Abstract
Herein, the biological activities including antibacterial, antifungal, and in-vitro cytotoxicity for some novel substituted pyrazolo[3,4-d]pyrimidinone, benzylidene dihydropyrimidine, pyrano[2,3-d]pyrimidine, hexahydropyrimido[4, 5-d]pyrimidinone, tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile, and pyrido[2, 3-d:6,5-d'] dipyrimidinone derivatives were investigated. The synthesized novel compounds were achieved through the incorporation of the active moieties such as halo compound, pyrazolo, pyrano, pyrimido, pyrido-derivatives with active methylene group in thiobarbituric acid derivatives at C-5. Structures of all synthesized compounds were characterized by spectral techniques including IR, 1H-NMR, MS, and 13C-NMR. All synthesized compounds were screened for their antibacterial and antifungal activity, while the most promising compounds were selected to investigate their in-vitro cytotoxic efficacy against normal Vero cells and cancerous Caco-2 cells. Data showed that the biological activities were concentration-dependent. All novel pyrimidine derivatives exhibited broad-spectrum antimicrobial activity with a varied zone of inhibition ranging between 11.3 ± 0.6 and 25.3 ± 0.6 mm. The MIC values are different according to a pathogenic organism (ranging between 3.91 and 500 µg mL−1), whereas the MBC/MFC were 2 × to 4 × MIC value. Data of in-vitro cytotoxicity confirm the efficiency of selected novel pyrimidine derivatives to target Caco-2 cancerous cells at low concentrations more Vero normal cells. Four selected compounds 4, 7b, 10, and 12 displayed IC50 values of 286.73 ± 4.54, 138.07 ± 8.21, 332.48 ± 18.75, and 241.18 ± 15.60 µg mL−1, respectively, for normal Vero cell line, whereas it was 271.55 ± 3.68, 65.94 ± 2.36, 121.16 ± 4.96, and 82.28 ± 4.08 µg mL−1, respectively, for Caco-2 cancerous cell line.
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References
G.M. Reddy, J.R. Garcia, G.V. Zyryanov, G. Sravya, N.B. Reddy, Bioorg. Chem. 82, 324 (2019)
E.F. El-Belely, M.M.S. Farag, H.A. Said, A.S. Amin, E. Azab, A.A. Gobouri, A. Fouda, Nanomaterials (Basel, Switzerland) 11, 95 (2021)
Y. Bi, X.X. Liu, H.Y. Zhang, X. Yang, Z.Y. Liu, J. Lu, P.J. Lewis, C.Z. Wang, J.Y. Xu, Q.G. Meng, C. Ma, C.S. Yuan, Molecules (Basel, Switzerland) 22 (2017).
A. Fouda, M.A. Awad, A.M. Eid, E. Saied, M.G. Barghoth, M.F. Hamza, M.F. Awad, S. Abdelbary, S.E. Hassan, Int. J. Mol. Sci. 22, 5096 (2021)
G. Wirnsberger, F. Zwolanek, T. Asaoka, I. Kozieradzki, L. Tortola, R.A. Wimmer, A. Kavirayani, F. Fresser, G. Baier, W.Y. Langdon, F. Ikeda, K. Kuchler, J.M. Penninger, Nat. Med. 22, 915 (2016)
D.W. Denning, M.J. Bromley, Science 347, 1414 (2015)
A.M. Soliman, W. Abdel-Latif, I.H. Shehata, A. Fouda, A.M. Abdo, Y.M. Ahmed, Biol. Trace Element Res. 199, 800 (2021)
U.M. Kocyigit, Y. Budak, M.B. Gürdere, F. Ertürk, B. Yencilek, P. Taslimi, İ Gülçin, M. Ceylan, Arch. Physiol. Biochem. 124, 61 (2018)
S. Kumar, S.M. Lim, K. Ramasamy, M. Vasudevan, S.A.A. Shah, M. Selvaraj, B. Narasimhan, Chem Cent J 11, 89 (2017)
J. O'Neill (2016). https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf
N. Kerru, S. Maddila, S.B. Jonnalagadda, Curr. Org. Chem. 23, 3154 (2019)
