Hexahydro-1,2,3-triazine Derivatives: Synthesis, Antimicrobial Evaluation, Antibiofilm Activity and Study of Molecular Docking Against Glucosamine-6-Phosphate

Nabel Bunyan Ayrim; Fadhel Rukhis Hafedh; Yasir Mohamed Kadhim; Abduljabbar Sabah Hussein; Ahmed Mutanabbi Abdula; Ghosoun Lafta Mohsen; Mohammed Mahdi Sami

doi:10.22146/ijc.85521

Hexahydro-1,2,3-triazine Derivatives: Synthesis, Antimicrobial Evaluation, Antibiofilm Activity and Study of Molecular Docking Against Glucosamine-6-Phosphate

https://doi.org/10.22146/ijc.85521

Nabel Bunyan Ayrim^(1*), Fadhel Rukhis Hafedh⁽²⁾, Yasir Mohamed Kadhim⁽³⁾, Abduljabbar Sabah Hussein⁽⁴⁾, Ahmed Mutanabbi Abdula⁽⁵⁾, Ghosoun Lafta Mohsen⁽⁶⁾, Mohammed Mahdi Sami⁽⁷⁾

(1) Department of Chemistry, College of Science, Mustansiriyah University, Baghdad 10052, Iraq
(2) Department of Chemistry, College of Science, Mustansiriyah University, Baghdad 10052, Iraq
(3) Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Nahrain University, Baghdad 10072, Iraq
(4) Department of Chemistry, College of Science, Mustansiriyah University, Baghdad 10052, Iraq
(5) Department of Chemistry, College of Science, Mustansiriyah University, Baghdad 10052, Iraq
(6) Department of Chemistry, College of Science, Al-Nahrain University, Baghdad 10072, Iraq
(7) Department of Remote Sensing and Geophysics, College of Science, Alkarkh University, Baghdad 10011, Iraq
(*) Corresponding Author

Abstract

The N,N',N''-trisubstituted hexahydro-1,3,5-triazine derivatives (3a–g) had been created and identified through infrared, nuclear magnetic resonance, and mass spectrometry according to their symmetric basic structure. Three molecules of diverse aromatic amines and three molecules of formaldehyde were assembled in a "1+1+1+1+1+1" condensation reaction to produce hexahydrotriazines. Two Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis) and two Gram-negative (Klebsiella pneumonia, Pseudomonas aeruginosa) bacteria were used to evaluate the antimicrobial activity of the produced compounds. The anti-biofilm activity of 3g against S. aureus was also examined. In this investigation, glucosamine-6-phosphate synthase was employed to investigate the binding affinity of 3g within the enzyme's binding site. The results demonstrated that most of the synthesized hexahydro-1,3,5-triazine compounds have mild antimicrobial effects in comparison with the commonly used drug ampicillin, whereas the compounds 3g are potentially anti-biofilm agents. Molecular docking with the Autodock 4.2 tool was applied to study the binding affinity. It was found to hit (3g) in the active center of glucosamine-6-phosphate synthase as the target enzyme for antimicrobial agents. In silico studies reveal that the discovered hit is a promising glucosamine-6-phosphate inhibitor, as well as that the docking data matched up to the in vitro assay.

Keywords

1,3,5-hexahydrotriazines; antimicrobial; antibiofilm; docking study

Full Text:

Full Text PDF

References

[1] Venkatesan, N., Perumal, G., and Doble, M., 2015, Bacterial resistance in biofilm-associated bacteria, Future Microbiol., 10 (11), 1743–1750.

[2] Nandakumar, V., Chittaranjan, S., Kurian, V.M., and Doble, M., 2013, Characteristics of bacterial biofilm associated with implant material in clinical practice, Polym. J., 45 (2), 137–152.

[3] Puligundla, P., and Mok, C., 2017, Potential applications of nonthermal plasmas against biofilm‐associated micro‐organisms in vitro, J. Appl. Microbiol., 122 (5), 1134–1148.

[4] Miquel, S., Lagrafeuille, R., Souweine, B., and Forestier, C., 2016, Anti-biofilm activity as a health issue, Front. Microbiol., 7, 592.

[5] Cheng, B., Zhang, X., Zhai, S., He, Y., Tao, Q., Li, H., Wei, J., Sun, H., Wang, T., and Zhai, H., 2020, Synthesis of 1,2,3,4‐tetrahydrobenzofuro[3,2‐d]pyrimidines via [4+2] annulation reaction of 1,3,5‐triazinanes and aurone‐derived α,β‐unsaturated imines, Adv. Synth. Catal., 362 (18), 3836–3840.

