An efficient approach for the synthesis, characterization, and antifungal studies of chlorantraniliprole carboxamide derivatives

Vikas Kumar  Tyagi; Ajay Kumar; Bhawana Bhatt; Sanjana Tewari

doi:10.18011/bioeng.2025.v19.1304

Authors

Vikas Kumar Tyagi Department of Chemistry, School of Sciences, IFTM University, Moradabad, India, 244001 https://orcid.org/0009-0004-5598-0218
Ajay Kumar Department of Chemistry, School of Applied and Life Sciences, Uttaranchal University, Dehradun 248007, Uttarakhand, India https://orcid.org/0000-0002-6045-7526
Bhawana Bhatt Department of Pharmacognosy, School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Dehradun-248001, Uttarakhand, India https://orcid.org/0000-0002-2202-6952
Sanjana Tewari Department of Chemistry, School of Sciences, IFTM University, Moradabad, India, 244001 https://orcid.org/0000-0003-3923-8801

DOI:

https://doi.org/10.18011/bioeng.2025.v19.1304

Keywords:

1-Hydroxybenzotriazole, Antifungal Activity, Carboxamide Derivatives, Mild Reaction, Substituted Amines

Abstract

The structural modification of established agrochemical scaffolds remains a powerful strategy for developing next-generation fungicidal agents with enhanced efficacy and safety. In this study, an efficient and mild peptide-coupling approach was developed for the synthesis of a new series of chlorantraniliprole (CTPR)-based carboxamide derivatives (1a–1j). The protocol employs a 1-hydroxybenzotriazole/1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (HOBt/EDC·HCl)-mediated amide bond formation between 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and a diverse set of aromatic, aliphatic, and cyclic amines under ambient conditions, affording the target compounds in good to excellent yields (65.33–93.68%). The method is operationally simple, reproducible, and avoids harsh reagents or elevated temperatures. Structural elucidation of the synthesized compounds was accomplished using ¹H NMR, FTIR, and ESI–MS analyses. The antifungal potential of all derivatives was evaluated in vitro against five major phytopathogenic fungi, such as Alternaria, Fusarium, Rhizoctonia, Helminthosporium, and Aspergillus, using the poisoned food technique, with hexaconazole as the reference fungicide. The biological results revealed a strong dependence of antifungal activity on amine substitution. Compounds bearing short-chain aliphatic or heterocyclic amines exhibited markedly superior activity compared to aromatic analogues. In particular, derivatives 1c, 1h, 1i, and 1j demonstrated broad-spectrum antifungal efficacy, frequently outperforming hexaconazole and, in some cases, achieving complete growth inhibition at higher concentrations. Structure-activity relationship (SAR) analysis indicated that smaller open-chain amines and polar heterocyclic substituents significantly enhance antifungal performance, likely due to improved hydrophobic and hydrogen-bonding interactions with fungal targets. Overall, this work presents a practical synthetic route to CTPR-based carboxamides and identifies several promising lead compounds for the development of novel, effective, and potentially eco-friendly fungicidal agents.

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References

Albeiicio, F., Chinchilla, R., Dodsworth, D. J., & Najera, C. (2001). New trends in peptide coupling reagents. Organic Preparations and Procedures International, 33(3), 203–303. https://doi.org/10.1080/00304940109356592 DOI: https://doi.org/10.1080/00304940109356592

Bentley, K. S., Fletcher, J. L., & Woodward, M. D. (2010). Chlorantraniliprole: An insecticide of the anthranilic diamide class. In R. Krieger (Ed.), Hayes’ handbook of pesticide toxicology (pp. 2231–2242). https://doi.org/10.1016/B978-0-12-374367-1.00102-6 DOI: https://doi.org/10.1016/B978-0-12-374367-1.00102-6

Busto, E., Gotor-Fernández, V., & Gotor, V. (2011). Hydrolases in the stereoselective synthesis of N-heterocyclic amines and amino acid derivatives. Chemical Reviews, 111(7), 3998–4035. https://doi.org/10.1021/cr100287w DOI: https://doi.org/10.1021/cr100287w

Chan, L. C., & Cox, B. G. (2007). Kinetics of amide formation through carbodiimide/N-hydroxybenzotriazole (HOBt) couplings. The Journal of Organic Chemistry, 72(23), 8863–8869.https://doi.org/10.1021/jo701558y DOI: https://doi.org/10.1021/jo701558y

Chauhan, S., Yadav, L. B., Kushwaha, K. P. S., & Chitara, M. K. (2020). Potential of botanicals and biocontrol agents against Rhizoctonia solani Kühn incitant of web blight disease of mung bean: An in vitro evaluation. International Journal of Current Microbiology and Applied Sciences, 9(6), 2627–2636. https://doi.org/10.20546/ijcmas.2020.906.319 DOI: https://doi.org/10.20546/ijcmas.2020.906.319

