DESIGN, In silico Modeling, Toxicity study and Synthesis of Novel Substituted Semicarbazide Derivatives of Pyrimidine: An Antitubercular Agent

Author(s): Jithendar R. Mandhadi*, Theivendren Panneerselvam, Pavadai Parasuraman

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 3 , 2020

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Graphical Abstract:


Abstract:

Background: A series of 1-(2-(2-amino-5-carbamoyl-6-(1-(substitutedphenyl) prop-1-enyl) pyrimidin-4-yloxy)acetyl) semicarbazide (4a-i) derivatives was synthesized from substituted aromatic aldehydes, ethyl cyanoacetate and guanidine hydrochloride and characterized by analytical and spectral data, FTIR, 1H-NMR and Mass spectroscopy data.

Methods: The antiTB action of the synthesized compounds was screened in comparison with the standard drug Rifampicin using MABA assay method. The SAR of substituted aromatic aldehydes with modification at ortho, meta and para positions with electron withdrawing group.

Result: The compounds 1-(2-(2-amino-5- carbamoyl-6-(1-(2-fluorophenyl) prop-1-enyl) pyrimidin-4- yloxy) acetyl) semicarbazide and 1-(2-(2-amino- 5-carbamoyl-6-(1-(3-chlorophenyl) prop-1-enyl) pyrimidin-4-yloxy) acetyl) semicarbazide showed equal MIC values against Mycobacterium tuberculosis H37Ra with the value of 3.90μg/ml.

Conclusion: The SAR study revealed that the antiTB activity of the synthesized compounds were affected by lipophilicity of the substituent.

Keywords: Pyrimidine, Molecular docking, antiTB activity, SAR, Rifampicin, calcium channel blockers.

