Synthesis and antibacterial evaluation of new azo-pyrimidine derivatives

Mohamed A. Abdelgawad

doi:10.7324/JAPS.2019.S102

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Abstract

The synthesis of potent antibacterial agents, free from side effects and resistant to bacterial enzymes, is the main objective for drug designers. Also, the multi-target drugs have an important role in advanced drug synthesis. The azo-malonate compounds II a & b were prepared from the diazo coupling reaction of aniline derivatives with the acidic methylene group of diethyl malonate. The new azo-malonate derivatives II a–c were reacted with urea or thiourea in the presence of sodium ethoxide, afforded the target new azo-pyrimidine compounds III a & b and IV a & b. The structure of the new compounds was elucidated by using NMR, IR, mass spectroscopy, and elemental analysis. The minimum inhibitory concentration of new azo-compounds III a & b and IV a & b was evaluated for their antibacterial activity. Two new synthesized azo-compounds showed weak (III b) to strong (IV b) antibacterial activity. The molecular operating environment docking program was used for the prediction of the compound IV b action mechanism.

Keyword: Antibacterial pyrimidine diethyl malonate pyrimidinone.

Citation:

Abdelgawad MA. Synthesis and antibacterial evaluation of new azo-pyrimidine derivatives. J Appl Pharm Sci, 2019; 9(S1):009–016.

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

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Abdelgawad MA, Labib MB, Ali WAM, Kamel G, Azouz AA, EL-Nahass ES. Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: histopathological and docking studies. Bioorg Chem, 2018; 78:103–14. https://doi.org/10.1016/j.bioorg.2018.03.011
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Bansal S, Bala M, Suthar SK, Choudhary S, Bhattacharya S, Bhardwaj V, Singla S, Joseph A. Design and synthesis of novel 2-phenyl-5-(1,3- diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity. Eur J Med Chem, 2014; 80:167–74. https://doi.org/10.1016/j.ejmech.2014.04.045
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Gadhaveb A, Gaikar R, Kuchekar S, Karale B. Synthesis and antimicrobial evaluations of some novel fluorinated chromones and pyrazoles. Indian J Chem, 2015; 54(3):383–90.
Kalluraya B, Isloor AM, Frank PV, Jagadeesha RL. Synthesis and pharmacological activity of 4-(substituted)-2-[4-aryl-hydrazono-3- methyl-5-oxo-2-pyrazolin-1-yl]-thiazoles. Indian J Heterocycl Chem, 2004; 13(3):245–8.
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Saundane AR, Verma VA, Vijaykumar K. Synthesis of some new indolo[2,3-c] isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities. Med Chem Res, 2013; 22:3787–93. https://doi.org/10.1007/s00044-012-0366-6
Sayed HH, Hashem AI, Yousif NM, El-Sayed WA. Conversion of 3-Arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity. Arch Pharm Chem Life Sci, 2007; 340:315–9. https://doi.org/10.1002/ardp.200700043
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Riyadh SM, Farghaly TA, Abdallah MA, Abdalla MM, Abd El-Aziz MR. New pyrazoles incorporating pyrazolylpyrazole moiety: Synthesis, anti-HCV and antitumor activity. Eur J Med Chem, 2010; 45:1042–50. https://doi.org/10.1016/j.ejmech.2009.11.050
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Vinita S, Nitin C, Ajay KA. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem, 2014; ID 202784:1–32.
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Abd-El Gawad NM, Georgey HH, Ibrahim NA, Amin NH, Abdelsalam RM. Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents. Arch Pharm Res, 2012; 35(5):807–21. https://doi.org/10.1007/s12272-012-0507-y

Abdelgawad MA, Bakr RB, Omar HA. Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents. Bioorg Chem, 2017; 74:82–90. https://doi.org/10.1016/j.bioorg.2017.07.007

Abdelgawad MA, Labib MB, Ali WAM, Kamel G, Azouz AA, EL-Nahass ES. Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: histopathological and docking studies. Bioorg Chem, 2018; 78:103–14. https://doi.org/10.1016/j.bioorg.2018.03.011

Awadallah FM, Piazza GA, Gary BD, Keeton AB, Canzoneri JC. Synthesis of some dihydropyrimidine-based compounds bearing pyrazoline moiety and evaluation of their antiproliferative activity. Eur J Med Chem, 2013; 70:273–9. https://doi.org/10.1016/j.ejmech.2013.10.003

Bakulev VA, Berseneva VS, Belskaia NP, Morzherin YY, Zaitsev A, Dehaen W, Luytenb I, Toppet S. Reactions of 5-mercaptoazoles and pyridine-2-thiones with acetylenic esters. Selectivity of the formation of novel fused thiazin-4-ones and thiazolidin-4-ones. Org Biomol Chem, 2003; 1:134–9. https://doi.org/10.1039/b207854f

