Synthesis, Antibacterial and Anti-Tumor Activity of Pyrazole Derivatives
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MedDocs eBooks Synthesis, Antibacterial and Anti-Tumor Activity of Pyrazole Derivatives Maria Marinescu; Christina-Marie Zalaru* Department of Organic Chemistry, Biochemistry and Catalysis, University of Bucharest, Bucharest, 90-92 Panduri Road, Romania. Corresponding Author: Christina-Marie Zalaru Abstract Department of Organic Chemistry, Biochemistry and The pyrazolic nucleus has a multitude of activities such Catalysis, University of Bucharest, Bucharest, 90-92 as analgesic, antiarrhythmic, local anesthetic, antimicrobial, Panduri Road, Romania. anticonvulsivant, anti-tumor, antidiabetic, antipyretic, anti- viral, antimalarial, and so forth. The literature is extremely Email: [email protected] abundant in the study of pyrazoles, their synthesis and me- dicinal applications. Published Online: Apr 16, 2021 Synthesis strategies on the pyrazolic nucleus have ex- panded in recent times, so that hybrid pyrazolic nuclei with eBook: Recent Trends in Biochemistry other heterocyclic nuclei have been obtained. Publisher: MedDocs Publishers LLC We propose in this chapter to present strategies of syn- Online edition: http://meddocsonline.org/ thesis of the pyrazolic nucleus, with antibacterial and anti- Copyright: © Zalaru CM (2021). tumor properties. The relationship structure-activity is de- This chapter is distributed under the terms of scribed. Creative Commons Attribution 4.0 International License Keywords: Pyrazole; Anti-tumor; Antimicrobial; Synthesis; Structure-activity relationship. F3C Cl O CH H3C N 3 O N OH N N CH3 N N H N N N CN Introduction N N S O O H3C CH3 The pyrazolic nucleus possesses a variety of activities such NH2 as antipyretic, antimicrobial, analgesic, anti-inflammatory, anti- Celecoxib Lonazolac CDPPB Mepirizole Anti-inflammatory Anti-inflammatory Anti-psychotic Anti-inflammatory tumor, antiviral, antidiabetic, anti-hypertensive, anesthetic lo- CH cal, antimicrobial, reno-protective, antioxidant and Monoamine N 3 NH CH H3C O 3 N oxidase B (MAO-B) inhibitory activities [1-20]. The pyrazolic O CH3 CH3 HN N N H3C N nucleus is found in a suite of drugs, as shown in N N N N HN N Cl NH2 Rimonabant Difenamizole Betazole Fezolamine Anti-obesity Analgesic H2-receptor antagonist Antidepressant Figure 1: Marketed pyrazole-containing drugs. Citation: Marinescu M, Zalaru CM (2021). Synthesis, Antibacterial and Anti-Tumor Activity of Pyrazole Derivatives. Recent Trends in Biochemistry, MedDocs Publishers. Vol. 2, Chapter 3, pp. 18-27. Recent Trends in Biochemistry 18 MedDocs eBooks 1. Characteristic properties as pyrazoles The pyrazolic nucleus forms cyclic dimers and trimers through intermolecular hydrogen associations (Figure 6). Pyrazole belongs to the fundamental heterocyclic system with aromatic character, from the azole class consisting of three carbon atoms and two nitrogen atoms of a pyrrolic type and N.. ..N pyridinic type, in positions 1 and respective 2 (Figure 2) [21,22]. N N Thus pyrazole itself boils at 187-188°C and melts at 70°C. It H forms intermolecular hydrogen bonds. Pyrazole and the lower H N H H homologes dissolve readily in the majority of organic solvents N.. and in water. Pyrazole has character amphoter though more .. N H notably basic than acidic [21]. Thus it forms easily hydrolyzed N .. salts with strong acids, whereas it can give sodium and potas- N N sium salts. These too are easily hydrolyzed by water (Figure 3) [21,22]. Figure 6: The association of pyrazoles. I. Pyrazoles as antibacterials N The resistance of microbial strains to classic drugs synthe- N sized in recent years is one of the central medical problems. Therefore, one of the research directions of chemists is the H synthesis of new compounds with antimicrobial properties. Pyrazole compounds are important components in antibacte- Figure 2: The chemical structure of pyrazole. rial drug discovery [23]. Akbas et al. reported the synthesis of a new 1H-pyrazole-3-carboxylic derivatives (Figure 7). All pyr- azoles were evaluated for the antibacterial activities againstBa - + _ cillus cereus, Staphylococcus aureus, Escherichia coli and Pseu- H3O B domonas putida. Compound 1 exhibited the best antibacterial activity against both Gram-positive and Gram-negative bacteria N N +N N N N_ (Figure 7) [24]. H H H OEt OEt O Ph Ph Ph O NH O Figure 3: Ion structure of the pyrazolic nucleus. O O NH Ph N O N O N N N Br NO2 Pyrazole exists in two identical and inseparable tautomere N Ph O2N O2N forms due to rapid interconversion (Figure 4) [21,22]. CH3 3 1 2 NO2 O2N O2N NO2 O N O O N O NH R2 NH HN N N HN N N N N N N N N Ph N Ph N H 1 2 R1 R , R = Cl, F NO2 Figure 4: Tautomers of unsubstituted pyrazole. NO2 4 5 6 It is more correct to explain the tautomerism of pyrazoles Figure 7: Pyrazoles with antimicrobial