Home >Current Issue

Volume: 9, Issue: 5, May, 2019
DOI: 10.7324/JAPS.2019.90517

Research Article

Synthesis and characterization of novel 1,6-dihydropyrimidine derivatives for their pharmacological properties

Basavaraj Padmashali1, Ballekere Nanjundaswamy Chidananda2, Banuprakash Govindappa3, Siddesh M. Basavaraj4, Sandeep Chandrashekharappa2, Katharigatta N. Venugopala5 & 6

  Author Affiliations


The present research work involves the use of commercially available thiophene-2-carbaldehyde as a starting material to construct novel pyrimidine compounds. Synthesis of pyrimidine derivatives has been done by the trimolecular Biginelli condensation reaction, which involves the use of thiophene-2-carbaldehyde with cyano ethylacetate and thiourea to yield 4-oxo-6-(thiophen-2-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (1). The intermediate 1 was methylated using methyl iodide and K2CO3 in dimethylformamide (DMF) which afforded dimethylated derivative 1-methyl-2-(methylthio)-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (2). The intermediate compound 2 when refluxed with hydrazine hydrate in ethanol as a solvent led to the formation of the parent compound 2-hydrazineyl-1-methyl-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (3), the parent compound 3 was used for the synthesis of carboxamides of N′-(5-cyano-1-methyl-6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidin- 2-yl)substituted benzohydrazide (4a–d) and Schiff bases of (E)-2-(2-substituted benzylidenehydrazineyl)-1-methyl- 6-oxo-4-(thiophen-2-yl)-1,6-dihydropyrimidine-5-carbonitrile (5a–g). Selected title compounds are screened for antibacterial, analgesic, and antifungal activities.


Substituted 1, 6-dihydropyrimidine, synthesis, antibacterial, antifungal, analgesic.

Citation: Padmashali B, Chidananda BN, Govindappa B, Basavaraj SM, Chandrashekharappa S, Venugopala KN. Synthesis and characterization of novel 1,6-dihydropyrimidine derivatives for their pharmacological properties. J Appl Pharm Sci, 2019; 9(05):133–140.

Copyright: The Author(s). This is an open access article distributed under the Creative Commons Attribution Non-Commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Amr AEG, Al-Omar MA, Abdalla MM. Pharmacological activity of some 2,6-bis(thieno[2,3-b]pyrimidine)pyridine derivatives as antiulcerogenic agents. J Comput Theor Nanosci, 2016; 13:7351-4. https://doi.org/10.1166/jctn.2016.5725

Aruna Kumari M, Triloknadh S, Harikrishna N, Vijjulatha M, Venkata Rao C. Synthesis, antibacterial activity, and docking studies of 1,2,3-triazole-tagged thieno[2,3-d]pyrimidinone derivatives. J Heterocycl Chem, 2017; 54:3672-81. https://doi.org/10.1002/jhet.2995

Bairagi KM, Venugopala KN, Mondal PK, Gleiser RM, Chopra D, García D, Odhav B, Nayak SK. Larvicidal study of tetrahydropyrimidine scaffolds against Anopheles arabiensis and structural insight by single crystal X-ray studies. Chem Biol Drug Des, 2018; 92:1924-32. https://doi.org/10.1111/cbdd.13351

Bari SB, Haswani NG. Design, synthesis and molecular docking study of thienopyrimidin-4(3H)-thiones as antifungal agents. J Saudi Chem Soc, 2017; 21:S264-74. https://doi.org/10.1016/j.jscs.2014.02.011

Borate HB, Annadate RA, Deokate SB. Preparation of thienopyrimidinone derivatives for use as antimycobacterial agents. Coun Sci Ind Res India, 2016; 56.

