Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies

Kotyan, Sukumar; Chandana, Shankaranahalli N.; Ganesha, Doddabasavanahalli P.; Lakshminarayana, Banavase N.; Pandikatte, Nefisath; Deb, Pran Kishore; Ghosh, Manik; Gleiser, Raquel M.; Mahomoodally, Mohamad Fawzi; Alherz, Sukainh Aiaysh; Morsy, Mohamed A.; Khalil, Hany Ezzat; Attimarad, Mahesh; Nagaraja, Sreeharsha; Almuqbil, Rashed M.; Balgoname, Abdulmalek Ahmed; Al-Dhubiab, Bandar E.; Asif, Afzal Haq; Venugopala, Katharigatta N.; Dasappa, Jagadeesh Prasad

doi:10.3390/ph18121804

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Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies

by

Sukumar Kotyan

¹

,

Shankaranahalli N. Chandana

²

,

Doddabasavanahalli P. Ganesha

³

,

Banavase N. Lakshminarayana

^4,*

,

Nefisath Pandikatte

⁵

,

Pran Kishore Deb

⁶

,

Manik Ghosh

⁶

,

Raquel M. Gleiser

⁷

,

Mohamad Fawzi Mahomoodally

^8,9,10,11,12

,

Sukainh Aiaysh Alherz

¹³

,

Mohamed A. Morsy

¹³

,

Hany Ezzat Khalil

¹³

,

Mahesh Attimarad

¹³

,

Sreeharsha Nagaraja

¹³

,

Rashed M. Almuqbil

¹³

,

Abdulmalek Ahmed Balgoname

¹³

,

Bandar E. Al-Dhubiab

¹³

,

Afzal Haq Asif

¹⁴

,

Katharigatta N. Venugopala

^13,15,*

and

Jagadeesh Prasad Dasappa

^1,*

¹

Department of Chemistry, Mangalore University, Mangalagangotri 574199, Karnataka, India

²

Department of Physics, Rajeev Institute of Technology, Hassan 573201, Karnataka, India

³

Department of Physics, Malnad College of Engineering, Affiliated to Visvesvaraya Technological University, Hassan 573201, Karnataka, India

⁴

Research Center, Department of Physics, Adichunchanagiri Institute of Technology, Affiliated to Visvesvaraya Technological University, Jyothinagara, Chikkamagaluru 577102, Karnataka, India

⁵

Department of PG Studies and Research in Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire 574240, Karnataka, India

⁶

Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra 835215, Jharkhand, India

⁷

CREAN-IMBIV (UNC-CONICET), Av. Valparaiso s.n., and FCEFyN, Universidad Nacional de Cordoba, Av. V. Sarsfield 299, Cordoba 5000, Argentina

⁸

Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam

⁹

School of Engineering & Technology, Duy Tan University, Da Nang 550000, Vietnam

¹⁰

Laboratory of Natural Products and Medicinal Chemistry (LNPMC), Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai 602105, Tamil Nadu, India

¹¹

Centre of Excellence for Pharmaceutical Sciences (Pharmacen), North West University, Potchefstroom 2520, South Africa

¹²

Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Reduit 80837, Mauritius

¹³

Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia

¹⁴

Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia

¹⁵

Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa

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Pharmaceuticals 2025, 18(12), 1804; https://doi.org/10.3390/ph18121804

Submission received: 23 October 2025 / Revised: 20 November 2025 / Accepted: 21 November 2025 / Published: 26 November 2025

(This article belongs to the Special Issue Research on Guanidine-Based Drugs: Synthesis, Antiparasitic, Antifungal, Antiviral, and Anticancer Activities)