activity. by saying that at protonation forms the same cation, and with the bases form the same anion, from either uncharged form of A series of pyrazole-3-carboxylic acid and pyrazole-3,4-dicar- pyrazoles (Figure 5) [22]. boxylic acid derivatives were synthesized and assessed for their R antimicrobial activities against five bacterial and five fungal pathogens. The molecules 2, 3, 4 and 5 showed good inhibitory effects on Candida tropicalis, Candida parapsilosis and Candida + glabrata strains [25]. A series of bifonazole heteroanalogues, N _ + + H H 4-[1H-imidazol-1-yl(phenyl)]-1,5-diphenyl-1H-pyrazole 6, was R H N R synthesized and evaluated for their in vitro antimicrobial activi- + + _ H H H ties against selected pathogens. Some dichloro- and trichloro- pyrazole derivatives showed outstanding antimicrobial effects N N H N R [26]. A series of 3-substituted-5-(benzofuran-2-yl)-pyrazoles + N _ + H posses remarkable antibacterial activities against Bacillus sub- H H tilis H + . 5(Benzofuran-2-yl)-1 -pyrazole-3-carbohydrazide 7 has _ _ H + N even larger inhibition zones than Amoxicillin (Figure 8) [27]. H H N The synthesis 5-amido-1-(2,4-dinitrophenyl)-1 -4-pyrazole car- bonitriles 8 was reported by Rahimizadeh et al. Their in vitro Figure 5: Tautomers of unsubstituted pyrazole. antimicrobial activity were showed against methicillin resistant and methicillin susceptibleStaphylococcus aureus. All pyrazoles Recent Trends in Biochemistry 19 MedDocs eBooks showed good activities, with MIC values of 25.1 and 91.0 μM, Cl HN N S N respectively, against both methicillin susceptible and methicillin O NH N O 2 HN S NH resistant S. aureus [28]. N O Cl N N O N N O NH O CN N SH H2N R O N R: 2-F, 2-NO2, NC N 4-NO2, 4-Br, 4-CF3 N N O 16 17 18 N N O S O NO2 NC O Figure 9: Pyrazoles with antimicrobial activity. NC O2N H2N N HN S N N N H2N N N S N O HN NH The synthesis and the antimicrobial activity of new quinoli- O N N N O HN H R O nyl pyrazole chalcones was reported by Prasath group (Figure NH CN 2 O F F 9). The best antimicrobial activity against all tested strains was 7 8 9 10 11 found for compound 19 (Figure 10) [38]. Kendre et al. reported O O CF3 O S the synthesis and the antimicrobial activity of a pyrazole com- N Br H2N S N N N pounds repoted to ampicillin and norcadine as standard drugs. N HN O R HN N The best antimicrobial activity was found for compounds 20 N CSNH2(COOH) N NHSO2NH2 and 21 [39]. 15 12 13 14 F Sayed group synthesized new pyrazole compounds and eval- Figure 8: Pyrazoles with antimicrobial activity [36-43]. uated their antimicrobial activity. The best antimicrobial activ- ity was found for compound 22 against the tested strains [40]. Thumar and Patel reported that 2-amino-4-(1,3-diphe- The synthesis of new antimicrobial pyrazoles was reported by nyl-1H-pyrazol-4-yl)-1-(4-fluoro phenyl) 7,7-dimethyl-5-oxo Al-Ghamdi et al. Compound 23 was found to possess moderate -1,4,5,6,7,8 -hexahydroquinoline-3-carbonitrile 9 and 2-amino- activity against Aspergillus fumigatus [41]. Barakat group syn- 1-(4--(4-fluorophenyl)thiazol-2-yl)-4-(3-(4-methoxyphenyl)-1- thesized pyrazole-dimedone compounds using an one-pot mul- phenyl-1H-pyrazol-4-yl)-5-oxo-1,4,5,6, 7,8-hexahydroquinoline ticomponent reaction and evaluated their antimicrobial activiy. -3-carbonitrile 10 displayed comparable activity to that of ampi- All synthesized pyrazoles were tested for their antifungal and cillin against Streptococcus pneumoniae (MIC=100 μg/mL) [29]. antibacterial activities against C. albicans ATCC 2091, S. aureus Vijesh et al. synthesized new substituted pyrazoles containing ATCC 29213, E. faecalis ATCC29212 and B. subtilis ATCC 10400. imidazole moiety. Compound 11 exhibited antimicrobial activ- The best antimicrobial activity against S. aureus with MIC value ity compared to streptomycin against P. aeruginosa at the con- of 16 μg/L was found for compounds 24 and 25 [42]. Cetin et centrations of 1 and 0.5 mg/mL [30]. Several 4-functionalized al. reported the synthesis of 4-acyl-pyrazole-3-carboxylic acids pyrazoles 12 were synthesized and their in vitro antibacterial 26-28. Their in vitro antibacterial activity against gram-positive activity was evaluated against four pathogens: Escherichia coli (B. subtilis, S. aureus) and gram-negative (K. pneumoniae, P. ae- and Pseudomonas aeruginosa (Gram-negative), Staphylococ- ruginosa, E. coli) bacteria was determined by diffusion method cus aureus and Bacillus subtilis (Gram-positive). Some of these (Figure 10). pyrazoles posess middle activity against Gram positive bacte- Br ria [31]. Nitulescu et al. reported the synthesis of N-(1-methyl- O O CH 1H-pyrazole-4-carbonyl)-thiourea derivatives. They found that Ph Ph 3 O Br compound 13 had an important action on the bacterial soluble N N N O N N N enzymatic factors expression and inhibited the caseinase pro- CH3 2 N N Ph TsO TsO duction inE.