Integrated In Silico and Chromatographic Evaluation of the Biological Properties of Novel Bis-Substituted Thiocarbohydrazone Derivatives
Suzana Apostolov, Dragana Mekić, Gorana Mrđan, Gyöngyi Vastag
Organics · pp. 19–19 · Published 12 May 2026
10.3390/org7020019Abstract
Thiocarbohydrazone derivatives represent a highly significant class in medicinal chemistry, characterized by a versatile scaffold defined with a thiocarbonyl (C=S) core and one or two imine (–C=N–) functionalities, allowing for precise modulation of their physicochemical and biological properties. The biological potential of a series of novel bis-substituted thiocarbohydrazone derivatives was predicted and evaluated through comprehensive in silico analysis. All investigated compounds complied with Lipinski’s Rule of 5, with most also satisfying the Rule of 3 while simultaneously exhibiting favorable pharmacokinetic properties and low predicted ecotoxicity. To substantiate these findings and elucidate the influence of para-substituents, chromatographic behavior of the studied derivatives was evaluated using reversed-phase thin-layer chromatography (RP-TLC). Initial linear regression analysis revealed statistically significant correlations between chromatographic parameters and in silico-derived descriptors of lipophilicity, pharmacokinetics, and ecotoxicity. Furthermore, cluster analysis and principal component analysis provided a robust and unambiguous interpretation of the structure–property relationships, highlighting substituent polarity as the leading factor controlling the bioactivity of bis-substituted thiocarbohydrazones, although the contribution of electronic effects cannot be neglected. Moreover, RM0 correlates with lipophilicity and pharmacokinetics, whereas m reflects ecotoxicity. Collectively, these findings emphasize the critical role of subtle structural variations in shaping the overall properties of these novel derivatives.
References (46)
- 1 de la Torre, B.G., and Albericio, F. (2026). The Pharmaceutical Industry in 2025: An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules, 31. [DOI]
- 2 Sertkaya, 2024, Costs of Drug Development and Research and Development Intensity in the US, 2000–2018 [DOI]
- 3 Gangarapu, 2014, Synthesis of thiocarbohydrazide and carbohydrazide derivatives as possible biologically active agents [DOI]
- 4 Shukla, 2024, Synthesis, crystal structure analysis, computational modelling and evaluation of anti-cervical cancer activity of novel 1,5-dicyclooctyl thiocarbohydrazone [DOI]
- 5 Menon, 2025, Fluorometric Detection of Sodium Ion Using Bis(2,4-dihydroxyphenylmethylene) Thiocarbohydrazone; Crystal Structure, DFT Studies, Anti-Cancer Assay, ADMET Study and Molecular Docking [DOI]
- 6 Bonaccorso, C., Marzo, T., and La Mendola, D. (2020). Biological Applications of Thiocarbohydrazones and Their Metal Complexes: A Perspective Review. Pharmaceuticals, 13. [DOI]
- 7 Muhammad, 2018, Synthesis of Thiocarbohydrazones and Evaluation of their in vitro Antileishmanial Activity [DOI]
- 8 Georgiou, N., Katsogiannou, A., Skourtis, D., Iatrou, H., Tzeli, D., Vassiliou, S., Javornik, U., Plavec, J., and Mavromoustakos, T. (2022). Conformational Properties of New Thiosemicarbazone and Thiocarbohydrazone Derivatives and Their Possible Targets. Molecules, 27. [DOI]
- 9 Emara, 2004, Metal complexes of some thiocarbohydrazone ligands: Synthesis and structure [DOI]
- 10 Biala, G., Kedzierska, E., Kruk-Slomka, M., Orzelska-Gorka, J., Hmaidan, S., Skrok, A., Kaminski, J., Havrankova, E., Nadaska, D., and Malik, I. (2023). Research in the Field of Drug Design and Development. Pharmaceuticals, 16. [DOI]
- 11 Wu, K., Kwon, S.H., Zhou, X., Fuller, C., Wang, X., Vadgama, J., and Wu, Y. (2024). Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches. Int. J. Mol. Sci., 25. [DOI]
- 12 Lipinski, 1997, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings [DOI]
- 13 Congreve, 2003, A ‘rule of three’ for fragment-based lead discovery? [DOI]
- 14 Martínez-Campos, Z., Hernandez-Dominguez, L.E., Romero-Rivera, F., López-López, D., Corona-González, M.V., López-Cortina, S.T., Palacios-Can, F.J., Razo-Hernández, R.S., and Fernández-Zertuche, M. (2025). Synthesis and In Silico Evaluation of GABA, Pregabalin and Baclofen N-Heterocyclic Analogues as GABAB Receptor Agonists. Organics, 6. [DOI]
- 15 Ghannay, 2020, Synthesis, in vitro antimicrobial assessment, and computational investigation of pharmacokinetic and bioactivity properties of novel trifluoromethylated compounds using in silico ADME and toxicity prediction tools [DOI]
- 16 Kon, 2016, Retention data of bile acids and their oxo derivatives in characterization of pharmacokinetic properties and in silico ADME modeling [DOI]
- 17 Malinowska, 2023, Comparison of computational and thin-layer chromatographic methods for prediction of biological properties of organic compounds [DOI]
- 18 Czopek, 2024, Reversed-phase thin-layer chromatography and ultra-performance liquid chromatography/mass spectrometry to estimate the drug likeness of phosphodiesterase 10A inhibitors with phthalimide core [DOI]
- 19 Wachtmeister, 1962, The relation between the composition of certain ternary two-phase solvent systems and RM values [DOI]
- 20 Biagi, 1994, Determination of lipophilicity by means of reversed-phase thin-layer chromatography. I. Basic aspects and relationship between slope and intercept of TLC equations [DOI]
- 21 Apostolov, 2026, Synthesis, characterization, intermolecular interactions, and antioxidant activity of novel derivatives of asymmetric bisthiocarbohydrazones [DOI]
- 22 (2025, March 20). Chemdraw. Available online: https://computing.ch.cam.ac.uk/software/chemdraw-and-chemoffice.