Chen, K., Liu, Q., Ni, J. P., Zhu, H. J., Li, Y. F., & Wang, Q. (2015). Synthesis, insecticidal activities and structure–activity relationship studies of novel anthranilic diamides containing pyridylpyrazole‐4‐carboxamide. Pest Management Science, 71(11), 1503–1512. https://doi.org/10.1002/ps.3954 DOI: https://doi.org/10.1002/ps.3954

Du, J., & Fu, Y. (2023). Diamide insecticides targeting insect ryanodine receptors: Mechanism and application prospect. Biochemical and Biophysical Research Communications, 670, 19–26. https://doi.org/10.1016/j.bbrc.2023.05.107 DOI: https://doi.org/10.1016/j.bbrc.2023.05.107

Fahmy, A. F. M., Rizk, S. A., Hemdan, M. M., El-Sayed, A. A., & Hassaballah, A. I. (2018). Efficient green synthesis and computational chemical study of some interesting heterocyclic derivatives as insecticidal agents. Journal of Heterocyclic Chemistry, 55(11), 2545–2555. https://doi.org/10.1002/jhet.3308 DOI: https://doi.org/10.1002/jhet.3308

Gudmestad, N. C., Arabiat, S., Miller, J. S., & Pasche, J. S. (2013). Prevalence and impact of SDHI fungicide resistance in Alternaria solani. Plant Disease, 97(7), 952–960. https://doi.org/10.1094/PDIS-12-12-1176-RE DOI: https://doi.org/10.1094/PDIS-12-12-1176-RE

Kaddah, M. M., Fahmi, A. A., Kamel, M. M., Rizk, S. A., & Ramadan, S. K. (2023). Rodenticidal activity of some quinoline-based heterocycles derived from hydrazide–hydrazone derivative. Polycyclic Aromatic Compounds, 43(5), 4231–4241. https://doi.org/10.1080/10406638.2022.2088576 DOI: https://doi.org/10.1080/10406638.2022.2088576

Kumar, A., Arya, S., Chandra, S., Kotnala, S., & Goswami, A. (2025). Synthesis and herbicidal evaluation of N-cinnamoyl-N-substituted hydroxylamine and its derivatives. Revista Brasileira de Engenharia de Biossistemas, 19. https://doi.org/10.18011/bioeng.2025.v19.1282 DOI: https://doi.org/10.18011/bioeng.2025.v19.1282

Kumar, A., Masroor, S., Kaya, S., Katin, K. P., Berisha, A., Khan, M. E., ... Zakri, W. (2025). Synthesis of sustainable heterocyclic aryl sulfonamide derivatives: Computational studies, molecular docking, and antibacterial assessment. Macromolecular Research, 33(3), 331–344. https://doi.org/10.1007/s13233-024-00335-w DOI: https://doi.org/10.1007/s13233-024-00335-w

Kumar, A., Masroor, S., Khan, M. E., Ali, S. K., Khamaj, A., & Zakri, W. (2025). Eco-friendly synthesis of benzoxazole-substituted chromene containing benzene sulfonamide derivatives: Antibacterial activity and molecular docking. Journal of Molecular Structure, 143429. https://doi.org/10.1016/j.molstruc.2025.143429 DOI: https://doi.org/10.1016/j.molstruc.2025.143429

Kumar, A., Prakash, O., Juyal, V. K., & Kasana, V. (2021). Diversity-oriented green synthesis of novel benzoxazole clubbed chromene arylsulfonamide derivatives using reusable catalyst. Pharma Innovation Journal, 10, 695–700. https://doi.org/10.22271/tpi.2021.v10.i1j.5606 DOI: https://doi.org/10.22271/tpi.2021.v10.i1j.5606

Lamberth, C., & Dinges, J. (2012). The significance of heterocycles for pharmaceuticals and agrochemicals. In C. Lamberth & J. Dinges (Eds.), Bioactive heterocyclic compound classes: Agrochemicals, 1–20. DOI: 10.1002/9783527664412 DOI: https://doi.org/10.1002/9783527664412.ch1

Main, E. R. G., Xiong, Y., Cocco, M. J., D’Andrea, L., & Regan, L. (2003). Design of stable α-helical arrays from an idealized TPR motif. Structure, 11(5), 497–508. DOI: 10.1016/S0969-2126(03)00076-5 DOI: https://doi.org/10.1016/S0969-2126(03)00076-5