Bugge S, Buene AF, Jurisch-Yaksi N, Moen IU, Skjoensfjell EM, Sundby E, Hoff BH. Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties. Eur J Med Chem, 2016; 107:255-74. https://doi.org/10.1016/j.ejmech.2015.11.012

Chandrashekharappa S, Venugopala KN, Nayak SK, Gleiser GR, García DA, Kumalo HM, Kulkarni RS, Mahomoodally FM, Venugopala R, Mohan MK, Odhav B. One-pot microwave assisted synthesis and structural elucidation of novel ethyl 3-substituted-7-methylindolizine-1-carboxylates with larvicidal activity against Anopheles arabiensis. J Mol Struct, 2018a; 1156:377-84. https://doi.org/10.1016/j.molstruc.2017.11.131

Chandrashekharappa S, Venugopala KN, Tratrat C, Mahomoodally FM, Aldhubiab BE, Haroun M, Venugopala R, Mohan MK, Kulkarni RS, Attimarad MV, Harsha S, Odhav B. Efficient synthesis and characterization of novel indolizines: exploration of in vitro COX-2 inhibitory activity and molecular modelling studies. New J Chem, 2018b; 42:4893-901. https://doi.org/10.1039/C7NJ05010K

Chandrashekharappa S, Venugopala KN, Venugopala R, Padmashali B. Qualitative anti-tubercular activity of synthetic ethyl 7-acetyl-2-substituted-3-(4-substituted benzoyl) indolizine-1-carboxylate analogues. J Appl Pharm Sci, 2019; 9(02):124-8. https://doi.org/10.7324/JAPS.2019.90217

Devi K, Venugopala KN, Rao GK. Synthesis of substituted 3, 4-dihydropyrimidine-2(1H)-thiones and their biological activity. Ind J Het Chem, 2009; 18:305-6.

Dharma Rao BD, Bhandary S, Chopra D, Venugopala KN, Gleiser RM, Kasumbwe K, Odhav B. Synthesis and characterization of a novel series of 1,4-dihydropyridine analogues for larvicidal activity against Anopheles arabiensis. Chem Biol Drug Des, 2017; 90:397-405. https://doi.org/10.1111/cbdd.12957

Ghith A, Ismail NSM, Youssef K, Abouzid KAM. Medicinal attributes of thienopyrimidine based scaffold targeting tyrosine kinases and their potential anticancer activities. Arch Pharm (Weinheim), 2017; 350. https://doi.org/10.1002/ardp.201700242

Joshi A, Venugopala KN, Rao GK, Devi K, Pathak A. Synthesis of 3-[4-(6-bromo-2-oxo-2H-chromen-3-yl)-1,3-thiazol-2-yl]-2-(substituted phenyl) 1,3-thiazolidin-4-ones and their biological activity. Ind J Het Chem, 2011; 20:295-6.

Kankanala J, Kirby KA, Huber AD, Casey MC, Wilson DJ, Sarafianos SG, Wang Z. Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H. Eur J Med Chem, 2017; 141:149-61. https://doi.org/10.1016/j.ejmech.2017.09.054

Klossowski S, Liu Y, Ren P, Feng J, Wu T, Li L, Pollock J, Borkin D, Cierpicki T, Grembecka J. Furo[2,3-d]pyrimidine and thieno[2,3-d] pyrimidine derivatives as composition inhibitors for the interaction of menin with MLL proteins and their preparation, pharmaceutical compositions and use in the treatment of diseases. Kura Oncology, Inc., The Regents of the University of Michigan, Ann Arbor, MI, 264 p, 2017.

Mallikarjuna SM, Sandeep C, Basavaraj P. Synthesis, antimicrobial activity of piperazin-1-yl (3,4,5-trimethoxyphenyl)methanone derivatives. Der Pharma Chem, 2016; 8:262-8.

Nagesh HK, Basavaraj P, Sandeep C, Musturappa TE, Lokesh MR. Synthesis and characterization of novel benzothiophene substituted oxadiazole derivatives and their antimicrobial activity. Der Pharma Chem, 2015; 7:129-36.

Nagesh HK, Basavaraj P, Sandeep C, Yuvaraj TCM, Siddesh MB, Mallikarjuna SM. Synthesis and antimicrobial activity of benzothiophene substituted coumarins, pyrimidines and pyrazole as new scaffold. Int J Pharm Sci Rev Res, 2014; 28:6-10.

Noravyan AS, Paronikyan EG, Sirakanyan SN, Akopyan SF. Synthesis and conversion of condensed thieno[2,3-d]- and thieno[3,2-d] pyrimidines. Hayastani Kim Handes, 2012; 65:447-73.