- 23 (2025, January 19). Molinspiration. Available online: https://www.molinspiration.com.
- 24 (2025, February 01). Chemaxon. Available online: https://www.certara.com/marvin.
- 25 (2026, February 10). Biosig Lab. Available online: https://biosig.lab.uq.edu.au/pkcsm/prediction.
- 26 (2026, January 31). SwissADME. Available online: http://www.swissadme.ch/.
- 27 (2025, December 10). PreADMET. Available online: https://preadmet.webservice.bmdrc.org.
- 28 Egan, 2000, Prediction of drug absorption using multivariate statistics [DOI]
- 29 Villoutreix, B.O., Laconde, G., Lagorce, D., Martineau, P., Miteva, M.A., and Dariavach, P. (2011). Tyrosine kinase syk non-enzymatic inhibitors and potential anti-allergic drug-like compounds discovered by virtual and in vitro screening. PLoS ONE, 6. [DOI]
- 30 Alsalim, 2026, Design, synthesis, and integrated in silico analysis of novel difluoroboron curcumin analogues as potent inhibitors of the K562 leukemia cell line [DOI]
- 31 Steyn, J.D., Haasbroek-Pheiffer, A., Pheiffer, W., Weyers, M., van Niekerk, S.E., Hamman, J.H., and van Staden, D. (2025). Evaluation of Drug Permeation Enhancement by Using In Vitro and Ex Vivo Models. Pharmaceuticals, 18. [DOI]
- 32 Angelis, 2011, Caco-2 Cells as a Model for Intestinal Absorption [DOI]
- 33 Irvine, 1999, MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening [DOI]
- 34 Sanz, 2004, A topological sub-structural approach for predicting human intestinal absorption of drugs [DOI]
- 35 Yamashita, 2000, Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells [DOI]
- 36 Potts, 1992, Predicting skin permeability [DOI]
- 37 Lobell, 2003, Recent advances in the prediction of blood-brain partitioning from molecular structure [DOI]
- 38 Pajouhesh, 2005, Medicinal chemical properties of successful central nervous system drugs [DOI]
- 39 Banker, 2008, Plasma/serum protein binding determinations [DOI]
- 40 1993, Lipophilicity determination of some monoamine oxidase inhibitors by reversed-phase thin-layer chromatography. The effect of pH [DOI]
- 41 Vastag, 2013, Multivariate analysis of chromatographic retention data and lipophilicity of phenylacetamide derivatives [DOI]
- 42 Kuzminac, 2022, Chemometrics of anisotropic lipophilicity of anticancer androstane derivatives determined by reversed-phase ultra high performance liquid chromatography with polar aprotic and protic modifiers [DOI]
- 43 Soubra, 2023, Total Hg levels distribution in fish and fish products and their relationships with fish types, weights, and protein and lipid contents: A multivariate analysis [DOI]
- 44 Apostolov, S., Mekić, D., Mitrović, M., Petrović, S., and Vastag, G. (2025). Profiling of Disubstituted Chloroacetamides’ Potential Biological Activity by Liquid Chromatography. Organics, 6. [DOI]
- 45 Fujita, 1964, A new substituent constant, π, derived from partition coefficients [DOI]
- 46 Hammett, 1937, The effect of structure upon the reactions of organic compounds; Benzene derivatives [DOI]
Cited by 0
No indexed citations yet.
Related research
- A Novel Catalytic Synthesis of Flavones under Autoclave Conditions and Comparative Study of Anti-cancer Activity — shares topic coverage
- Thermostability and in-vitro Antibacterial Activity of Aqueous Extracts of Tetrapleura tetraptera Pods on Multidrug Resistant Clinical Isolates — shares topic coverage
- Acute Toxicity, Phytochemistry and Anti-diarrheal Effects of Celtis integrifolia Lam. Aqueous Leaf Extract in Wistar Albino Rats — shares topic coverage
- Understanding the Reactivity of Trimethylsilyldiazoalkanes Participating in [3+2] Cycloaddition Reactions towards Diethylfumarate with a Molecular Electron Density Theory Perspective — shares topic coverage
- Understanding the Origin of the Regioselectivity in Non-Polar [3+2] Cycloaddition Reactions through the Molecular Electron Density Theory — shares topic coverage
Article metrics
Real usage data collected on this platform.
0
Page views
0
PDF downloads
0
Outbound clicks
0
Citations
Views by country
Approximate, from request IP at view time — not citizenship or institution. Countries with fewer than 5 views are grouped as "Other".
No views recorded yet.
Traffic sources
Referring site, by host.
No traffic recorded yet.
Views and downloads exclude known bots/crawlers. Citations combines this platform's own DOI-resolved index with each external source's own reported total — see Cited by above for individually listed citing works. Last refreshed 0 seconds ago.