[1]
Sharma, P.; Rane, N.; Gurram, V.K. Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorg. Med. Chem. Lett., 2004, 14(16), 4185-4190.
[http://dx.doi.org/10.1016/j.bmcl.2004.06.014] [PMID: 15261267]
[2]
Prakash, O.; Bhardwaj, V.; Kumar, R.; Tyagi, P.; Aneja, K.R. Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents. Eur. J. Med. Chem., 2004, 39(12), 1073-1077.
[http://dx.doi.org/10.1016/j.ejmech.2004.06.011] [PMID: 15571869]
[3]
Botta, M.; Artico, M.; Massa, S. Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives. Eur. J. Med. Chem., 1992, 27(3), 251-257.
[http://dx.doi.org/10.1016/0223-5234(92)90009-P]
[4]
Agarwal, N.; Srivastava, P.; Raghuwanshi, S.K.; Upadhyay, D.N.; Sinha, S.; Shukla, P.K.; Ji Ram, V. Chloropyrimidines as a new class of antimicrobial agents. Bioorg. Med. Chem., 2002, 10(4), 869-874.
[http://dx.doi.org/10.1016/S0968-0896(01)00374-1] [PMID: 11836092]
[5]
Roth, B.; Rauckman, B.S. 2,4-Diamino-5-(1,2,3,4-tetrahydro-(substituted or unsubsti-tuted)-6-quinolylmethyl)-pyrimidines, useful as antimicrobi-als U.S. Patent 4, 587, 341, 1986.
[6]
Marquais-Bienewald, S.; Holzol, W.; Preuss, A.; Mehlin, A. Use of substituted 2,4-bis (alkylamino) pyrimidines U.S. Patent, 0188453 A1 2006.
[7]
Daluge, S.M.; Skonezny, P.; Roth, B.; Raukman, B.S. 2,4-Diamino-5-(substituted) pyrimidine, useful as antimicro-bials U.S. Patent 4, 590, 271 1986.
[8]
Ito, S.; Masuda, K.; Kusano, S. Pyrimidine derivative, process for preparing same and agri-cultural or horticultural fungicidal composition containing same U.S. Patent 4, 988, 704, 1991.
[9]
Nakagawa, Y.; Bobrov, S.; Semer, C.R.; Kucharek, T.A.; Harmoto, M. Fungicidal pyrimidine derivatives U.S. Patent 6, 818, 631 B1, 2004.
[10]
Agarwal, N.; Raghuwanshi, S.K.; Upadhyay, D.N.; Shukla, P.K.; Ram, V.J. Suitably functionalised pyrimidines as potential antimycotic agents. Bioorg. Med. Chem. Lett., 2000, 10(8), 703-706.
[http://dx.doi.org/10.1016/S0960-894X(00)00091-3] [PMID: 10782668]
[11]
Basavaraja, H.S.; Sreenivasa, G.M.; Jayachandran, E. Synthesis and biological activity of novel pyrimidino imidazolines. Indian J. Heterocycl. Chem., 2009, 15, 69.
[12]
Ram, V.J.; Haque, N.; Guru, P.Y. Chemotherapeutic agents XXV: synthesis and leishmanicidal activity of carbazolylpyrimidines. Eur. J. Med. Chem., 1992, 27(8), 851-855.
[http://dx.doi.org/10.1016/0223-5234(92)90121-G]
[13]
Amir, M.; Javed, S.A.; Kumar, H. Pyrimidine as anti-inflammatory agent: a review. Indian J. Pharm. Sci., 2007, 68, 337.
[http://dx.doi.org/10.4103/0250-474X.34540]
[14]
Sondhi, S.M.; Jain, S.; Dwivedi, A.D.; Shukla, R.; Raghubir, R. Synthesis of condensed pyrimidines and their evaluation for anti-inflammatory and analgesic activities. Indian Journal of Chemistry B., 2008, 47(1), 136-143.
[15]
Vega, S.; Alonso, J.; Diaz, J.A.; Junquera, F. Synthesis of 3-substituted-4-phenyl-2-thioxo-1,2,3,4,5,6,7,8-octahydrobenzo[4,5]thieno[2,3-d]pyrimidines. J. Heterocycl. Chem., 1990, 27(2), 269-273.
[http://dx.doi.org/10.1002/jhet.5570270229]
[16]
Hannah, D.R.; Stevens, M.F.G. Structural studies on bioactive compounds-part 38.1: reactions of 5-aminoimidazole-4-carboxamide: synthesis of imidazo[1,5-a]quinazoline-3-carboxamides. Journal of Chemical Research S., 2003, 7, 398-401.
[http://dx.doi.org/10.3184/030823403103174533]
[17]
Rana, K.; Kaur, B.; Kumar, B. Synthesis and anti-hypertensive activity of some dihydropyrimidines. Indian Journal of Chemistry B., 2004, 43(7), 1553-1557.
[18]
Smith, P.A.S.; Kan, R.O. Cyclization of isothiocyanates as a route to phthalic and homophthalic acid derivatives. J. Org. Chem., 1964, 29(8), 2261-2265.
[http://dx.doi.org/10.1021/jo01031a037]
[19]
Balzarini, J.; McGuigan, C. Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication. J. Antimicrob. Chemother., 2002, 50(1), 5-9.
[http://dx.doi.org/10.1093/jac/dkf037] [PMID: 12096000]
[20]
Von Borstel, R.W. Treatment of chemotherapeutic agent and antiviral agent tox-icity with acylated pyrimidine nucleosides U.S. Patent 6, 2002, 344(447 B2)
[21]
Storer, R.; Moussa, A.; La Colla, P.; Artico, M. Oxo-pyrimidine compounds U.S. Patent, 0014774 A1, 2005.
[22]
Lee, H.W.; Kim, B.Y.; Ahn, J.B.; Kang, S.K.; Lee, J.H.; Shin, J.S.; Ahn, S.K.; Lee, S.J.; Yoon, S.S. Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione. Eur. J. Med. Chem., 2005, 40(9), 862-874.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.019] [PMID: 15908051]
[23]