D. Zárate-Zárate, R. Aguilar, R.I. Hernández-Benitez, E.M. Labarrios, F. Delgado, J. Tamariz, Tetrahedron 71, 6961 (2015)
T.V. Sravanthi, S.L. Manju, Eur. J. Pharm. Sci. 91, 1 (2016)
A. De, S. Sarkar, A. Majee, Chem. Heterocycl. Compd. 57, 410 (2021)
M.A. Abu-Zaied, S.F. Hammad, F.T. Halaweish, G.H. Elgemeie, ACS Omega 5, 14645 (2020)
M. Albratty, K.A. El-Sharkawy, H.A. Alhazmi, Acta Pharm 69, 261 (2019)
K.P. Cheremnykh, V.A. Savelyev, M.A. Pokrovskii, D.S. Baev, T.G. Tolstikova, A.G. Pokrovskii, E.E. Shults, Med. Chem. Res. 28, 545 (2019)
N. Kahriman, V. Serdaroğlu, K. Peker, A. Aydın, A. Usta, S. Fandaklı, N. Yaylı, Bioorg. Chem. 83, 580 (2019)
S.B. Bari, N.G. Haswani, J. Saudi Chem. Soc. 21, S264 (2017)
N. Singh, S.K. Pandey, N. Anand, R. Dwivedi, S. Singh, S.K. Sinha, V. Chaturvedi, N. Jaiswal, A.K. Srivastava, P. Shah, M.I. Siddiqui, R.P. Tripathi, Bioorg. Med. Chem. Lett. 21, 4404 (2011)
B. Kumar, M. Kumar, A.R. Dwivedi, V. Kumar, ChemMedChem 13, 705 (2018)
S. de Castro, O. Familiar, G. Andrei, R. Snoeck, J. Balzarini, M.-J. Camarasa, S. Velázquez, ChemMedChem 6, 686 (2011)
S.S. Undare, N.J. Valekar, A.A. Patravale, D.K. Jamale, S.S. Vibhute, L.S. Walekar, G.B. Kolekar, M.B. Deshmukh, P.V. Anbhule, Res. Chem. Intermed. 42, 4373 (2016)
A.R. Bhat, R.S. Dongre, F.A. Almalki, M. Berredjem, M. Aissaoui, R. Touzani, T.B. Hadda, M.S. Akhter, Bioorg. Chem. 106, 104480 (2021)
C. Valgas, S.M. Souza, E.F. Smânia, A. Smânia Jr., Brazil. J. Microbiol. 38, 369 (2007)
A. Fouda, S.E. Hassan, A.M. Abdo, M.S. El-Gamal, Biol. Trace Element Res. 195, 707 (2020)
P. Wayne, CLSI 2008A 28, 6 (2008)
Clinical, L. S. Institute, CLSI, M07-A9, 32, 2 (2012)
X.-Q. Bai, C.-S. Li, M.-Y. Cui, Z.-W. Song, X.-Y. Zhou, C. Zhang, Y. Zhao, T.-Y. Zhang, T.-Y. Jiang, Mol. Divers. 24, 1165 (2020)
A. Fouda, S. El-Din Hassan, S.S. Salem, T.I. Shaheen, Microb. Pathog. 125, 252 (2018)
J. Wang, H. Liu, J. Zhao, H. Gao, L. Zhou, Z. Liu, Y. Chen, P. Sui, Mol. Basel Switz. 15, 5807 (2010)
K.S. Caiaffa, L. Massunari, M. Danelon, G.F. Abuna, T.B.L. Bedran, N.A. Santos-Filho, D.M.P. Spolidorio, N.L. Vizoto, E.M. Cilli, C. Duque, Biofouling 33, 807 (2017)
T.I. Shaheen, A. Fouda, S.S. Salem, Ind. Eng. Chem. Res. 60, 1553 (2021)
H.M. Aly, R.H. Taha, N.M. El-Deeb, A. Alshehri, Inorg. Chem. Front. 5, 454 (2018)
H.M. Aly, M.M. Kamal, Eur. J. Med. Chem. 47, 18 (2012)
H.M. Aly, N.M. Saleh, Int. J. Adv. Res. 2, 694 (2014)
R. Gallo, C. Roussel, U. Berg, Adv. Heterocycl. Chem. 43, 173 (1988)
V. Ahluwalia, P. Bhagat, R. Aggarwal, R. Chandra, I.K. International Pvt, Ltd, Delhi, 376 (2005)
P. Rathee, R. Tonk, A. Dalal, M. Ruhil, A. Kumar, Cell. Mol. Biol 62, 4172 (2016)
J.A. Bikker, J. Kubanek, D.F. Weaver, Epilepsia 35, 411 (1994)
P.R. Andrews, L.C. Mark, D.A. Winkler, G.P. Jones, J. Med. Chem. 26, 1223 (1983)
N.M. Saleh, M.G. El-Gazzar, H.M. Aly, R.A. Othman, Front Chem 7, 917 (2019)
H.M. Aly, J. Iran. Chem. Soc. 13, 999 (2016)
P.B. Oshiro, P.S. da Silva Gomes Lima, M.L. de Menezes, L.C. da Silva-Filho, Tetrahedron Lett. 56, 4476 (2015)
N. Sudhapriya, P.T. Perumal, C. Balachandran, S. Ignacimuthu, M. Sangeetha, M. Doble, Eur. J. Med. Chem. 83, 190 (2014)
H.M. Aly, N.M. Saleh, H.A. Elhady, Eur. J. Med. Chem. 46, 4566 (2011)
