Skip to main content

Advertisement

SpringerLink
Log in

Design, synthesis, and biological evaluation of novel fluorinated pyrazole encompassing pyridyl 1,3,4-oxadiazole motifs

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A rational approach was adopted for the synthesis of 1-(2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)prop-2-en-1-ones (5a–n) using conventional heating as well as microwave irradiation techniques. Compounds 5a–n were tested for their in vitro antimicrobial activity and cytotoxicity. Compounds 5g showed most potent antibacterial activity, while compound 5k emerged as the most effective antifungal agent. The most active compounds 5f, 5g, 5l, and 5m were also screened against methicillin-resistant Staphylococcus aureus. Among these compounds, 5g and 5m inhibited the growth against MRSA at low level of cytotoxicity. A binary quantitative structure–activity relationship based recursive partitioning model was developed to probe the physico-chemical properties influencing the structure-activity relationship for this class of molecules, which was used to correctly classify active and inactive compounds.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Ahmad M, Siddiqui HL, Zia-ur-Rehman M, Parvez M (2010) Anti-oxidant and anti-bacterial activities of novel N′-arylmethylidene-2-(3, 4-dimethyl-5, 5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-2(4H)-yl) acetohydrazides. Eur J Med Chem 45:698–704

    Article  CAS  PubMed  Google Scholar 

  • Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  • Banks RE, Smart BE, Tatlow JC (2013) Organofluorine chemistry: principles and commercial applications. Springer, New York

  • Bégué JP, Bonnet-Delpon D (2008) Bioorganic and medicinal chemistry of fluorine. Wiley, New Jersey

  • Bekhit AA, Ashour HM, Abdel Ghany YS, Bekhit Ael D, Baraka A (2008) Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem 43:456–463

    Article  CAS  PubMed  Google Scholar 

  • Blower P, Fligner M, Verducci J, Bjoraker J (2002) On combining recursive partitioning and simulated annealing to detect groups of biologically active compounds. J Chem Inf Comput Sci 42:393–404

    Article  CAS  PubMed  Google Scholar 

  • Brun P, Dean A, Di Marco V, Surajit P, Castagliuolo I, Carta D, Ferlin MG (2013) Peroxisome proliferator-activated receptor-gamma mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: synthesis and biological evaluation. Eur J Med Chem 62:486–497

    Article  CAS  PubMed  Google Scholar 

  • Choi SY, Shin JH, Ryu CK, Nam KY, No KT, Park Choo HY (2006) The development of 3D-QSAR study and recursive partitioning of heterocyclic quinone derivatives with antifungal activity. Bioorg Med Chem 14:1608–1617

    Article  CAS  PubMed  Google Scholar 

  • Dandia A, Arya K, Sati M, Gautam S (2004) Microwave assisted green chemical synthesis of novel spiro[indole-pyrido thiazines]: a system reluctant to be formed under thermal conditions. Tetrahedron 60:5253–5258

    Article  CAS  Google Scholar 

  • Dandia A, Singh R, Khaturia S, Merienne C, Morgant G, Loupy A (2006) Efficient microwave enhanced regioselective synthesis of a series of benzimidazolyl/triazolyl spiro [indole-thiazolidinones] as potent antifungal agents and crystal structure of spiro[3H-indole-3,2’-thiazolidine]-3’(1,2,4-triazol-3-yl)-2,4’(1H)-dione. Bioorg Med Chem 14:2409–2417

    Article  CAS  PubMed  Google Scholar 

  • de la Hoz A, Loupy A (2013) Microwaves in organic synthesis, 2 volume set. Wiley, New Jersey

  • Desai NC, Bhatt N, Somani H, Trivedi A (2013) Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles. Eur J Med Chem 67:54–59

    Article  CAS  PubMed  Google Scholar 

  • Desai NC, Dodiya AM (2011) Conventional and microwave techniques for synthesis and antimicrobial studies of novel 1-[2-(2-chloro(3-quinolyl))-5-(4-nitrophenyl)-(1,3,4-oxadiazolin-3-yl)]-3-(aryl)prop-2-en-1-ones. Med Chem Res 21:1480–1490

    Article  Google Scholar 

  • Desai NC, Joshi VV, Rajpara KM, Vaghani HV, Satodiya HM (2012) Facile synthesis of novel fluorine containing pyrazole based thiazole derivatives and evaluation of antimicrobial activity. J Fluorine Chem 142:67–78

    Article  CAS  Google Scholar 

  • Desai NC, Somani H, Trivedi A, Bhatt K, Nawale L, Khedkar VM, Jha PC, Sarkar D (2016) Synthesis, biological evaluation and molecular docking study of some novel indole and pyridine based 1,3,4-oxadiazole derivatives as potential antitubercular agents. Bioorganic & Medicinal Chemistry Letters 26:1776–1783

    Article  CAS  Google Scholar 

  • Deshayes S, Liagre M, Loupy A, Luche J-L, Petit A (1999) Microwave activation in phase transfer catalysis. Tetrahedron 55:10851–10870