[6] Chauhan, D.S., Quraishi, M.A., Wan Nik, W.B., and Srivastava, V., 2020, Triazines as a potential class of corrosion inhibitors: Present scenario, challenges and future perspectives, J. Mol. Liq., 321, 114747.

[7] Singh, S., Manda, M.K., Masih, A., Saha, A., Ghosh, S.K., Bhat, H.R., and Singh, U.P., 2021, 1,3,5-Triazine: A versatile pharmacophore with diverse biological activities, Arch. Pharm., 354 (6), 2000363.

[8] Bae, S.M., Kang, S.Y., and Song, J.H., 2021, Synthesis and cytotoxic activity of hexahydro‐1,3,5‐triazine derivatives through ring condensation, Bull. Korean. Chem. Soc., 42 (6), 840–846.

[9] Qin, Y.G., Yang, Z.K., Fan, J., Jiang, X., Yang, X.L., and Chen, J.L., 2020, Synthesis, crystal structure and bioactivities of N-(5-(4-chlorobenzyl)-1,3,5-triazinan-2-ylidene)nitramide, Crystals, 10 (4), 245.

[10] Elmorsy, M.R., Abdel-Latif, E., Gaffer, H.E., Mahmoud, S.E., and Fadda, A.A., 2023, Anticancer evaluation and molecular docking of new pyridopyrazolo‑triazine and pyridopyrazolo‑triazole derivatives, Sci. Rep., 13 (1), 2782.

[11] Mena, L., Billamboz, M., Charlet, R., Desprès, B., Sendid, B., Ghinet, A., and Jawhara, S., 2022, Two new compounds containing pyridinone or triazine heterocycles have antifungal properties against Candida albicans, Antibiotics, 11 (1), 72.

[12] Al-Sabagh, A.M., Kandile, N.G., Nasser, N.M., Mishrif, M.R., and El-Tabey, A.E., 2013, Novel surfactants incorporated with 1,3,5-triethanolhexahydro-1,3,5-triazine moiety as corrosion inhibitors for carbon steel in hydrochloric acid: Electrochemical and quantum chemical investigations, Egypt. J. Pet., 22 (3), 351–365.

[13] Liu, H., Long, S., Rakesh, K.P., and Zha, G.F., 2020, Structure-activity relationships (SAR) of triazine derivatives: Promising antimicrobial agents, Eur. J. Med. Chem., 185, 111804.

[14] Dandia, A., Saini, P., Kumar, K., Sethi, M., Rathore, K.S., Meena, M.L., and Parewa, V., 2021, Synergetic effect of functionalized graphitic carbon nitride catalyst and ultrasound in aqueous medium: An efficient and sustainable synthesis of 1,3,5-trisubstituted hexahydro-1,3,5-triazines, Curr. Res. Green Sustainable Chem., 4, 100170.

[15] Sujayev, A., Taslimi, P., Kaya, R., Safarov, B., Aliyeva, L., Farzaliyev, V., and Gulcin, I., 2019, Synthesis, characterization and biological evaluation of N‐substituted triazinane‐2‐thiones and theoretical–experimental mechanism of condensation reaction, Appl. Organomet. Chem., 34 (2), e5329.

[16] Pham, T.X., Pham, M.T., Cao, H.T., Nguyen, B.N., Nguyen, Q.H., and Trang, B.T., 2021, Study on the synthesis of 1,3,5-triazinane derivatives on copper-ferrite nanoparticles catalyst, IOP Conf. Ser.: Earth Environ. Sci., 947 (1), 012028.

[17] Shah, D.R., Modh, R.P., and Chikhalia, K.H., 2014, Privileged s-triazines: Structure and pharmacological applications, Future Med. Chem., 6 (4), 463–477.

[18] Chmara, H., Andruszkiewicz, R., and Borowski, E., 1984, Inactivation of glucosamine-6-phosphate synthetase from Salmonella typhimurium LT 2 SL 1027 by N^β-fumarylcarboxyamido-L-2,3-diaminopropionic acid, Biochem. Biophys. Res. Commun., 120 (3), 865–872.