H.A. Elhady, H.M. Aly, N.M. Saleh, Int. J. Adv. Res. 2, 806 (2014)
H.M. Aly, Monatshefte für Chem. Chem. Mon 142, 935 (2011)
A.R. Renslo, R.L. Danheiser, J. Org. Chem. 63, 7840 (1998)
S. Saraç, M. Yarim, M. Ertan, S. Boydağ, K. Erol, Pharmazie 53, 91 (1998)
E.M. AbedelRehim, M. AbdEllatif, J. Heterocycl. Chem. 55, 419 (2018)
C. Kurumurthy, P. Sambasiva Rao, B. Veera Swamy, G. Santhosh Kumar, P. Shanthan Rao, B. Narsaiah, L.R. Velatooru, R. Pamanji, J. Venkateswara Rao, Eur. J. Med. Chem. 46, 3462 (2011)
V.J. Ram, D.A. Vanden Berghe, A.J. Vlietinck, J. Heterocycl. Chem. 25, 217 (1988)
J.R. Piper, G.S. McCaleb, J.A. Montgomery, R.L. Kisliuk, Y. Gaumont, F.M. Sirotnak, J. Med. Chem. 29, 1080 (1986)
H. Madkour, M.A. Salem, T. Abdel-Rahman, M.E. Azab, Heterocycles 38, 57 (1994)
E.A. Motaal, M. Salem, M. Helal, M. El-Gaby, Oriental J. Chem. 31(2015), 875 (2015)
M. El-Gaby, S. Abdel-Gawad, M. Ghorab, H. Heiba, H. Aly, Phosphorus, Sulfur Silicon Relat. Elem. 181, 279 (2006)
R. Samson, J. Houbraken, R. Summerbell, B. Flannigan, J. Miller, Microorganisms in Home and Indoor Work Environments 287 (2001)
J. Berman, P.E. Sudbery, Nat. Rev. Genet. 3, 918 (2002)
M.F. Hamza, A. Fouda, K.Z. Elwakeel, Y. Wei, E. Guibal, N.A. Hamad, Molecules (Basel, Switzerland) 26 (2021)
N. Kahriman, K. Peker, V. Serdaroğlu, A. Aydın, A. Usta, S. Fandaklı, N. Yaylı, Bioorg. Chem. 99, 103805 (2020)
S.S. Salem, A. Fouda, Biol. Trace Elem. Res. 199, 344 (2021)
B. Veeraswamy, D. Madhu, G. Jitender Dev, Y. Poornachandra, G. Shravan Kumar, C. Ganesh Kumar, B. Narsaiah, Bioorg. Med. Chem. Lett. 28, 1670 (2018)
I. Lashin, A. Fouda, A.A. Gobouri, E. Azab, Z.M. Mohammedsaleh, R.R. Makharita, Biomolecules 11 (2021)
S.E. Hassan, A. Fouda, A.A. Radwan, S.S. Salem, M.G. Barghoth, M.A. Awad, A.M. Abdo, M.S. El-Gamal, J. Biol. Inorg. Chem. JBIC Publ. Soc. Biol. Inorg. Chem. 24, 377 (2019)
Y.A. Ammar, A.A. Farag, A.M. Ali, S.A. Hessein, A.A. Askar, E.A. Fayed, D.M. Elsisi, A. Ragab, Bioorg. Chem. 99, 103841 (2020)
G.M. Reddy, J.R. Garcia, G. Yuvaraja, M. Venkata Subbaiah, J.-C. Wen, J Heterocycl Chem 57, 2288 (2020)
A.M. Eid, A. Fouda, G. Niedbała, S.E. Hassan, S.S. Salem, A.M. Abdo, H.F. Hetta, T.I. Shaheen, Antibiotics 9 (2020)
R. Zein, I. Alghoraibi, C. Soukkarieh, A. Salman, A. Alahmad, Heliyon 6, e04594 (2020)
S.S. Salem. E.F. El-Belely. G. Niedbała. M.M. Alnoman. S.E. Hassan. A.M. Eid. T.I. Shaheen. A. Elkelish, A. Fouda, Nanomaterials (Basel, Switzerland) 10 (2020)
A. Fouda. G. Abdel-Maksoud. H.A. Saad. A.A. Gobouri. Z.M. Mohammedsaleh, M. Abdel-Haleem El-Sadany, Catalysts 11 (2021).
S. Sheikhi-Mohammareh, A. Shiri, E.H. Maleki, M.M. Matin, H. Beyzaei, P. Baranipour, F. Oroojalian, T. Memariani, ChemistrySelect 5, 10060 (2020)
E.H. Maleki, A.R. Bahrami, H. Sadeghian, M.M. Matin, Toxicol. Vitro Int. J. Publ. Assoc. BIBRA 63, 104745 (2020)
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Abd-Elaziz, A.M., Aly, H.M., Saleh, N.M. et al. Synthesis and characterization of the novel pyrimidine’s derivatives, as a promising tool for antimicrobial agent and in-vitro cytotoxicity. J IRAN CHEM SOC 19, 2279–2296 (2022). https://doi.org/10.1007/s13738-021-02448-w
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DOI: https://doi.org/10.1007/s13738-021-02448-w