Synthesis of Novel 3(N,N-dialkylamino)alkyl/phenyl Substituted Thieno [2,3-d]pyrimidinones as H1-Anti-Histaminic and Antimicrobial Agents

Author(s): Shiv Dev Singh*, Arvind Kumar, Firoz Babar, Neetu Sachan, Arun Kumar Sharma.

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 1 , 2019

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Abstract:

Background: Thienopyrimidines are the bioisoster of quinazoline and unlike quinazoline exist in three isomeric forms corresponding to the three possible types annulation of thiophene to the pyrimidine ring viz thieno[2,3-d] pyrimidine, thieno[3,2-d] pyrimidine and thieno[3,4-d]pyrimidine. Heterocyclic containing the thienopyrimidinone moiety exhibits various pronounced activities such as anti-hypertensive, analgesic and anti-inflammatory, antiviral, platelet aggregation inhibitory, antiprotozoal bronchodilatory, phosphodiesterase inhibitory, antihistaminic, antipsychotic and antimicrobial activity.

Objective: Synthesis of novel 3(N,N-dialkylamino)alkyl/phenyl substituted thieno[2,3-d]pyrimidinones as H1-anti-histaminic and antimicrobial agents.

Methods: A series of 3-[(N,N-dialkylamino)alkyl/phenyl]-2-(1H)thioxo-5,6,7,8-tetrahydrobenzo(b) thieno(2,3-d)pyrimidine-4(3H)-ones[4a-d], their oxo analogous [5a-d] and 3-[(N,N-dialkylamino)alkyl]- 2-chlorophenyl-5,6,7,8-tetrahydrobenzo(b)thieno(2,3-d)pyrimidine- 4 (3H)-ones[6a-d]derivative were synthesized from 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acid by nucleophilic substitution of different N,N-dialkyl alkylene/phenylene diamines on activated 3-acylchloride moiety followed by cyclocondensation with carbon disulfide and ethanolic potassium hydroxide to get [4a-d] and in second reaction by condensation with 4-chlorobenzoyl chloride to get [6a-d] by single pot novel innovative route. The oxo analogous [5a-d] were prepared by treating derivatives [4a-d] with potassium permagnate in ethanolic KOH. The synthesized compound were evaluated for H1-antihistaminic and antimicrobial activities.

Results: All synthesized compounds exhibited significant H1-antihistaminic activity by in vitro and in vivo screening methods and data were verified analytically and statistically. The compound 4a, 4b, 5a and 5b showed significant H1-antihistaminiic activity than the reference standard chlorpheniramine maleate. The compound 6d, 6c, 5c and 4c exhibited significant antimicrobial activity.

Keywords: Thieno[2, 3-d]pyrimidinones, H1-antihistaminic, antibacterial activity, antifungal activity, cyclocondensation, bioisoster.