Bansal S, Bala M, Suthar SK, Choudhary S, Bhattacharya S, Bhardwaj V, Singla S, Joseph A. Design and synthesis of novel 2-phenyl-5-(1,3- diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity. Eur J Med Chem, 2014; 80:167–74. https://doi.org/10.1016/j.ejmech.2014.04.045

Belal A, Abdelgawad MA. New benzothiazole/benzoxazole-pyrazole hybrids with potential as COX inhibitors: design, synthesis and anticancer activity evaluation. Res Chem Intermediat, 2017; 43 (7):3859–72. https://doi.org/10.1007/s11164-016-2851-x

Cheng CC, Roth B. Recent progress in the medicinal chemistry of 2,4-diaminopyrimidines. Prog Med Chem 1982; 19:269–331. https://doi.org/10.1016/S0079-6468(08)70332-1

Etman HA, Sadek MG, Khalil AGM. Synthesis of some new heterocycles derived from 3-amino-5hydrazinopyrazole dihydrochloride. Res J Pharm Biol Chem Sci, 2015; 6(2):247–54.

Gadhaveb A, Gaikar R, Kuchekar S, Karale B. Synthesis and antimicrobial evaluations of some novel fluorinated chromones and pyrazoles. Indian J Chem, 2015; 54(3):383–90.

Kalluraya B, Isloor AM, Frank PV, Jagadeesha RL. Synthesis and pharmacological activity of 4-(substituted)-2-[4-aryl-hydrazono-3- methyl-5-oxo-2-pyrazolin-1-yl]-thiazoles. Indian J Heterocycl Chem, 2004; 13(3):245–8.

Koca M, Servi S, Kirilmis C, Ahmedazade M, Kazaz C, Özbek B, Ötük G. Synthesis and antimicrobial activity of (benzofuran-2-yl) (3-phenyl-3-methylcyclobutyl) ketoxime derivatives. Eur J Med Chem, 2005; 40:1351–8. https://doi.org/10.1016/j.ejmech.2005.07.004

Mallikarjunaswamya C, Malleshab L, Bhadregowda DG, Pintoa O. Studies on synthesis of pyrimidine derivatives and their antimicrobial activity. Arab J Chem, 2017; 10(Supplement 1):S484–90. https://doi.org/10.1016/j.arabjc.2012.10.008

Mandha SR, Siliveri S, Alla M, Bommena VR, Bommineni MR, Balasubramanian S. Eco-friendly synthesis and biological evaluation of substituted pyrano[2,3-c]pyrazoles. Bioorg Med Chem Lett, 2012; 22:5272–8. https://doi.org/10.1016/j.bmcl.2012.06.055

Rahmi K, Metin B, Seckin B, Arslan BG. Synthesis, characterization and antiglaucoma activity of some novel pyrazole derivatives of 5-amino-1,3,4-thiadiazole-2-sulfonamide. Eur J Med Chem, 2010; 45:4769–73. https://doi.org/10.1016/j.ejmech.2010.07.041

Sader HS, Flamm RK, Jones RN. Antimicrobial activity of daptomycin tested against Gram-positive pathogens collected in Europe, Latin America, and selected countries in the Asia-Pacific Region. Diagn Microbiol Infect Dis, 2013; 75:417–22. https://doi.org/10.1016/j.diagmicrobio.2013.01.001

Saundane AR, Verma VA, Vijaykumar K. Synthesis of some new indolo[2,3-c] isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities. Med Chem Res, 2013; 22:3787–93. https://doi.org/10.1007/s00044-012-0366-6

Sayed HH, Hashem AI, Yousif NM, El-Sayed WA. Conversion of 3-Arylazo-5-phenyl-2(3H)-furanones into other heterocycles of anticipated biological activity. Arch Pharm Chem Life Sci, 2007; 340:315–9. https://doi.org/10.1002/ardp.200700043

Schneider P, Hawser S, Islam K. Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. Bioorg Med Chem Lett, 2003; 13(23):4217–21. https://doi.org/10.1016/j.bmcl.2003.07.023

Riyadh SM, Farghaly TA, Abdallah MA, Abdalla MM, Abd El-Aziz MR. New pyrazoles incorporating pyrazolylpyrazole moiety: Synthesis, anti-HCV and antitumor activity. Eur J Med Chem, 2010; 45:1042–50. https://doi.org/10.1016/j.ejmech.2009.11.050

Tarek, N, Hassan HM, AbdelGhani SM, Radwan IA, Hammouda O, El-Gendy AO. Comparative chemical and antimicrobial study of nine essential oils obtained from medicinal plants growing in Egypt. Beni-Suef Univ J Basic Appl Sci, 2014; 3:149–56. https://doi.org/10.1016/j.bjbas.2014.05.009

Vinita S, Nitin C, Ajay KA. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem, 2014; ID 202784:1–32.

Zaini E, Sumirtapura YC, Halim A, Fitriani L, Soewandhi SN. Formation and characterization of sulfamethoxazole-trimethoprim cocrystal by milling process. J Appl Pharm Sci, 2017; 7(12):169–73.