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Drug Res (Stuttg) 2014; 64(01): 31-39
DOI: 10.1055/s-0033-1351315
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Pyrimidine-5-carbonitriles II[*]: Synthesis and Antimicrobial Activity of Novel 6-Alkyl-2,4-disubstituted pyrimidine-5-carbonitriles

E. S. Al-Abdullah
1   Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
A. A. Al-Turkistani
1   Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
O. A. Al-Deeb
1   Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
N. R. El-Brollosy
1   Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
,
E. E. Habib
2   Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Medinah, Saudi Arabia
,
A. A. El-Emam
1   Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
› Author Affiliations
Further Information

Publication History

received 17 May 2013

accepted 10 July 2013

Publication Date:
15 August 2013 (online)

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Abstract

New series of 6-alkyl-2,4-disubstituted pyrimidine-5-carbonitriles namely, 6-alkyl-2-thiouracil-5-carbonitriles 4c,d, 6-alkyl-2-arylmethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 5a–p, 6-alkyl-2-(2-methoxyethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 6a–d, 6-alkyl-2-benzyloxymethylsulfanyl-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 7a–c, 6-alkyl-2-(5-nitrofuran-2-ylmethylsulfanyl)-3,4-dihydro-4-oxopyrimidine-5-carbonitriles 8a–d, 6-alkyl-4-arylthio-2-(benzylsulfanyl)pyrimidine-5-carbonitriles 10a, b and 2-benzylsulfanyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-6-pentylpyrimidine-5-carbonitrile 11, were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 4d, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5 l, 5p, 7a, 7b, 7c, 8a, 8b, 8c, 8d and 11 ­displayed marked antibacterial activity particularly against the tested Gram-positive bacteria. Meanwhile, none of these compounds were proved to be active against Candida albicans.

Key words

synthesis - pyrimidines - dihydro-4-oxopyrimidines - antimicrobial activity

* Part I: See ref. [30].


 