    Article  CAS  Google Scholar 

  • El-Emam AA, Al-Deeb OA, Al-Omar M, Lehmann J (2004) Synthesis, antimicrobial, and anti-HIV-1 activity of certain 5-(1-adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones. Bioorg Med Chem 12:5107–5113

    Article  CAS  PubMed  Google Scholar 

  • Fioravanti R, Bolasco A, Manna F, Rossi F, Orallo F, Ortuso F, Alcaro S, Cirilli R (2010) Synthesis and biological evaluation of N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cyclooxygenase (COX-2) inhibitors. Eur J Med Chem 45:6135–6138

    Article  CAS  PubMed  Google Scholar 

  • Hannan PC (2000) Guidelines and recommendations for antimicrobial minimum inhibitory concentration (MIC) testing against veterinary mycoplasma species. International Research Programme on Comparative Mycoplasmology. Vet Res 31:373–395

    Article  CAS  PubMed  Google Scholar 

  • Jiao Y, Xin BT, Zhang Y, Wu J, Lu X, Zheng Y, Tang W, Zhou X (2015) Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents. Eur J Med Chem 90:170–183

    Article  CAS  PubMed  Google Scholar 

  • Khidre RE, Abu-Hashem AA, El-Shazly M (2011) Synthesis and anti-microbial activity of some 1- substituted amino-4,6-dimethyl-2-oxo-pyridine-3-carbonitrile derivatives. Eur J Med Chem 46:5057–5064

    Article  CAS  PubMed  Google Scholar 

  • Ladani GG, Patel MP (2015) Novel 1,3,4-oxadiazole motifs bearing a quinoline nucleus: synthesis, characterization and biological evaluation of their antimicrobial, antitubercular, antimalarial and cytotoxic activities. N J Chem 39:9848–9857

    Article  CAS  Google Scholar 

  • Manvar A, Khedkar V, Patel J, Vora V, Dodia N, Patel G, Coutinho E, Shah A (2013) Synthesis and binary QSAR study of antitubercular quinolylhydrazides. Bioorg Med Chem Lett 23:4896–4902

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • Movassaghi M, Hill MD, Ahmad OK (2007) Direct synthesis of pyridine derivatives. J Am Chem Soc 129:10096–10097

    Article  CAS  PubMed  Google Scholar 

  • Prasanthi G, Prasad KV, Bharathi K (2014) Synthesis, anticonvulsant activity and molecular properties prediction of dialkyl 1-(di(ethoxycarbonyl)methyl)-2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-d icarboxylates. Eur J Med Chem 73:97–104

    Article  CAS  PubMed  Google Scholar 

  • Purser S, Moore PR, Swallow S, Gouverneur V (2008) Fluorine in medicinal chemistry. Chem Soc Rev 37:320–330

    Article  CAS  PubMed  Google Scholar 

  • Reichart B, Kappe CO (2012) High-temperature continuous flow synthesis of 1,3,4-oxadiazoles via N-acylation of 5-substituted tetrazoles. Tetrahedron Lett 53:52–955

    Article  Google Scholar 

  • Rostamizadeh S, Housaini SAG (2004) Microwave assisted syntheses of 2,5-disubstituted 1,3,4-oxadiazoles. Tetrahedron Lett 45:8753–8756

    Article  CAS  Google Scholar 

  • Rusinko 3rd A, Young SS, Drewry DH, Gerritz SW (2002) Optimization of focused chemical libraries using recursive partitioning. Comb Chem High Throughput Screen 5:125–133

    Article  CAS  PubMed  Google Scholar 

  • Samal RP, Khedkar VM, Pissurlenkar RR, Bwalya AG, Tasdemir D, Joshi RA, Rajamohanan PR, Puranik VG, Coutinho EC (2013) Design, synthesis, structural characterization by IR, (1) H, (13) C, (15) N, 2D-NMR, X-ray diffraction and evaluation of a new class of phenylaminoacetic acid benzylidene hydrazines as pfENR inhibitors. Chem Biol Drug Des 81:715–729

    Article  CAS  PubMed  Google Scholar 

  • Sharma D, Narasimhan B, Kumar P, Judge V, Narang R, De Clercq E, Balzarini J (2009) Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives. Eur J Med Chem 44:2347–2353

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Rane N, Gurram VK (2004) Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorg Med Chem Lett 14:4185–4190

    Article  CAS  PubMed  Google Scholar 

  • Strobl C, Malley J, Tutz G (2009) An introduction to recursive partitioning: rationale, application, and characteristics of classification and regression trees, bagging, and random forests. Psychol Methods 14:323–348

    Article  PubMed  PubMed Central  Google Scholar 

  • Suresh Kumar GV, Rajendraprasad Y, Mallikarjuna BP, Chandrashekar SM, Kistayya C (2010) Synthesis of some novel 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole and 1,3,4-oxadiazoles as potential antimicrobial and antitubercular agents. Eur J Med Chem 45:2063–2074

    Article  CAS  PubMed  Google Scholar 

  • Tan TM, Chen Y, Kong KH, Bai J, Li Y, Lim SG, Ang TH, Lam Y (2006) Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents. Antiviral Res 71:7–14