Marchán, V., & Grandas, A. (2007). Synthesis of peptide-oligonucleotide conjugates by Diels–Alder cycloaddition in water. Current Protocols in Nucleic Acid Chemistry, 31(1), 4.32.1–4.32.17. https://doi.org/10.1002/0471142700.nc0432s31 DOI: https://doi.org/10.1002/0471142700.nc0432s31

Nozaki, S. (2006). Delay of coupling caused by excess additives. Journal of Peptide Science, 12(2), 147–153. https://doi.org/10.1002/psc.689 DOI: https://doi.org/10.1002/psc.689

Procopio, D., Siciliano, C., & Di Gioia, M. L. (2024). Reactive deep eutectic solvents for EDC-mediated amide synthesis. Organic & Biomolecular Chemistry, 22(7), 1400–1408. DOI: 10.1039/D3OB01673K DOI: https://doi.org/10.1039/D3OB01673K

Ramadan, S. K., Ibrahim, N. A., El-Kaed, S. A., & El-Helw, E. A. (2021). New potential fungicides pyrazole-based heterocycles derived from 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl) acryloyl isothiocyanate. Journal of Sulfur Chemistry, 42(5), 529–546. https://doi.org/10.1080/17415993.2021.1909591 DOI: https://doi.org/10.1080/17415993.2021.1909591

Ren, J., Yuan, H., Liu, X., Yu, Z., Meng, F., Xiong, L., ... Fan, Z. (2022). Novel fluorinated aniline anthranilic diamides improved insecticidal activity targeting the ryanodine receptor. Journal of Agricultural and Food Chemistry, 70(34), 10453–10465. https://doi.org/10.1021/acs.jafc.2c03134 DOI: https://doi.org/10.1021/acs.jafc.2c03134

Ribeiro, E. C., Araújo, E. K. N., Penha, M. S. C., Nascimento, A. S. D., da Silva, D. F., & Miranda, R. D. C. M. D. (2025). Optimisation of potato dextrose agar culture medium for actinobacteria growth. Microorganisms, 13(3), 654. https://doi.org/10.3390/microorganisms13030654 DOI: https://doi.org/10.3390/microorganisms13030654

Rusu, A., Moga, I. M., Uncu, L., & Hancu, G. (2023). The role of five-membered heterocycles in the molecular structure of antibacterial drugs used in therapy. Pharmaceutics, 15(11), 2554. https://doi.org/10.3390/pharmaceutics15112554 DOI: https://doi.org/10.3390/pharmaceutics15112554

Singh, M. V., Tiwari, A. K., Sharma, Y. K., Chauhan, M. S., Sethi, M., & Guo, Z. (2023). Synthetic procedures, properties, and applications of thiophene-based azo scaffolds. ES Food & Agroforestry, 12(2), 887. DOI:10.30919/esfaf887 DOI: https://doi.org/10.30919/esfaf887

Slingerland, C. J., Lysenko, V., Chaudhuri, S., Wesseling, C. M., Barnes, D., Masereeuw, R., & Martin, N. I. (2023). Semisynthetic polymyxins with potent antibacterial activity and reduced kidney cell toxicity. RSC Medicinal Chemistry, 14(11), 2417–2425. https://doi.org/10.1039/D3MD00456B DOI: https://doi.org/10.1039/D3MD00456B

Sparks, T. C., & Bryant, R. J. (2022). Innovation in insecticide discovery: Approaches to the discovery of new classes of insecticides. Pest Management Science, 78(8), 3226–3247. https://doi.org/10.1002/ps.6942 DOI: https://doi.org/10.1002/ps.6942

Subhash, S., Babu, P., Vijayakumar, A., Suresh, R. A., Madhavan, A., Nair, B. G., & Pal, S. (2022). Aspergillus niger culture filtrate (ACF) mediated biocontrol of enteric pathogens in wastewater. Water, 14(1), 119. https://doi.org/10.3390/w14010119 DOI: https://doi.org/10.3390/w14010119

Tiwari, A. K., & Singh, M. V. (2023). Insights into the origin and therapeutic implications of benzopyran and its derivatives. ChemistrySelect, 8(20), e202300220. https://doi.org/10.1002/slct.202300220 DOI: https://doi.org/10.1002/slct.202300220

Tiwari, S. K., Nazeef, M., Verma, A., Kumar, A., Yadav, V., Yadav, N., ... Siddiqui, I. R. (2022). BF3-etherate promoted facile access to vinyloxyimidazopyridines: A metal-free sustainable approach. Molecular Diversity, 26(2), 1259–1266. https://doi.org/10.1007/s11030-021-10228-0 DOI: https://doi.org/10.1007/s11030-021-10228-0

Tiwari, S. K., Shivhare, K. N., Patel, M. K., Yadav, V., Nazeef, M., & Siddiqui, I. R. (2022). A metal-free, Hantzsch synthesis for privileged scaffold 1,4-dihydropyridines: A glycerol-promoted sustainable protocol. Polycyclic Aromatic Compounds, 42(4), 1035–1047. https://doi.org/10.1080/10406638.2020.1764988 DOI: https://doi.org/10.1080/10406638.2020.1764988

Varma, S. (2019). Efficacy of bioagents and fungicide against root rot of chilli caused by Rhizoctonia solani Kuhn. International Journal of Chemical Studies, 7(1), 1933–1936.