  • References

  • 1 Ghoshal K, Jacob ST. An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochem Pharmacol 1997; 53: 1569-1575
    CrossrefPubMedSearch in Google Scholar
  • 2 Mai A, Perrone A, Nebbioso A et al. Novel uracil-based 2-aminoanilide and 2-aminoanilide-like derivatives: Histone deacetylase inhibition and in-cell activities. Bioorg Med Chem 2008; 18: 2530-2535
    CrossrefPubMedSearch in Google Scholar
  • 3 Al-Safarjalani ON, Zhou X, Rais RH et al. 5-(Phenylthio)acyclouridine: a powerful enhancer of oral uridine bioavailability: relevance to chemotherapy with 5-fluorouracil and other uridine rescue regimens. Cancer Chemother Pharmacol 2005; 55: 541-551
    CrossrefPubMedSearch in Google Scholar
  • 4 Sirisoma N, Kasibhatla S, Nguyen B et al. 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: 7761-7773
    CrossrefPubMedSearch in Google Scholar
  • 5 Klein RS, Lenzi M, Lim TH et al. Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase. Biochem Pharmacol 2001; 62: 1257-1263
    CrossrefPubMedSearch in Google Scholar
  • 6 Hopkins AL, Ren J, Esnouf RM et al. Complexes of HIV-1 reverse transcriptase with Inhibitors of the HEPT Series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J Med Chem 1996; 39: 1589-1600
    CrossrefPubMedSearch in Google Scholar
  • 7 Lu X, Chen Y, Guo Y et al. The design and synthesis of N-1-alkylated-5-aminoaryalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors. Bioorg Med Chem 2007; 15: 7399-7407
    CrossrefPubMedSearch in Google Scholar
  • 8 Artico M, Massa S, Mai A et al. 3,4-Dihydro-2-alkyloxy-6-benzyl-4-oxoypyrimidines (DABOs): a new class of specific inhibitors of human immunodeficiency virus type 1. Antiviral Chem Chemother 1993; 4: 361-368
    PubMedSearch in Google Scholar
  • 9 Mugnaini C, Manetti F, Esté JA et al. Synthesis and biological investigation of S-aryl-S-DABO derivatives as HIV-1 inhibitors. Bioorg Med Chem Lett 2006; 16: 3541-3544
    CrossrefPubMedSearch in Google Scholar
  • 10 Ragno R, Mai A, Sbardella S et al. Computer-aided design, synthesis, and anti-HIV-1 activity in vitro of 2-alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones as novel potent non-nucleoside reverse transcriptase inhibitors also active against the Y181C variant. J Med Chem 2004; 47: 928-934
    CrossrefPubMedSearch in Google Scholar
  • 11 Van Herrewege Y, Michiels J, Van Roey J et al. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother 2004; 48: 337-339
    CrossrefPubMedSearch in Google Scholar
  • 12 Goebel F, Yakovlev A, Pozniak AL et al. Short-term antiviral activity of TMC278 – a novel NNRTI-in treatment-native HIV-1-infected subjects. AIDS 2006; 20: 1721-1726
    CrossrefPubMedSearch in Google Scholar
  • 13 Qin H, Liu C, Guo Y et al. Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem 2010; 18: 3231-3237
    CrossrefPubMedSearch in Google Scholar
  • 14 Vingerhoets J, Azijn H, Fransen E et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 2005; 79: 12773-12782
    CrossrefPubMedSearch in Google Scholar
  • 15 Kumar R, Semaine W, Johar M et al. Effect of various pyrimidines possessing the 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] moiety, able to mimic natural 2‘-deoxyribose, on wild-type and mutant hepatitis B virus replication. J Med Chem 2006; 49: 3693-3700
    CrossrefPubMedSearch in Google Scholar
  • 16 Brunelle MN, Lucifora J, Neyts J et al. In vitro activity of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine against multidrug-resistant hepatitis B virus mutants. Antimicrob Agents Chemother 2007; 51: 2240-2243
    CrossrefPubMedSearch in Google Scholar
  • 17 Ding Y, Girardet JL, Smith KL et al. Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase. Bioorg Chem 2006; 34: 26-38
    CrossrefPubMedSearch in Google Scholar
  • 18 Gauni KK, Kohlhage H. In vitro and in vivo virostatic properties of alkylated pyrimidines against DNA and RNA viruses. Chemotherapy 1969; 14: 158-169
    CrossrefPubMedSearch in Google Scholar
  • 19 Cresswell RM, Mentha JW, Searman RL. Method of preparing 2,4-diamino-5-benzylpyrimidines. US Patent 1976; 3 956 327
    PubMedSearch in Google Scholar
  • 20 Brumfitt W, Hamilton-Miller JM. Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines. J Chemother 1993; 5: 465-946