Ortikov IS, Turdibaev ZE, Islamova ZI, Elmuradov BZ, Abdurazakov AS, Bektemirov AM, Osipova SO, Khushbaktova ZA, Syrov VN, Shakhidoyatov KM. Search for Bactericides among derivatives of deoxyvasicinone, mackinazolinone, and thienopyrimidinones. Pharm Chem J, 2017; 51:456-64. https://doi.org/10.1007/s11094-017-1633-0

Pisal MM, Nawale LU, Patil MD, Bhansali SG, Gajbhiye JM, Sarkar D, Chavan SP, Borate HB. Hybrids of thienopyrimidinones and thiouracils as anti-tubercular agents: SAR and docking studies. Eur J Med Chem, 2017; 127:459-69. https://doi.org/10.1016/j.ejmech.2017.01.009

Ram VJ, Vanden Berghe DA, Vlietinck AJ. Chemotherapeutical agents. V. Synthesis and activities of novel pyrimidines derived from 5-cyano-6-aryl-2-thiouracil. Liebigs Ann Chem, 1987; 797-801. https://doi.org/10.1002/jlac.198719870831

Ramesh B, Bhalgat CM. Novel dihydropyrimidines and its pyrazole derivatives: synthesis and pharmacological screening. Eur J Med Chem, 2011; 46:1882-91. https://doi.org/10.1016/j.ejmech.2011.02.052

Ravez S, Arsenlis S, Barczyk A, Dupont A, Frederick R, Hesse S, Kirsch G, Depreux P, Goossens L. Synthesis and biological evaluation of di-aryl urea derivatives as c-Kit inhibitors. Bioorg Med Chem, 2015; 23:7340-7. https://doi.org/10.1016/j.bmc.2015.10.035

Rosado LA, Wahni K, Degiacomi G, Pedre B, Young D, de la Rubia AG, Boldrin F, Martens E, Marcos-Pascual L, Sancho-Vaello E, Albesa-Jove D, Provvedi R, Martin C, Makarov V, Versees W, Verniest G, Guerin ME, Mateos LM, Manganelli R, Messens J. The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis. J Biol Chem, 2017; 292:13097-110. https://doi.org/10.1074/jbc.M117.797837

Sandeep C, Basavaraj P, Rashmi SK, Mallikarjuna SM, Siddesh MB, Nagesh HK., Thriveni KS. Synthesis of substituted 5-acetyl-3- benzoylindolizine-1-carboxylate from substituted 2-acetyl pyridinium bromides. Het Lett, 2014; 4:371-6.

Sandeep C, Padmashali B, Kulkarni RS. Efficient synthesis of indolizines and new imidazo[1,2-a]pyridines via the expected cyclization of aromatic cycloimmonium ylides with electron deficient alkynes and ethyl cyanoformate. Tet Lett, 2013a; 54:6411-4. https://doi.org/10.1016/j.tetlet.2013.09.033

Sandeep C, Padmashali B, Kulkarni RS. Synthesis of isomeric subtituted 6-acetyl-3-benzoylindolizine-1-carboxylate and 8-acetyl-3- benzoylindolizine-1-carboxylate from subtituteded 3-acetyl pyridinium bromides and their antimicrobial activity. J Appl Chem, 2013b; 2:1049-56.

Sandeep C, Padmashali B, Venugopala KN, Kulkarni RS, Venugopala R, Odhav B. Synthesis and characterization of ethyl 7-acetyl- 2-substituted 3-(substituted benzoyl)indolizine-1-carboxylates for in vitro anticancer activity. Asian J Chem, 2016a; 28:1043-8. https://doi.org/10.14233/ajchem.2016.19582

Sandeep C, Venugopala KN, Gleiser RM, Chetram A, Padmashali B, Kulkarni RS, Venugopala R, Odhav B. Greener synthesis of indolizine analogues using water as a base and solvent: study for larvicidal activity against Anopheles arabiensis. Chem Biol Drug Des, 2016b; 88:899-904. https://doi.org/10.1111/cbdd.12823

Shishoo C, Ananthan S, Bhadti V, Ullas G, Chhabria M, Bariwal J, Venkatesh L, Nargund G, Jain K. Synthesis of pyrimidines and condensed pyrimidines through reactions of nitriles with o-aminocarbonyl substrates under acidic conditions. Heterocycles, 2009; 78:1627-65. https://doi.org/10.3987/REV-08-639

Siddesh MB, Basavaraj P, Thriveni KS, Sandeep C. Synthesis of polynuclear pyrimidine derivatives and their pharmacological activities. Heter Lett, 2014a; 4:503-14.

