruginosa, E. coli, S. aureus and compared to the standards [36]. S.pyogenes as examples of bacterial strains, C. albicans, A. Rizk et al. developed azo dye of pyrazole and trichloro- niger and A. clavatus as fungal strains, while ampicillin and triazine moieties and assessed for their antimicrobial activity griseofulvin to be used as antibacterial and antifungal drugs against S. aureus, S. marcescens, S. dysenteriae, E. cloacae, respectively. Among the tested compounds, compound (50) E. coli and C. albicans species. Out of the tested compounds, 218 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al. compound (52) has shown the most potent antimicrobial chloramphenicol at an amount of 100 µg/ml. It has been es- activity with diameters of inhibition zones ranging from 11- tablished that the compounds having chloro substituent on 24 mm at 10 mg/mL. On the other hand, the standard drug the aryl ring acknowledged the maximum activity [69]. ampicillin displayed activity up to a maximum zone diameter Some pyrazole containing tri-substituted imidazoles were of 30 mm at the same concentration. The MIC values were screened for antioxidant activity and antibacterial activity by also calculated for these derivatives [68]. Brahmbhatt et al. The in vitro antimicrobial activity was performed against the common kinds of pathogens namely SO3H E. coli, P. aeruginosa, B. subtilis, Staphylococcus while the results obtained were compared with amikacin, ampicillin and chloramphenicol. Most of the screened derivatives found N Cl to exhibit antimicrobial activity against the microbial strains. N N Out of the tested compounds, compound (54) has displayed N excellent antibacterial activity against B. subtilis with MIC N Cl value of 31.0 µg/mL and against S. aureus with MIC value N N N H of 63.0 µg/mL than the standards [70]. Hafez et al. investigated anticancer and antimicrobial ac- tivities of pyrazole containing oxa/ thiadiazolyl and pyrazo- lo[4,3-d]-pyrimidine compounds. Among the tested com- (52) pounds, compound (55) with a 3-chloro pyrazolyl derivative attached with the pyrazole scaffold exhibited the most potent N broad-spectrum antibacterial activity compared with the H2N N standard drug of cefatoxime with low MIC values against Streptococcus lactis and Staphylococcus aureus (MIC values NH 2 of 5, 10 μg/mL) respectively, while against Pseudomonas ae- ruginosa, it was found equipotent with MIC value of 10 Cl Cl O μg/mL as cefotaxime. It was concluded that the basic frame of O the molecules and the heterocyclic ring attached with the py- (53) razole component have the superior activity of the compounds Padmaja et al. designed a new series of various substitut- [71]. ed heterocyclic compounds containing pyrazoles derivatives DamLjanovic et al. investigated some new pyrazole con- and screened for their antimicrobial activity against bacterial taining ferrocene derivatives and their antimicrobial activity. strains like. K. pneumonia, S. aureus, P. vulgaris, B. subtilis, The in vitro antimicrobial activity was carried out against 11 and fungi viz. F. solani, A. niger and C. lunata. The tested bacteria, and three fungal strains at the dose of 250 µg/disc derivative (53) displayed significant activity against the bac- and the results were compared with tetracycline, amikacin, terial strains (inhibitory zone > 24-28 mm) as compared to bifonazole and nystatin drugs. The biological studies re-

Br Cl

N N CH3 NH N 2 N HN Cl N N H3C N CH O 3 (54) (55)

N N N N NH NH

H3C CH3 Fe CH3 Fe

(56) (57) Synthetic Methods and Antimicrobial Perspective Anti-Infective Agents, 2020, Vol. 18, No. 3 219

Table 1. List of some important Patents related to antimicrobial activity of pyrazole.

Sr. No. Publication Date Patent No. Invention Enclosed Reference No.

