SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY OF PYRIMIDINE DERIVATIVES
Abstract
In the present work an easy access to a series of pyrimidines bearing a pyronyl side chain in the 4-position is described. These unreported compounds are obtained starting from commercially available dehydroacetic acid (DHA), aromatic aldehydes and S-benzylisothiouronium chloride (SBT). A series of compounds (3a-j) were prepared and tested for their antimicrobial activity. These synthesized compounds showed mild activity against gram +ve bacteria and very less activity against gram -ve bacteria. Compounds 3b, 3i, 3j showed mild activity against gram +ve Bacillus subtilis bacteria while against gram -ve Pseudomonas aeruginosa compound 3i showed minor activity.
Keywords:
Pyrimidine derivatives, Synthesis, Zone of inhibition,, Antimicrobial activityDOI
https://doi.org/10.25004/IJPSDR.2012.040306References
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14. Mai A, Rotili D, Massa S, Brosch G, Simonetti G, Passariello C, Palamara AT. Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans. Bioorg. Med. Chem. Lett. 2007; 17:1221-1225.
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16. Ingaral N, Saravanan G, Amutha P, Nagarajan S. Synthesis, in vitro antibacterial and antifungal evaluations of 2-amino-4-(1-naphthyl)-6-arylpyrimidines. Eur. J. Med. Chem. 2007; 42: 517-520.
17. McCarthy O, Musso-Buendia A, Kaiser M, Brun R, Ruiz-Perez LM, Johansson NG, Pacanowska DG, Gilbert IH. Design, Synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase. Eur. J. Med. Chem. 2009; 44:678-688.
18. Nguyen C, Ruda GF, Schipani A, Kasinathan G, Leal I, Musso-Buendia A, Kaiser M, Brun R, Ruiz-Pérez LM, Sahlberg BL, Johansson NG, González-Pacanowska D, Gilbert IH. Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. J. Med. Chem.2006; 49: 4183-4195.
19. McCarthy OK, Schipani A, Buendía AM, Ruiz-Perez LM, Kaiser M, Brun R, González-Pacanowska D, Gilbert IH. Design, synthesis and evaluation of novel uracil amino acid conjugates for the inhibition of Trypanosoma cruzi dUTPase. Bioorg. Med. Chem. Lett. 2006; 16: 3809-3812.
20. Suryawanshi SN, Bhat BA, Pandey S, Chandra N, Gupta S. Chemotherapy of leishmaniasis. Part VII: synthesis and bioevaluation of substituted terpenyl pyrimidines. Eur. J. Med. Chem. 2007; 42: 1211-1217.
21. Singh BK, Mishra M, Saxena N, Yadav GP, Maulik PR, Sahoo MK, Gaur RL, Murthy PK, Tripathi RP. Synthesis of 2-sulfanyl-6-methyl-1, 4-dihydropyrimidines as a new class of antifilarial agents. Eur. J. Med. Chem. 2008; 43:2717-2723.
22. Amin KM, Awadalla FM, Eissa AAM, Abou-Seri SM, Hassan GS. Design, synthesis and vasorelaxant evaluation of novel coumarin–pyrimidine hybrids. Bioorg. and Med. Chem. 2011; 19:6087-6097.
23. Alam O, Khan SA, Siddiqui N, Ahsan W, Verma SP, Gilani SJ. Antihypertensive activity of newer 1, 4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation. Eur. J. Med. Chem. 2010; 45:5113-5119.
24. Rahaman SA, Pasad YR , Kumar P , Kumar B. Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharmaceutical Journal.2009; 17: 255-258.
25. Da S. Falcao EP, De Melo SJ, Srivastava RM, De A.Catanho MTJ, Nascimento SCD. Synthesis and anti-inflammatory activity of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines. Eur. J. Med. Chem. 2006; 41:276-282.
26. Isobe Y, Tobe M, Inoue Y, Isobe M, Tsuchiya M, Hayashi H. Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Bioorg. Med. Chem. 2003; 11:4933-4940.
27. Brunton LL, Lazo JS, Parker KL, Goodman LS, Gilman A. Goodman & Gilman’s Pharmacological Basis of Therapeutics. McGraw-Hill, 2005.
28. Gillespie RJ, Bamford SJ, Clay A, Gaur S, Haymes T, Jackson PS, Jordan AM, Klenke B, Leonardi S, Liu J, Mansell HL, Ng S, Saadi M, Simmonite H, Stratton GC, Todd RS, Williamson DS, Yule IA. Antagonists of the human A (2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides. Bioorg. Med. Chem. 2009; 17:6590-6605.