Siddesh MB, Basavaraj P, Thriveni KS, Sandeep C, Goudarshivnnanava BC. Synthesis and pharmacological evaluation of some novel pyrimidine derivatives. J Applicable Chem, 2013; 2:1281-8.

Siddesh MB, Padmashali B, Thriveni KS, Sandeep C. Synthesis of thiophene-linked pyrimidopyrimidines as pharmaceutical leads. J Chem Sci, 2014b; 126:821-6. https://doi.org/10.1007/s12039-014-0614-z

Srnivasula RVM, Mannem LB, Ratnam KG, Gokuladoss V, Yerramsetti VS. Thieno[2,3-d]pyrimidin-4(3H)-one compounds with antimycobacterial properties. Coun Sci Ind Res India, 2016; 56.

Teo T, Yang Y, Yu M, Basnet SKC, Gillam T, Hou J, Schmid RM, Kumarasiri M, Diab S, Albrecht H, Sykes MJ, Wang S. An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis. Eur J Med Chem, 2015; 103:539- 50. https://doi.org/10.1016/j.ejmech.2015.09.008

Thriveni KS, Padmashali B, Siddesh MB, Sandeep C. Synthesis of Pyrimidine incorporated piperazine derivatives and their antimicrobial activity. Indian J Pharm Sci, 2014; 76:332-8.

Venugopala KN, Gleiser RM, Chalannavar KR, Odhav B. Antimosquito properties of 2-substituted phenyl/benzylamino-6-(4- chlorophenyl)-5-methoxycarbonyl-4-methyl-3,6-dihydropyrimidin-1-ium chlorides against Anopheles arabiensis. Med Chem, 2014; 10:211-9. https://doi.org/10.2174/157340641002140131164945

Venugopala KN, Nayak SK, Pillay M, Prasanna R, Coovadia YM, Odhav B. Synthesis and antitubercular activity of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4- methyl-3, 6-dihydropyrimidin-1-ium chlorides. Chem Biol Drug Des, 2013; 81:219-27. https://doi.org/10.1111/cbdd.12065

Venugopala KN, Rao GD, Bhandary S, Pillay M, Chopra D, Aldhubiab BE, Attimarad M, Alwassil OI, Harsha S, Mlisana K. Design, synthesis, and characterization of (1-(4-aryl)-1H-1, 2, 3-triazol-4-yl) methyl, substituted phenyl-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine- 5-carboxylates against Mycobacterium tuberculosis. Drug Des Devel Ther, 2016; 10:2681. https://doi.org/10.2147/DDDT.S109760

Wu YJ. Heterocycles and medicine: a survey of the heterocyclic drugs approved by the U.S. FDA from 2000 to present. Prog Heterocycl Chem, 2012; 24:1-53.

Yong J, Lu C, Wu X. Synthesis of Isoxazole moiety containing thieno[2,3-d]pyrimidine Derivatives and preliminarily in vitro anticancer activity (Part II). Anti-Cancer Agents Med Chem, 2015; 15:1148-55. https://doi.org/10.2174/1871520615666150305103122

Zhang L, Wang ZY, Ding YJ. Synthesis and antitumor activity of fluorinated thieno-[2,3-d] pyrimidine derivatives containing 1,3,4-thiadiazole. Jingxi Huagong, 2015; 32:611-5.

Zhang Q, Zhang L, Yu J, Li H, He S, Tang W, Zuo J, Lu W. Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold. RSC Adv, 2017; 7: 26060-9. https://doi.org/10.1039/C7RA04261B

Article Metrics

Similar Articles

Three component one pot synthesis of 5-Substituted 1-Aryl-2,3-diphenyl imidazoles: A novel class of promising antioxidants
Nagaraja Naik, H. Vijay Kumar, J. Rangaswamy, S.T. Harinia and T.C. Umeshkumar

The Study of Base Catalysed Synthesis of 2-Chloro- 4-Amino-5-Flouropyrimidine from a biologically active Compound 5-Flouro Pyrimidine
S. Venkat Rao, S. K. Ameer, K.Neveen Reddy, S. D. V. V. S. Raju, Kumaraswamy S.

Synthesis and Antimicrobial studies of novel Benzimidazole derivatives
Parmender Singh Rathee,Ritu Dhankar, Sunny Bhardwaj,Monika Gupta, Rakesh Kumar