Anti-Infective Agents, 2020, 18, 207-223 MINI-REVIEW ARTICLE
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Send Orders for Reprints to [email protected] 207 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