29. Siddiqui AA, Rajesh R, Islam MU, Alagarsamy V, De Clercq E. Synthesis, Antiviral, Antituberculostic, and Antibacterial Activities of Some Novel, 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-(substituted imino)pyrimidines. Arch. Pharm. Chem. Life Sci. 2007; 340:95-102.
30. Dodson RM, Seyler JK. The reaction of amidines with α, β-unsaturated ketones. J. Org. Chem. 1951; 16 (3): 461-465.
2. Sirisoma N, Kasibthala S, Nguyen B, Pervin A, Wang Y, Claassen G, Tseng B, Drewe J, Cai SX. Discovery of substituted 4-anilino-2-(2-pyridyl) pyrimidines as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. Part 1: structure-activity relationships of the 4-anilino group. Bioorg. Med. Chem. 2006; 14(23): 7761-7773.
3. Xie F, Zhao HB, Zhao L, Luo L, Hu Y. Synthesis and biological evaluation of novel 2, 4, 5-substituted pyrimidine derivatives for anticancer activity. Bioorg. Med. Chem. Lett. 2009; 19:275-278.
4. Kamal A, Dastagiri D, Ramaiah MJ, Reddy JS, Bharathi EV, Reddy MK, Prem Sagar MV, Reddy TL, Pushpavalli S.N.C.V.L., Bhandra M. Synthesis and Apoptosis Inducing Ability of New Anilino-Substituted Pyrimidine Sulfonamides as Potential Anticancer agents. Eur. J. Med.Chem. 2011; 46:5817-5824.
5. Pontikis R, Benhida R, Aubertin AH, Grieson DS, Monneret C. Synthesis and anti-HIV activity of novel N-1 side chain-modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). J. Med. Chem. 1997; 40:1845-1854.
6. Lu X, Chen Y, Guo Y, Liu Z, Shi Y, Xu Y, Wang X, Zhang Z, Liu J. The design and synthesis of N-1-alkylated-5-aminoarylalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors. Bioorg. Med.Chem. 2007; 15:7399-7407.
7. Das K, Clark Jr. AD, Lewi PJ, Heeres J, de Jonge MR, Koymans LMH, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Béthune MP, Boyer PL, Clark P, Hughes SH, Janssen PAJ, Arnold E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 2004; 47(10):2550-2560.
8. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M, Ferrara M, Fiore F, Gardelli C, Paz OG, Hazuda DJ, Jones P, Kinzel O, Laufer R, Monteagudo E, Muraglia E, Nizi E, Orvieto F, Pace P, Pescatore G, Scarpelli R, Stillmock K, Witmer MV, Rowley M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 2008; 51:5843-5855.
9. Tagat JR, McCombie SW, Nazareno D, Labroli MA, Xiao Y, Steensa RW, Strizki JM, Baroudy BM, Cox K, Lachowicz J, Varty G, Watkins R. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4, 6-dimethyl-5-pyrimidinyl) carbonyl] - 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl) phenyl] ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist. J. Med. Chem. 2004; 47: 2405-2408.
10. Huckova D, Holy A, Masojidkova M, Andrei G, Snoeck R, De Clercq E, Balzarini J, Synthesis and antiviral activity of 2,4-diamino-5-cyano-6-[2-(phosphonomethoxy) ethoxy] pyrimidine and related compounds, Bioorg. Med. Chem. 2004; 12(12): 3197-3202.
11. Deshmukh MB, Salunkhe SM, Patil DR, Anbhule PV. A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-arylpyrimidines and their anti bacterial activity. Eur. J. Med. Chem. 2009; 44: 2651–2654.
12. Roth B, Strelitz JZ, Rauckman BS. 2, 4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 2. C-Alkylation of pyrimidines with Mannich bases and application to the synthesis of trimethoprim and analogs. J. Med. Chem. 1980; 23(3): 379-384.
13. Chandrashekaran S, Nagarajan S. Microwave-assisted synthesis and anti-bacterial activity of some 2-Amino-6-aryl-4-(2-thienyl) pyrimidines. IL Farmaco. 2005; 60:279-282.
14. Mai A, Rotili D, Massa S, Brosch G, Simonetti G, Passariello C, Palamara AT. Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans. Bioorg. Med. Chem. Lett. 2007; 17:1221-1225.
15. Gholap AR, Toti KS, Shirazi F, Deshpande MV, Srinivasan KV. Efficient Synthesis of Antifungal Pyrimidines via Palladium Catalyzed Suzuki/Sonogashira Cross-Coupling Reaction from Biginelli 3, 4-Dihydropyrimidin-2(1H)-ones. Tetrahedron 2008; 64:10214-10223.
