Abstract
A series of novel α,α-difluoro-β-hydroxyl pyrazole esters was prepared by Reformatsky reaction. Subsequently, these esters were converted to acids and hydrazides. All the synthesized compounds were evaluated for their in vitro antioxidant, anti-inflammatory and anticancer potential at various concentrations (50, 100 μM). Compounds 4d and 6e were found to be potent (93.19 and 90.91 %) and compounds 5d, 6c and 5f were good OH radical scavengers (79.55–72.73 %) as compared to the standard drug ascorbic acid (88.63 %). Compounds 6a, 5c, 6f, 4d and 5a showed significant 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity (75.95–70.89 %). All the compounds have shown higher cyclooxygenase-1 (COX-1) inhibition over cyclooxygenase-2 (COX-2) at concentrations 100 and 50 μM. Compounds 5f, 6b, 4a, 5c, 4f, 5 and 6d showed significant COX-2 inhibition (38.56–28.30 %) at a concentration of 100 μM compared to standard drug aspirin (11.11 %). Compounds 6f, 6e and 5f have shown significant cytotoxicity against MCF-7 (51.03–40.59 %), whereas 6d, 5f and 5a showed moderate cytotoxicity against HL-60 (26.98–20.21 %) cancer cell lines compared to the methotrexate as reference standard (68.42 and 54.29 % respectively). All compounds have shown almost neglisible cytotoxicity against normal cell line 293.
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References
Bandgar BP, Chavan HV, Adsul LK, Thakare VN, Shringare SN, Shaikh R, Gacche RN (2013) Design, synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones. Bioorg Med Chem Lett 23:912–916
Bandgar BP, Gawande SS, Bodade RG, Gawande NM, Khobragade CN (2009) Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, antioxidant and antimicrobial agents. Bioorg Med Chem 17:8168–8173
Bégué J-P, Bonnet-Delpon D (2008) Bioorganic and medicinal chemistry of fluorine. Wiley, Hoboken, N. J
Blois MS (1958) Antioxidant determinations by the use of a stable free radical. Nature 181:1199–1200
Bohacek RS, McMartin C, Guida WC (1996) The art and practice of structure-based drug design: a molecular modeling perspective. Med Res Rev 16:3–50
Burkholder CR, Dolbier Jr. WR, Médebielle M (1998) Tetrakis(dimethylamino)ethylene as a useful reductant of some bromodifluoromethyl heterocycles. Application to the synthesis of new gem-difluorinated heteroarylated compounds. J Org Chem 63:5385–5394
Burkholder CR, Dolbier Jr. WR, Médebielle M (2000) The syntheses of nonnucleoside, HIV-1 reverse transcriptase inhibitors containing a CF2 group: the SRN1 reactions of 2-(bromodifluoromethyl)benzoxazole with the anions derived from heterocyclic thiols and phenolic compounds. J Fluorine Chem 102:369–376
Chavan HV, Adsul LK, Kotmale AS, Dhakane VD, Thakare VN, Bandgar BP (2015) Design, synthesis, characterization and in vitro and in vivo anti-inflammatory evaluation of novel pyrazole-based chalcones. J Enz Inhib Med Chem 30:22–31
Chavan HV, Bandgar BP, Adsul LK, Dhakane VD, Bhale PS, Thakare VN, Masand V (2013) Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones. Bioorg Med Chem Lett 23:1315–1321
Chou T-S, Heath PC, Patterson LE, Poteet LM, Lakin RE, Hunt AH (1992) Stereospecific synthesis of 2-deoxy-2,2-difluororibonolactone and its use in the preparation of 2′-deoxy-2′,2′-difluoro-β-D-ribofuranosyl pyrimidine nucleosides: the key role of selective crystallization. Synthesis 1992(6):565–570