    PubMedSearch in Google Scholar
  • 21 Amyes SG. Comparative antibacterial spectrum of trimethoprim and brodimoprim. J Chemother 1993; 5: 417-421
    PubMedSearch in Google Scholar
  • 22 Locher HH, Schlunegger H, Hartman PG et al. Antibacterial activities of epiroprim, a new dihydrofolate reductase inhibitor, alone and in combination with dapsone. Antimicrob Agents Chemother 1996; 40: 1376-1381
    PubMedSearch in Google Scholar
  • 23 Sincak CA. Iclaprim, a novel diaminopyrimidine for the treatment of resistant Gram-positive infections. Ann Pharmacother 2009; 43: 1107-1114
    CrossrefPubMedSearch in Google Scholar
  • 24 Tassel D, Madoff MA. Treatment of candida sepsis and cryptococcus meningitis with 5-fluorocytosine. A new antifungal agent. J Am Med Assoc 1968; 206: 830-832
    CrossrefPubMedSearch in Google Scholar
  • 25 Mai A, Rotili D, Massa S et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 26 Deshmukh MB, Salunkhe SM, Patil DR et al. A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-aryl pyrimidines and their antibacterial activity. Eur J Med Chem 2009; 44: 2651-2654
    CrossrefPubMedSearch in Google Scholar
  • 27 Agarwal N, Srivastava P, Raghuwanshi SK et al. Chloropyrimidines as a new class of antimicrobial agents. Bioorg Med Chem 2002; 10: 869-874
    CrossrefPubMedSearch in Google Scholar
  • 28 Agarwal N, Raghuwanshi SK, Upadhyay DN et al. Suitably functionalised pyrimidines as potential antimycotic agents. Bioorg Med Chem Lett 2000; 10: 703-706
    CrossrefPubMedSearch in Google Scholar
  • 29 Taher AT, Abou-Seri SM. Synthesis and bioactivity evaluation of new 6-aryl-5-cyano thiouracils as potential antimicrobial and anticancer agents. Molecules 2012; 17: 9868-9886
    CrossrefPubMedSearch in Google Scholar
  • 30 Al-Abdullah ES, Al-Obaid AM, Al-Deeb OA et al. Synthesis of novel 6-phenyl-2,4-disubstituted pyrimidine-5-carbonitriles as potential antimicrobial agents. Eur J Med Chem 2011; 46: 4642-4647
    CrossrefPubMedSearch in Google Scholar
  • 31 El-Brollosy NR, Al-Deeb OA, El-Emam AA et al. Synthesis of novel uracil non-nucleoside derivatives as potential reverse transcriptase inhibitors of HIV-1. Arch Pharm 2009; 342: 663-670
    CrossrefPubMedSearch in Google Scholar
  • 32 El-Brollosy NR, Al-Omar MA, Al-Deeb OA et al. Synthesis of novel uracil non-nucleosides analogues of 3,4-dihydro-2-alkylthio-6-benzyl-4-oxopyrimidines and 6-benzyl-1-ethoxymethyl-5-isopropyluracil. J Chem Res 2007; 263-267
    PubMedSearch in Google Scholar
  • 33 El-Emam AA, Massoud MA, El-Bendary ER et al. Synthesis of certain 6-substituted uracils and related derivatives as potential antiviral agents. Bull Kor Chem Soc 2004; 25: 991-996
    CrossrefPubMedSearch in Google Scholar
  • 34 El-Emam AA, Nasr MNA, Pedersen EB et al. Synthesis of certain 6-arylthio)uracils as potential antiviral agents. Phosphorus Sulfur Silicon 2001; 174: 25-35
    CrossrefPubMedSearch in Google Scholar
  • 35 El-Emam AA, Al-Deeb OA, Al-Turkistani AA et al. 2-Benzylsulfanyl-4-pentyl-6-(phenylsulfanyl)pyrimidine-5-carbonitrile. Acta Cryst 2011; E67: o3126
    PubMedSearch in Google Scholar
  • 36 El-Emam AA, Al-Deeb OA, El-Brollosy NR et al. 2-Benzylsulfanyl-6-[(4-methylphenyl)sulfanyl]-6-pentylpyrimidine-5-carbonitrile. Acta Cryst 2012; E68: o2054
    PubMedSearch in Google Scholar
  • 37 Kambe S, Saito K, Kishi H et al. A one-step synthesis of 4-oxo-2-thioxopyrimidine derivatives by ternary condensation of ethyl cyanoacetate, aldehydes, and thiourea. Synthesis 1979; 287-289
    Thieme ConnectPubMedSearch in Google Scholar
  • 38 Murray PR, Baron EJ, Pfaller MA et al. In: Wood GL, Washington JA. (eds.) Manual of Clinical Microbiology, Am Soc Microbiol. 1995. Washington DC:
    Search in Google Scholar
  • 39 Richards AW, Riss E, Kass EH et al. Nitrofurantoin: Clinical and laboratory studies in urinary tract infections. Arch Intern Med 1955; 96: 437-450
    CrossrefPubMedSearch in Google Scholar
  • 40 McCalla DR, Reuvers A, Kaiser C. Mode of action of nitrofurazone. J Bacteriol 1970; 104: 1126-1134
    PubMedSearch in Google Scholar
  • 41 National Committee for Clinical Laboratory Standards (NCCLS). Approved standard document M-7A. Villanova, PA 1985
    Search in Google Scholar