Vavre, K., Kakade, D., Patait, N., & Sahane, P. (2020). Morphological and cultural characteristics of Fusarium oxysporum f. sp. gladioli. Journal of Pharmacognosy and Phytochemistry, 10(1), 594–597.

Verma, A., Srivastava, A., Tiwari, S. K., Yadav, N., Ansari, M. D., Yadav, V. B., ... Siddiqui, I. R. (2020). Visible light promoted formation of N–S bond by photocatalyst eosin Y. Journal of Heterocyclic Chemistry, 57(9), 3493–3498. https://doi.org/10.1002/jhet.4069 DOI: https://doi.org/10.1002/jhet.4069

Wang, B. L., Zhu, H. W., Ma, Y., Xiong, L. X., Li, Y. Q., Zhao, Y., ... Li, Z. M. (2013). Synthesis, insecticidal activities, and SAR studies of novel pyridylpyrazole acid derivatives based on amide bridge modification of anthranilic diamide insecticides. Journal of Agricultural and Food Chemistry, 61(23), 5483–5493. https://doi.org/10.1021/jf4012467 DOI: https://doi.org/10.1021/jf4012467

Wang, S., Qiao, S. T., Li, P. Z., Xie, Y., Guo, F. R., Liu, J. W., ... Gao, C. F. (2025). Y4667D mutation in the ryanodine receptor confers high level resistance to diamide insecticides in the rice stem borer, Chilo suppressalis Walker (Lepidoptera: Crambidae). Journal of Agricultural and Food Chemistry, 73(16), 9920–9931. https://doi.org/10.1021/acs.jafc.5c00470 DOI: https://doi.org/10.1021/acs.jafc.5c00470

Wang, Y., Luo, X., Chen, Y., Peng, J., Yi, C., & Chen, J. (2023). Recent research progress of heterocyclic nematicidal active compounds. Journal of Heterocyclic Chemistry, 60(8), 1287–1300. https://doi.org/10.1002/jhet.4616 DOI: https://doi.org/10.1002/jhet.4616

Xiang, S. Z., Liu, K. J., Wang, J. J., Ye, H. J., Fan, L. J., Song, L., ... Wang, P. Y. (2024). From proline to chlorantraniliprole mimics: Computer-aided design, simple preparation, and excellent insecticidal profiles. Journal of Agricultural and Food Chemistry, 72(41), 22451–22463. https://doi.org/10.1021/acs.jafc.4c03125 DOI: https://doi.org/10.1021/acs.jafc.4c03125

Xu, Z. Y., Feng, T., Liu, Q., Li, H. T., Wei, W., Shi, R. C., ... Liu, S. Z. (2023). Design, synthesis, fungicidal and insecticidal activities of novel diamide compounds combining pyrazolyl and polyfluoro-substituted phenyl into alanine or 2-aminobutyric acid skeletons. Molecules, 28(2), 561. https://doi.org/10.3390/molecules28020561 DOI: https://doi.org/10.3390/molecules28020561

YL, R. (2019). Assessment of pathogenicity in Helminthosporium maydis causing southern corn leaf blight disease in the region of Karnataka. Journal of Drug Delivery & Therapeutics, 9(4), 146. DOI: 10.22270/jddt.v9i4.2991 DOI: https://doi.org/10.22270/jddt.v9i4.2991

Zhang, H. J., & Qiang, Y. U. E. (2021). Molecular characterization of the ryanodine receptor from Adoxophyes orana and its response to lethal and sublethal doses of chlorantraniliprole. Journal of Integrative Agriculture, 20(6), 1585–1595. https://doi.org/10.1016/S2095-3119(20)63356-1 DOI: https://doi.org/10.1016/S2095-3119(20)63356-1

Zucchi, R., & Ronca-Testoni, S. (1997). The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: Modulation by endogenous effectors, drugs and disease states. Pharmacological Reviews, 49(1), 1–51. DOI: 10.1016/S0031-6997(24)01312-7 DOI: https://doi.org/10.1016/S0031-6997(24)01312-7