Garg HG, Prakash C (1971) Potential antidiabetics. 9. Biological activity of some pyrazoles. J Med Chem 14:649–650
Hagmann WK (2008) The many roles for fluorine in medicinal chemistry. J Med Chem 51:4359–4359
Hallinan EA, Fried J (1984) 2,2-Difluoro-3-hydroxyesters by reformatskii reaction. Tetrahedron Lett 25:2301–2302
Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, Ogawa M, Mitsudomi T, Sugiura T, Takahashi T (1998) Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 58:3761–3764
Holla BS, Mahalinga M, Karthikeyan MS, Akberali PM, Shetty NS (2006) Synthesis of some novel pyrazolo[3,4-d]pyrimidine derivatives as potential antimicrobial agents. Bioorg Med Chem 14:2040–2047
Kawase M, Motohashi N, Satoh K, Sakagami H, Nakashima H, Tan S, Shıratak Y, Kurihara T, Spengler G, Wolfard K, Molnar J (2003) Biological activity of persimmon (Diospyros kaki) peel extracts. Phytother Res 17:495–500
Kirk KL (2008) Fluorination in medicinal chemistry: methods, strategies, and recent developments. Org Process Res Dev 12:305–321
Legters J, Thijs L, Zwanenburg B (1991) Synthesis of naturally occurring (2S,3S)-(+)-aziridine-2,3-dicarboxylic acid. Tetrahedron 47:5287–5294
Liu F, Ooi VEC, Chang ST (1997) Free radical scavenging activities of mushroom polysaccharide extracts. Life Sci 60:763–771
Manna F, Chimenti F, Fioravanti R, Bolasco A, Secci D, Chimenti P, Ferlini C, Scambia G (2005) Synthesis of some pyrazole derivatives and preliminary investigation of their affinity binding to P-glycoprotein. Bioorg Med Chem Lett 15:4632–4635
Mantani N, Imanishi N, Kawamata H, Terasawa K, Ochiai H (2001) Inhibitory effect of (+)-catechin on the growth of influenza A/PR/8 virus in MDCK cells. Planta Med 67:240–243
Meth-Cohn O, Tarnowski B (1982) Cyclizations under vilsmeier conditions. Adv Heterocycl Chem 31:207–236
Mulder R, Wellinga K, van Daalen JJ (1975) A new class of insecticides. Naturwissenschaften 62:531–532
Murias M, Handler N, Erker T, Pleban K, Ecker G, Saiko P, Szekeres T, Jäger W (2004) Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure–activity relationship. Bioorg Med Chem 12:5571–5578
Ojima I (2009) Fluorine in medicinal chemistry and chemical biology. Blackwell
Purser S, Moore PR, Swallow S, Gouverneur V (2008) Fluorine in medicinal chemistry. Chem Soc Rev 37:320–330
Roesler R, Malta LG, Carrasco LC, Pastore G (2006) Evaluation of the antioxidant properties of the Brazilian Cerrado fruit Annona crassiflora (Araticum). J Food Sci 71:102–107
Rollet-Labelle E, Gragne MS, Elbim C, Marquetty C, Gougerot-Pocidalo MA (1998) Hydroxyl radical as a potential intracellular mediator of polymorphonuclear neutrophil apoptosis. Free Rad Biol Med 24:563–572
Ruiz van Haperen VWT, Veerman G, Vermorken JB, Peters GJ (1993) 2′,2′-Difluoro-deoxycytidine (gemcitabine) incorporation into RNA and DNA of tumour cell lines. Biochem Pharmacol 46:762–766
Saha A, Kumar R, Kumar R, Devakumar (2010) Development and assessment of green synthesis of hydrazides. Ind J Chem B 49:526–531
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Mukarram, S., Bandgar, B.P., Shaikh, R.U. et al. Synthesis of novel α,α-difluoro-β-hydroxycarbonyl pyrazole derivatives as antioxidant, anti-inflammatory and anticancer agents. Med Chem Res 26, 262–273 (2017). https://doi.org/10.1007/s00044-016-1744-2
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DOI: https://doi.org/10.1007/s00044-016-1744-2