Juby, P.F.; Hudyma, T.W.; Brown, M.; Essery, J.M.; Partyka, R.A. Antiallergy agents. 1. 1,6-Dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acids and esters. J. Med. Chem., 1979, 22(3), 263-269.
[http://dx.doi.org/10.1021/jm00189a009] [PMID: 423208]
[24]
Gupta, A.K. Sanjay, Kayath, H.P.; Singh, A.; Sharma, G.; Mishra, K.C. Anticonvulsant activity of pyrimidine thiols. Indian J. Pharmacol., 1994, 26(3), 227-228.
[25]
Abu-Hashem, A.A.; Youssef, M.M.; Hussein, H.A.R. Synthesis, antioxidant, antituomer activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J. Chin. Chem. Soc. (Taipei), 2011, 58(1), 41-48.
[http://dx.doi.org/10.1002/jccs.201190056]
[26]
Abu-Hashem, A.A.; El-Shehry, M.F.; Badria, F.A. Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm., 2010, 60(3), 311-323.
[http://dx.doi.org/10.2478/v10007-010-0027-6] [PMID: 21134865]
[27]
Rahaman, S.A.; Rajendra Pasad, Y.; Kumar, P.; Kumar, B. Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharm. J., 2009, 17(3), 255-258.
[http://dx.doi.org/10.1016/j.jsps.2009.08.001] [PMID: 23964169]
[28]
Nezu, Y.; Miyazaki, M.; Sugiyama, K.; Kajiwara, I. Dimethoxypyrimidine as novel herbicides-part 1: synthesis and herbicidal activity of dimethoxyphenoxyphenoxypyrimidines and analogues. Pestic. Sci., 1996, 47, 103-113.
[http://dx.doi.org/10.1002/(SICI)1096-9063(199606)47:2<103:AID-PS396>3.0.CO;2-Z]
[29]
Coe, J.W.; Fliri, A.F.J.; Kaneko, T.; Larson, E.R. Pyrimidine derivatives enhancing antitumour activity U.S. Patent 5, 491, 234, 1996.
[30]
Breault, G.A.; Newcombe, N.J.; Thomas, A.P. Imidazolo-5-YL-2-anilino-pyrimidines as agents for the inhi-bition of the cell proliferation U.S. Patent 6, 969, 714 B2, 2005.
[31]
Xie, F.; Zhao, H.; Zhao, L.; Lou, L.; Hu, Y. Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity. Bioorg. Med. Chem. Lett., 2009, 19(1), 275-278.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.067] [PMID: 19028425]
[32]
Kaldrikyan, M.A.; Grigoryan, L.A.; Geboyan, V.A.; Arsenyan, F.G.; Stepanyan, G.M.; Garibdzhanyan, B.T. Synthesis and antitumor activity of some disubstituted 5-(3-methyl-4-alkoxybenzyl)pyrimidines. Pharm. Chem. J., 2000, 34(10), 521-524.
[http://dx.doi.org/10.1023/A:1010398911988]
[33]
Rodrigues, A.L.S.; Rosa, J.M.; Gadotti, V.M.; Goulart, E.C.; Santos, M.M.; Silva, A.V.; Sehnem, B.; Rosa, L.S.; Gonçalves, R.M.; Corrêa, R.; Santos, A.R. Antidepressant-like and antinociceptive-like actions of 4-(4′-chlorophenyl)-6-(4′'-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice. Pharmacol. Biochem. Behav., 2005, 82(1), 156-162.
[http://dx.doi.org/10.1016/j.pbb.2005.08.003] [PMID: 16153700]
[34]
Tani, J.; Yamada, Y.; Oine, T.; Ochiai, T.; Ishida, R.; Inoue, I. Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fluoromethyl)-3-aryl-4(3H)-quinazolinone derivatives. J. Med. Chem., 1979, 22(1), 95-99.
[http://dx.doi.org/10.1021/jm00187a021] [PMID: 423189]
[35]
Kumar, B.; Kaur, B.; Kaur, J.; Parmar, A.; Anand, R.D.; Kumar, H. Thermal/microwave assisted synthesis of substituted tetrahydropyrimidines as potent calcium channel blockers. Indian Journal of Chemistry B., 2002, 41(7), 1526-1530.
[http://dx.doi.org/10.1002/chin.200243181]
[36]
Parasuraman, P.; Suresh, R.; Premnath, D. Searching antiviral drugs for ebola virus from phytoconstituents of Azadirachta indica: Application of molecular modeling studies. Int. J. Pharm. Pharm. Sci., 2014, 6, 571-574.
[37]
Perumal, P.; Pandey, V.P.; Parasuraman, P. Docking studies on antimicrobial peptides related to apidaecinǧia and human histatin against glutamine synthetase and RNA polymerase in mycobacterium tuberculosis. Asian J Pharm Clin Res., 2014, 7(5), 195-200.
[38]
Choi, T.A.; Czerwonka, R.; Fröhner, W.; Krahl, M.P.; Reddy, K.R.; Franzblau, S.G.; Knölker, H.J. Synthesis and activity of carbazole derivatives against Mycobacterium tuberculosis. ChemMedChem, 2006, 1(8), 812-815.
[http://dx.doi.org/10.1002/cmdc.200600002] [PMID: 16902934]
[39]
Saravanan, G.; Selvam, T.P.; Alagarsamy, V.; Kunjiappan, S.; Joshi, SD.; Indhumathy, M.; Kumar, P.D. Graph theoretical analysis, in silico modeling, synthesis, anti-microbial and anti-TB evaluation of novel quinoxaline derivatives. Drug Research,, 2018 May;, 68(05), 250-62.


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VOLUME: 16
ISSUE: 3
Year: 2020
Page: [294 - 301]
Pages: 8
DOI: 10.2174/1573407214666181001112601
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