[1]
Vorobev, E.V.; Kletskii, M.E.; Krasnikov, V.V.; Mezheritskii, V.V.; Steglenko, D. Studies on mechanisms of the rearrangement of thieno [3,2-e][1,2,4]triazolo [4,3-c]pyrimidines into thieno [3,2-e][1,2,4]triazolo [1,5-c]pyrimidines. Russ. Chem. Bull., 2006, 55(12), 2247-2255.
[2]
Gewald, K. Heterocyclen aus CH-aciden Nitrilen, VII. 2-Amino-thiophene aus α-Oxo-mercaptanen und methylenaktiven Nitrilen. Eur. J. Inorg. Chem., 1965, 98(11), 3571-3577.
[3]
Gewald, K.; Schinke, E.; Bottcher, H. Heterocyclen aus CH-aciden Nitrilen, VIII. 2-Amino-thiophene aus methylenaktiven nitrilen, carbonylverbindungen und Schwefel. Eur. J. Inorg. Chem., 1966, 99(1), 94-100.
[4]
Sabnis, R.W. The Gewald Synthesis. Sulfur Reports, 1994, 16, 1-17.
[5]
Huang, W.; Li, J.; Tang, J.; Liu, H.; Shen, J.; Jiang, H. Microwave‐assisted synthesis of 2‐amino‐thiophene‐3‐carboxylic derivatives under solvent‐free conditions. Synth. Commun., 2005, 36(10), 1351-1357.
[6]
Chengynan, L.; Zhishu, T.; Weidong, Q.; Chunyang, S. Ultrasound-promoted synthesis of 2-aminothiophenes accelerated by DABCO utilizing PEG-200 as solvent. J. Chem. Pharm. Res., 2014, 6(4), 798-802.
[7]
Russell, R.K.; Press, J.B.; Rampulla, R.A.; McNally, J.J.; Falotico, R.; Keiser, J.A.; Bright, D.A.; Tobia, A. Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents. J. Med. Chem., 1988, 31(9), 1786-1793.
[8]
Jain, K.S.; Bariwal, J.B.; Kathiravan, M.K.; Phoujdar, M.S.; Sahne, R.S.; Chauhan, B.S.; Shah, A.K.; Yadav, M.R. Recent advances in selective α1-adrenoreceptor antagonists as antihypertensive agents. Bioorg. Med. Chem., 2008, 16(9), 4759-4800.
[9]
El-Kerdawy; Yousif, M.M; El-Emam, A.A; Moustafa, M.A; El-Sherbeny, M.A Synthesis and anti-inflammatory activity of certain thienopyrimidine derivatives. Boll. Chim. Farm., 1996, 135, 301-305.
[10]
Alagarsamy, V.; Meena, S.; Ramseshu, K.V.; Solomon, V.R.; Thirumurugan, K.; Dhanabal, K.; Murugan, M. Synthesis, analgesic, anti-inflammatory, ulcerogenic index and antibacterial activities of novel 2-methylthio-3-substituted-5,6,7,8-tetrahydrobenzo (b) thieno [2,3-d]pyrimidin-4(3H)-ones. Eur. J. Med. Chem., 2006, 41(11), 1293-1300.
[11]
Kaur, R.; Rao, A.R.R.; Chadha, R.; Thakur, N. Afacile microwave assisted synthesis and anti-inflammatory activity of thiophene [3,2-e][1,2,4]triazolo [1,5]pyrimidin-5(6H)-one derivatives. Int. J. Pharm. Sci. Rev. Res., 2016, 40(1), 104-111.
[12]
Nasr, M.N.; Gineinah, M.M. Synthesis and biological activity pyrido [2,3-d]pyrimidine and pyrimido [5,4-5,6]pyrido [2,3-d]pyrimidine as new antiviral agents. Arch. Pharm. Med. Chem., 2002, 335, 289-295.
[13]
Rajendra, D.; Asma, S.; Vijaya, K.; Kalyani, G. Synthesis, characterization and pharmacological evaluation of novel mannich bases of thienopyrimidine derivatives. Sch. Acad. J. Pharm., 2016, 5(4), 100-111.
[14]
Leistner, S.; Wagner, G.; Gütschow, M.; Glusa, E. [Synthesis of 7-benzyl-5,6,7,8-tetrahydro-pyrido[4′,3′:4,5]thieno [2,3-d]pyrimidine-4(3H)-ones with alkylthioester groups in position 2 and examination of their platelet aggregation-inhibiting activity]. Pharmazie, 1986, 41(1), 54-55.
[15]
Zaidi, S.L.; Agarwal, S.M.; Azam, A. Thienopyrimidin sulphonamide hydrids: design, synthesis, antiprotozoal activity and molecular docking studied RSC adv, 2016. 6, 371-383.
[16]
Bahekar, R.H.; Rao, A.R. Synthesis, evaluation and structural-activity relationship of 5-alkyl-2,3-dihydroimidazo [1,2-c]quinazolin-5(6H)-thiones and their oxo analogues as new potential bronchodilators. Arzneim Forsch. Drug Res., 2001, 51, 284-292.
[17]
Maria, I.C.; Pagès, L.; Vega, A.; Segarra, V.; López, M.; Doménech, T.; Miralpeix, M. Design, synthesis, and biological activities of new thieno [3,2-d] pyrimidines as selective type 4 phosphodiesterase inhibitors. J. Med. Chem., 1998, 41(21), 4021-4035.
[18]