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Abstract

Background/Objectives: Vector-borne diseases like malaria remain a major global health concern, worsened by insecticide resistance in mosquito populations. Quinoline-based compounds have been extensively studied for their pharmacological effects, including antimalarial and larvicidal properties. Modifying quinoline structures with hydrazone groups may enhance their biological activity and physicochemical properties. This study reports the synthesis, structural characterization, and larvicidal testing of a new series of aryl hydrazones (6a–i) derived from 8-trifluoromethyl quinoline. Methods: Compounds 6a–i were prepared via condensation reactions and characterized using ¹H NMR, ¹⁹F-NMR, ¹³C NMR, and HRMS techniques. Their larvicidal activity was tested against Anopheles arabiensis. Single-crystal X-ray diffraction (XRD) was performed on compound 6d to determine its three-dimensional structure. Hirshfeld surface analysis, fingerprint plots, and interaction energy calculations (HF/3-21G) were used to examine intermolecular interactions. Quantum chemical parameters were computed using density functional theory (DFT). Molecular docking studies were performed for the synthesized compounds 6a–i against the target acetylcholinesterase from the malaria vector (6ARY). In silico ADMET properties were also calculated to evaluate the drug-likeness of all the tested compounds. Results: Compound 6a showed the highest larvicidal activity, causing significant mortality in Anopheles arabiensis larvae. Single-crystal XRD analysis of 6d revealed a monoclinic crystal system with space group P2₁/c, stabilized by N–H···N intermolecular hydrogen bonds. Hirshfeld analysis identified H···H (22.0%) and C···H (12.1%) interactions as key contributors to molecular packing. Density functional theory results indicated a favorable HOMO–LUMO energy gap, supporting molecular stability and good electronic distribution. The most active compounds, 6a and 6d, also showed strong binding interactions with the target protein 6ARY and satisfactory ADMET properties. The BOILED-Egg model is a powerful tool for predicting both blood–brain barrier (BBB) and gastrointestinal permeation by calculating the lipophilicity and polarity of the reported compounds 6a–i. Conclusions: The synthesized arylhydrazone derivatives demonstrated promising larvicidal activity. Combined crystallographic and computational studies support their structural stability and suitability for further development as eco-friendly bioactive agents in malaria vector control.

Keywords: 8-trifluoromethyl quinolone; hydrazine; larvicidal activity; XRD; DFT; Anopheles arabiensis

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MDPI and ACS Style

Kotyan, S.; Chandana, S.N.; Ganesha, D.P.; Lakshminarayana, B.N.; Pandikatte, N.; Deb, P.K.; Ghosh, M.; Gleiser, R.M.; Mahomoodally, M.F.; Alherz, S.A.; et al. Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies. Pharmaceuticals 2025, 18, 1804. https://doi.org/10.3390/ph18121804

AMA Style

Kotyan S, Chandana SN, Ganesha DP, Lakshminarayana BN, Pandikatte N, Deb PK, Ghosh M, Gleiser RM, Mahomoodally MF, Alherz SA, et al. Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies. Pharmaceuticals. 2025; 18(12):1804. https://doi.org/10.3390/ph18121804

Chicago/Turabian Style

Kotyan, Sukumar, Shankaranahalli N. Chandana, Doddabasavanahalli P. Ganesha, Banavase N. Lakshminarayana, Nefisath Pandikatte, Pran Kishore Deb, Manik Ghosh, Raquel M. Gleiser, Mohamad Fawzi Mahomoodally, Sukainh Aiaysh Alherz, and et al. 2025. "Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies" Pharmaceuticals 18, no. 12: 1804. https://doi.org/10.3390/ph18121804

APA Style

Kotyan, S., Chandana, S. N., Ganesha, D. P., Lakshminarayana, B. N., Pandikatte, N., Deb, P. K., Ghosh, M., Gleiser, R. M., Mahomoodally, M. F., Alherz, S. A., Morsy, M. A., Khalil, H. E., Attimarad, M., Nagaraja, S., Almuqbil, R. M., Balgoname, A. A., Al-Dhubiab, B. E., Asif, A. H., Venugopala, K. N., & Dasappa, J. P. (2025). Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies. Pharmaceuticals, 18(12), 1804. https://doi.org/10.3390/ph18121804

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Synthesis of Novel Arylhydrazones Bearing 8-Trifluoromethyl Quinoline: Crystal Insights, Larvicidal Activity, ADMET Predictions, and Molecular Docking Studies

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