    Article  CAS  PubMed  Google Scholar 

  • Teague SJ (2008) Synthesis of heavily substituted 2-aminopyridines by displacement of a 6-methylsulfinyl group. J Org Chem 73:9765–9766

    Article  CAS  PubMed  Google Scholar 

  • Varma RS, Kumar D, Liesen PJ (1998) Solid state synthesis of 2-aroylbenzo[b]furans, 1,3-thiazoles and 3-aryl-5,6-dihydroimidazo[2,1-b][1,3]thiazoles from [small alpha]-tosyloxyketones using microwave irradiation [dagger]. J Chem Soc, Perkin Trans 1:4093–4096

    Article  Google Scholar 

  • Wang Y, Sauer DR, Djuric SW (2006) A simple and efficient one step synthesis of 1,3,4-oxadiazoles utilizing polymer-supported reagents and microwave heating. Tetrahedron Lett 47:105–108

    Article  CAS  Google Scholar 

  • Wang G, Wan J, Hu Y, Wu X, Prhavc M, Dyatkina N, Rajwanshi VK, Smith DB, Jekle A, Kinkade A, Symons JA, Jin Z, Deval J, Zhang Q, Tam Y, Chanda S, Blatt L, Beigelman L (2016) Synthesis and anti-influenza activity of pyridine, pyridazine, and pyrimidine C-nucleosides as favipiravir (T-705) analogues. J Med Chem 59:4611–4624

    Article  CAS  PubMed  Google Scholar 

  • Wang XM, Xu J, Li YP, Li H, Jiang CS, Yang GD, Lu SM, Zhang SQ (2013) Synthesis and anticancer activity evaluation of a series of [1,2,4]triazolo[1,5-a]pyridinylpyridines in vitro and in vivo. Eur J Med Chem 67:243–251

    Article  CAS  PubMed  Google Scholar 

  • Wang P-Y, Zhou L, Zhou J, Wu Z-B, Xue W, Song B-A, Yang S (2016) Synthesis and antibacterial activity of pyridinium-tailored 2,5-substituted-1,3,4-oxadiazole thioether/sulfoxide/sulfone derivatives. Bioorg Med Chem Lett 26:1214–1217

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Chen Q, Tai A, Jiang G, Ouyang G (2015) Synthesis and antiviral activity of 2-substituted methylthio-5-(4-amino-2-methylpyrimidin-5-yl)-1,3,4-oxadiazole derivatives. Bioorg Med Chem Lett 25:2243–2246

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Feng JT, Lin KC, Zhang X (2012) Synthesis and herbicidal activity of substituted pyrazole isothiocyanates. Molecules 17:12187–12196

    Article  CAS  PubMed  Google Scholar 

  • Yadlapalli RK, Chourasia OP, Vemuri K, Sritharan M, Perali RS (2012) Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group. Bioorg Med Chem Lett 22:2708–2711

    Article  CAS  PubMed  Google Scholar 

  • Young SS, Hawkins DM (2004) Using recursive partitioning analysis to evaluate compound selection methods. Methods Mol Biol 275:317–334

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Kijima T, Kuwahara S, Watanabe M, Izumi T (2008) Synthesis of ethyl 5-cyano-6-hydroxy-2-methyl-4-(1-naphthyl)-nicotinate. Tetrahedron Lett 49:3757–3761

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are thankful to the University Grants Commission, New Delhi and Department of Science & Technology, New Delhi for financial support under the NON-SAP and DST-FIST programs respectively. Authors, G. M. Kotadiya, A. R. Trivedi, and Prakash C. Jha are thankful to UGC, New Delhi for providing “Research Fellowships in Science to Meritorious Students”, “Dr. D. S. Kothari Post-Doctoral Fellowship”, and start-up grants respectively. We are also thankful to Schrödinger Inc. for providing the Demo of Schrodinger molecular modeling Suite, and especially Vinod Devarji for giving the online support.

Author information

Authors and Affiliations

  1. Division of Medicinal Chemistry, Department of Chemistry, (UGC NON-SAP & DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, 364 002, Gujarat, India

    Nisheeth C. Desai, Ghanshyam M. Kotadiya & Amit R. Trivedi

  2. CombiChem Bio Resource Center, National Chemical Laboratory, Pune, 411008, India

    Vijay M. Khedkar

  3. School of Health Sciences, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville, Durban, 4000, South Africa

    Vijay M. Khedkar

  4. School of Chemical Sciences, Central University of Gujarat, Sector-30, Gandhinagar, 382030, India

    Prakash C. Jha

Authors
  1. Nisheeth C. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ghanshyam M. Kotadiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amit R. Trivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vijay M. Khedkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Prakash C. Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nisheeth C. Desai.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Desai, N.C., Kotadiya, G.M., Trivedi, A.R. et al. Design, synthesis, and biological evaluation of novel fluorinated pyrazole encompassing pyridyl 1,3,4-oxadiazole motifs. Med Chem Res 25, 2698–2717 (2016). https://doi.org/10.1007/s00044-016-1683-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-016-1683-y

Keywords

Search

Navigation