16. Ingaral N, Saravanan G, Amutha P, Nagarajan S. Synthesis, in vitro antibacterial and antifungal evaluations of 2-amino-4-(1-naphthyl)-6-arylpyrimidines. Eur. J. Med. Chem. 2007; 42: 517-520.
17. McCarthy O, Musso-Buendia A, Kaiser M, Brun R, Ruiz-Perez LM, Johansson NG, Pacanowska DG, Gilbert IH. Design, Synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase. Eur. J. Med. Chem. 2009; 44:678-688.
18. Nguyen C, Ruda GF, Schipani A, Kasinathan G, Leal I, Musso-Buendia A, Kaiser M, Brun R, Ruiz-Pérez LM, Sahlberg BL, Johansson NG, González-Pacanowska D, Gilbert IH. Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase. J. Med. Chem.2006; 49: 4183-4195.
19. McCarthy OK, Schipani A, Buendía AM, Ruiz-Perez LM, Kaiser M, Brun R, González-Pacanowska D, Gilbert IH. Design, synthesis and evaluation of novel uracil amino acid conjugates for the inhibition of Trypanosoma cruzi dUTPase. Bioorg. Med. Chem. Lett. 2006; 16: 3809-3812.
20. Suryawanshi SN, Bhat BA, Pandey S, Chandra N, Gupta S. Chemotherapy of leishmaniasis. Part VII: synthesis and bioevaluation of substituted terpenyl pyrimidines. Eur. J. Med. Chem. 2007; 42: 1211-1217.
21. Singh BK, Mishra M, Saxena N, Yadav GP, Maulik PR, Sahoo MK, Gaur RL, Murthy PK, Tripathi RP. Synthesis of 2-sulfanyl-6-methyl-1, 4-dihydropyrimidines as a new class of antifilarial agents. Eur. J. Med. Chem. 2008; 43:2717-2723.
22. Amin KM, Awadalla FM, Eissa AAM, Abou-Seri SM, Hassan GS. Design, synthesis and vasorelaxant evaluation of novel coumarin–pyrimidine hybrids. Bioorg. and Med. Chem. 2011; 19:6087-6097.
23. Alam O, Khan SA, Siddiqui N, Ahsan W, Verma SP, Gilani SJ. Antihypertensive activity of newer 1, 4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation. Eur. J. Med. Chem. 2010; 45:5113-5119.
24. Rahaman SA, Pasad YR , Kumar P , Kumar B. Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharmaceutical Journal.2009; 17: 255-258.
25. Da S. Falcao EP, De Melo SJ, Srivastava RM, De A.Catanho MTJ, Nascimento SCD. Synthesis and anti-inflammatory activity of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines. Eur. J. Med. Chem. 2006; 41:276-282.
26. Isobe Y, Tobe M, Inoue Y, Isobe M, Tsuchiya M, Hayashi H. Structure and activity relationships of novel uracil derivatives as topical anti-inflammatory agents. Bioorg. Med. Chem. 2003; 11:4933-4940.
27. Brunton LL, Lazo JS, Parker KL, Goodman LS, Gilman A. Goodman & Gilman’s Pharmacological Basis of Therapeutics. McGraw-Hill, 2005.
28. Gillespie RJ, Bamford SJ, Clay A, Gaur S, Haymes T, Jackson PS, Jordan AM, Klenke B, Leonardi S, Liu J, Mansell HL, Ng S, Saadi M, Simmonite H, Stratton GC, Todd RS, Williamson DS, Yule IA. Antagonists of the human A (2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides. Bioorg. Med. Chem. 2009; 17:6590-6605.
29. Siddiqui AA, Rajesh R, Islam MU, Alagarsamy V, De Clercq E. Synthesis, Antiviral, Antituberculostic, and Antibacterial Activities of Some Novel, 4-(4-substituted phenyl)-6-(4-nitrophenyl)-2-(substituted imino)pyrimidines. Arch. Pharm. Chem. Life Sci. 2007; 340:95-102.
30. Dodson RM, Seyler JK. The reaction of amidines with α, β-unsaturated ketones. J. Org. Chem. 1951; 16 (3): 461-465.
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01-07-2012
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“SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY OF PYRIMIDINE DERIVATIVES”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 4, no. 3, July 2012, pp. 199-04, https://doi.org/10.25004/IJPSDR.2012.040306.
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“SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY OF PYRIMIDINE DERIVATIVES”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 4, no. 3, July 2012, pp. 199-04, https://doi.org/10.25004/IJPSDR.2012.040306.