1 08 Jan 1963 US 3,072,525 Fungicidal composition comprising a salicylate and a pyrazole. [77] 2 30 Mar 1976 US 3,947,467 3-(5-Nitro-2-imidazolyl) pyrazoles [78] 3 10 Jun 1980 US 4207326 Antimicrobial quaternary pyrazole derivatives [79] Quaternary pyrazole derivatives, synthesis and their use as fungicides and bacteri- 4 10 Dec 1980 EP 0020077 A1 [80] cides 5 03 Feb 1981 US 4,248,881 Imidazolylethoxymethyl dervatives of pyrazole [81] 6 21 Nov 1985 EP 0161418A1 Antimicrobial agents containing 2-(1H-pyrazol-1-yl)-4-(3H)-quinazolinones [82] Synergistic antimicrobial compositions containing 1-hydroxymethylpyrazole and a 7 19 Oct 2000 AU 725628 B2 [83] preservative 8 26 July 2001 WO 2001/052846 A1 Gyrase inhibitors and uses thereof [84] 5(3)-Phenyl-4-phenylazo-3(5)-pyrazole carboxylic acid eliciting antibacterial 9 10 Feb 2003 RU2198165 C2 [85] activity 10 06 Jan 2004 US 6,673,923 B2 Pyrazole antimicrobial agents [86] 11 04 Nov 2004 WO 2004/094370 A2 Antibacterial pyrazole carboxylic acid hydrazides [87] Pyrazole carboxamides and agents for control of microorganism and fungus-based 12 20 Nov 2004 RU 2240314 C2 [88] on thereof 13 28 April 2005 EA005680 B1 Gyrase inhibitors and uses thereof for treating bacterial infections [89] 14 05 May 2007 EP 1558203 B1 Hair treatment composition containing a styryl-pyrazole compound [90] Aryl substituted pyrazoles, oxazoles, imidazoles, thiazoles, pyrroles and the use 15 12 May 2010 EP 1173169 B1 [91] thereof 16 31 Jul 2012 US 8,232,391 B2 Bicyclic pyrazole compounds as antibacteral agents [92] 17 19 Aug 2014 US 8,809,333 B2 Imidazole, triazole and pyrazole derivatives useful as antibacterial agents [93] 18 27 Apr 2016 EP 2 864 293 B1 Fungicidal 4-methylanilino-pyrazoles [94] 19 13 Oct 2016 US 2016/0297766A1 Fungicide pyrazole carboxamides derivatives [95] 20 01 Jun 2017 US 2017/0150719 A1 Fungicidal pyrazoles and their mixtures [96] 21 30 Nov 2017 US 2017/0340609 A1 Antimicrobial agents and the method of synthesizing the Pyrazole [97] Preparing method and uses of 3,5-disubstituted methylpyrazolo[1,5-a]pyrimidin- 22 04 Apr 2018 WO 2018/177218 A1 [98] 7-phenolate analogs and derivatives vealed that compounds (56) and (57) were found potent with standard ceftriaxone drug. The synthesized compound compounds from the series, which have shown a decrease of (58) showed excellent activity against S. aureus, P. aeru- microbial growth comparable or elevated than that of tetra- ginosa, B. subtilis and E.coli by exhibiting MIC value of cycline and nystatin (zone diameter 21-32 mm). Further- 1.6125 µg/mL in comparison to standard (MIC values of more, the MIC values were obtained below 100 µg/mL. 3.125 µg/mL and 1.6125 µg/mL) [73]. Hence, such non-selective antimicrobial agent could be used as novel antimicrobial agents to combat the problem of anti- 2.2. Some Important Patents Related to the Antimicrobial biotic-resistant strains [72]. Activity of Pyrazole N N The researchers have observed the spread of drug re- N SH sistance in the recent novel compounds and phenomenon has also been extended to first and second-line antimicrobials, N such as fluoroquinolones and certain cephalosporins [74, 75]. This has been known to be the major problem. Pyrazole and its derivatives have proven their efficacy in the progres- sion of developing new potent antimicrobial agents with the HN N improved mode of action. The utility of such derivatives can (58) also be assessed by the fact that a large number of patents have been granted to this scaffold [76]. This section com- Malladi et al. have developed a series of pyrazole based prises some of the important patents granted to pyrazole nu- Schiff bases and assessed their antibacterial effect against E. cleus endowed with antimicrobial activity and also DNA coli, S. aureus, P. aeruginosa and B. subtilis by comparing gyrase as a target enzyme (Table 1) [77-98]. 220 Anti-Infective Agents, 2020, Vol. 18, No. 3 Kumar et al.

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