[19] Borowski, E., 2000, Novel approaches in the rational design of antifungal agents of low toxicity, Farmaco, 55 (3), 206–208.

[20] Bearne, S.L., and Blouin, C., 2000, Inhibition of Escherichia coli glucosamine-6-phosphate synthase by reactive intermediate analogues: The role of the 2-amino function in catalysis, J. Biol. Chem., 275 (1), 135–140.

[21] You, S., Ma, S., Dai, J., Jia, Z., Liu, X., and Zhu, J., 2017, Hexahydro-s-triazine: A trial for acid-degradable epoxy resins with high performance, ACS Sustainable Chem. Eng., 5 (6), 4683–4689.

[22] Kayarmar, R., Nagaraja, G.K., Naik, P., Manjunatha, H., Revanasiddappa, B.C., and Arulmoli, T., 2014, Synthesis and characterization of novel imidazoquinoline based 2-azetidinones as potent antimicrobial and anticancer agents, J. Saudi Chem. Soc., 21, S434–S444.

[23] Ayrim, N.B., Balakit, A.A., and Lafta, S.J., 2022, Synthesis, characterization, molecular docking and biological activity studies of hydrazones with 3,4,5-trimethoxyphenyl moiety, Egypt. J. Chem., 65 (6), 159–169.

[24] Rambabu, N., Ram, B., Dubey, P.K., Vasudha, B., and Balram, B., 2017, Synthesis and biological activity of novel (E)-N’-(substituted)-3,4,5-trimethoxybenzohydrazide analogs, Orient. J. Chem., 33 (1), 226–234.

[25] Matiadis, D., Karagiaouri, M., Mavroidi, B., Nowak, K., Katsipis, G., Pelecanou, M., Pantazaki, A., and Sagnou, M., 2020, Synthesis and antimicrobial evaluation of a pyrazoline-pyridine silver(I) complex: DNA-interaction and anti-biofilm activity, BioMetals, 34 (1), 67–85.

[26] Tomi, I.H.R., Al-Daraji, A.H.R., Abdula, A.M., and Al-Marjani, M.F., 2016, Synthesis, antimicrobial, and docking study of three novel 2,4,5-triarylimidazole derivatives, J. Saudi Chem. Soc., 20, S509–S516.

[27] Ismail, A.H., Abdula, A.M., Tomi, I.H.R., Al-Daraji, A.H.R., and Baqi, Y., 2021, Synthesis, antimicrobial, evaluation and docking study of novel 3,5-disubstituted-2-isoxazoline and 1,3,5-trisubstituted-2-pyrazoline derivatives, Med. Chem., 17 (5), 462–473.

[28] Ferhati, A., Malki, S., Bouchemma, A., Lefrada, L., Mazzouz, W., and Bouhenguel, M., 2019, Synthesis, characterization and antimicrobial activity of a new 1,3-bis(4-fluorophenyl)-5-butyl-1,3,5-triazacyclohexane, J. New Technol. Mater., 9 (2), 17–21.

[29] Gondru, R., Kanugala, S., Raj, S., Ganesh Kumar, C., Pasupuleti, M., Banothu, J., and Bavantula, R., 2021, 1,2,3-Triazole-thiazole hybrids: Synthesis, in vitro antimicrobial activity and antibiofilm studies, Bioorg. Med. Chem. Lett., 33, 127746.

[30] Schilcher, K., Andreoni, F., Dengler Haunreiter, V., Seidl, K., Hasse, B., and Zinkernagel, A.S., 2016, Modulation of Staphylococcus aureus biofilm matrix by subinhibitory concentrations of clindamycin, Antimicrob. Agents Chemother., 60 (10), 5957–5967.

[31] Shang, W., Rao, Y., Zheng, Y., Yang, Y., Hu, Q., Hu, Z., Yuan, J., Peng, H., Xiong, K., Tan, L., Li, S., Zhu, J., Li, M., Hu, X., Mao, X., and Rao, X., 2019, β-Lactam antibiotics enhance the pathogenicity of methicillin-resistant Staphylococcus aureus via SarA-controlled lipoprotein-like cluster expression, MBio, 10 (3), 00880–19.

[32] More, P.G., Karale, N.N., Lawand, A.S., Narang, N., and Patil, R.H., 2013, Synthesis and anti-biofilm activity of thiazole Schiff bases, Med. Chem. Res., 23 (2), 790–799.

DOI: https://doi.org/10.22146/ijc.85521