Shireesha, B.; Uma, S.K.; Rao, A.R.; Rajan, K.S.; Raghuprasad, M. Design, synthesis and H1-antihistaminic activity of novel thieno(2,3-d)pyrimidinones. International J. Pharm. Nano., 2008, 2, 136-143.
[19]
Gollapolle, L.; Priyadarshini, B.J.; Hanumanthappa, S. Synthesis and antihistaminic activity of 3H-benzo [4,5]thieno(2,3-d)[1,2,3]triazin-4-ones. Saudi Pharm. J., 2012, 20(1), 45-52.
[20]
Sharma, C.; Yerande, S.; Chavan, R.; Bhosale, A.V. Synthesis of thienopyrimidines and their antipsychotic activity. E-J. Chem., 2010, 7(2), 655-664.
[21]
Chambhare, R.V.; Khadse, B.G.; Bobde, A.S.; Bahekar, R.H. Synthesis and preliminary evaluation of some N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno [2,3-d]pyrimidin-3-yl]-carboxamide and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno [2,3-d]pyrimidin-4-ones as antimicrobial agents. Eur. J. Med. Chem., 2003, 38(1), 89-100.
[22]
Shetty, N.S.; Lamani, R.S.; Khazil, A.M. Synthesis and antimicrobial activity of some novel thienopyrimidines and triazolothienopyrimidines. J. Chem. Sci., 2009, 121(3), 301-307.
[23]
Haswani, N.G.; Bari, S.B. Synthesis and antimicrobial activity of novel 2(pyrimidin-2yl)thieno [2,3-d]pyrimidin-4(3H)-ones. Turk. J. Chem., 2011, 35(6), 915-924.
[24]
Prabhakar, V.; Babu, K.S.; Ravindranath, L.K. Design, synthesis, characterization and biological activity of thieno [2,3-d]pyrimidine derivatives. J. Adv. Chem. Sci., 2017, 5(1), 30-42.
[25]
Raju, V.S.; Raju, M.B.; Bahekar, R.H.; Rajan, K.S.; Rao, A.R. Synthesis and H1-antihistaminic evaluation of 3-(N,N-dialkylamino)alkyl derivatives of 2-phenyl-3,4-dihydroquinazolin-4(3H)-ones. Indian Drugs, 1999, 36, 759-761.
[26]
Singh, S.D.; Raju, M.B.; Bahekar, R.H.; Rajan, K.S.; Rao, A.R. Synthesis and H1-antihistaminic evaluation of 3-[(N,N-dialkylamino)alkyl]-6-halo-2-phenyl-3,4-dihydroquinazolin-4(3H)-ones. Indian J. Chem., 2001, 40B, 813-816.
[27]
Vogel, G.H.; Vogel, W.H. Drug discovery and evaluation, Pharmacological Assay, 2nd ed; Springer Verlay: Germany, 1997.
[28]
Armitage, A.K.; Boswood, J.; Large, B.J. Thioxanthines with potent brochodilator and coronary dilator properties. Br. J. Pharmacol. Chemother., 1961, 16, 59-76.
[29]
Vadnere, G.P.; Somani, R.S.; Singhai, A.K. Studies on antiasthmatic activity of aqueous extract of Clerodendron phlomidis. Pharmacol. Online, 2007, 1, 487-494.
[30]
Lambasiya, K.K.; Modi, V.R.; Tirgar, P.R. Evaluation of antihistaminic activity of dried whole plant extract of Leucas aspera using various experimental models. Int. J. Phycol., 2013, 3(3), 291-298.
[31]
Cruickshank, R.; Duguid, J.P.; Marmion, B.P.; Swain, R.H.A. The enterobacteriaceae: Salmonella, (12th Edition.); Medical Microbiology, 1975, Vol. 11, pp. 403-419.
[32]
Atta-ur-Rahman. Choudhary, M.I.; Thomson W.J. Bioassay Techniques for Drug Development; Harwood Academic Publishers: India, 2001.
[33]
Bharat, S.; Ram, A.S. Anti-Inflammatory and Antimicrobial Effects of Flavonoids from Heliotropium ellipticum Exudate. Curr. Bioact. Compd., 2016, 12, 123-131.
[34]
Rathore, H.S.; Mittal, S.; Kumar, S. Synthesis, characterization and antifungal activities of 3d-transition metal complexes of 1-acetylpiperazinyldithiocarbamate, M (acpdtc) 2. Pestic. Res. J., 2000, 12, 103-107.
[35]
Kamala, K.V.; Hemantkumar, D.I.; Sneha, R.S.; Jayesh, A.S.; Dhaivat, H.P.; Milee, A. 2-((1H-1,2,3-triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones: Design, Synthesis and Evaluation as Anti-cancer Agents. Curr. Bioact. Compd., 2017, 13, 1-10.
[36]
Kalpesh, P.; Dhaval, S.; Deepkumar, J. Antibacterial and Antifungal Screening of Novel α-amino Acid Conjugated Bile Acid Derivatives. Curr. Bioact. Compd., 2014, 10, 260-270.


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Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [63 - 70]
Pages: 8
DOI: 10.2174/1573407214666180226130957
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