Planta Med 2023; 89(13): 1236-1249
DOI: 10.1055/a-1770-7581
Natural Product Chemistry and Analytical Studies
Original Papers

Molecular Descriptors and QSAR Models for Sedative Activity of Sesquiterpenes Administered to Mice via Inhalation

Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
Michiho Ito
Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
› Author Affiliations


Essential oils are often utilized for therapeutic purposes and are composed of complex structural molecules, including sesquiterpenes, with high molecular weight and potential for stereochemistry. A detailed study on the properties of selected sesquiterpenes was conducted as part of a broader investigation on the effects of sesquiterpenes on the central nervous system. A set of 18 sesquiterpenes, rigorously selected from an original list of 114, was divided into 2 groups i.e., the training and test sets, with each containing 9 compounds. The training set was evaluated for the sedative activity in mice through inhalation, and all compounds were sedatives at any dose in the range of 4 × 10−4–4 × 10−2 mg/cage, except for curzerene. Molecular determinants of the sedative activities of sesquiterpenes were evaluated using quantitative structure–activity relationship (QSAR) and structure–activity relationship (SAR) analyses. An additional test set of six compounds obtained from the literature was utilized for validating the QSAR model. The parental carbonyl cation and an oxygen-containing groups are possible determinants of sedative activity. The QSAR study using multiple regression models could reasonably predict the sedative activity of sesquiterpenes with statistical parameters such as the correlation coefficient r2 = 0.82 > 0.6 and q2 LOO = 0.71 > 0.5 obtained using the leave-one-out cross-validation technique. Molar refractivity and the number of hydrogen bond acceptors were statistically important in predicting the activities. The present study could help predict the sedative activity of additional sesquiterpenes, thus accelerating the process of drug development.

Supporting Information

Publication History

Received: 16 November 2021

Accepted after revision: 11 February 2022

Accepted Manuscript online:
14 February 2022

Article published online:
03 July 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Agorastos A, Chrousos GP. The neuroendocrinology of stress: the stress-related continuum of chronic disease development. Mol Psychiatry 2022; 27: 502-513
  • 2 Shiner B, Westgate CL, Bernardy NC, Schnurr PP, Watts B. Trends in opioid use disorder diagnoses and medication treatment among veterans with posttraumatic stress disorder. J Dual Diagn 2017; 13: 201-212
  • 3 Berlin HA. Antiepileptic drugs for the treatment of post-traumatic stress disorder. Curr Psychiatry Rep 2007; 9: 291-300
  • 4 Guina J, Merrill B. Benzodiazepines I: Upping the care on downers: The evidence of risks, benefits and alternatives. J Clin Med 2018; 7: 17
  • 5 Takemoto H, Ito M, Asada Y, Kobayashi Y. Inhalation administration of the sesquiterpenoid aristolen-1(10)-en-9-ol from Nardostachys chinensis has a sedative effect via the GABAergic system. Planta Med 2015; 81: 343-347
  • 6 Ascari J, Sens SL, Nunes DS, Wisniewski A, Arbo MD, Linck VM, Lunardi P, Leal MB, Elisabetsky E. Sedative effects of essential oils obtained from Baccharis uncinella . Pharm Biol 2012; 50: 113-119
  • 7 Miyoshi T, Ito M, Kitayama T, Isomori S, Yamashita F. Sedative effects of inhaled benzylacetone and structural features contributing to its activity. Biol Pharm Bull 2013; 36: 1474-1481
  • 8 Dougnon G, Ito M. Sedative effects of the essential oil from the leaves of Lantana camara occurring in the Republic of Benin via inhalation in mice. J Nat Med 2020; 74: 159-169
  • 9 Dougnon G, Ito M. Role of ascaridole and p-cymene in the sleep-promoting effects of Dysphania ambrosioides essential oil via the GABAergic system in a ddY mouse inhalation model. J Nat Prod 2021; 84: 91-100
  • 10 Dougnon G, Ito M. Inhalation administration of the bicyclic ethers 1,8- and 1,4-cineole prevent anxiety and depressive-like behaviours in mice. Molecules 2020; 25: 1884
  • 11 Oshima T, Ito M. Sedative effects of l-menthol, D-camphor, phenylethyl alcohol, and geraniol. J Nat Med 2021; 75: 319-325
  • 12 Buckle J. Basic Plant Taxonomy, Basic Essential Oil Chemistry, Extraction, Biosynthesis, and Analysis. In: Clinical Aromatherapy. United Kingdom: Elsevier Health Sciences; 2015: 37-72
  • 13 Abe AE, de Oliveira CE, Dalboni TM, Chagas-Paula DA, Rocha BA, de Oliveira RB, Gasparoto TH, da Costa FB, Campanelli AP. Anti-inflammatory sesquiterpene lactones from Tithonia diversifolia trigger different effects on human neutrophils. Rev Bras Farmacogn 2015; 25: 111-116
  • 14 Recio MC, Giner RM, Máñez S, Ríos JL, Cerdá M. In vivo activity of pseudoguaianolide sesquiterpene lactones in acute and chronic inflammation. Life Sci 2000; 66: 2509-2518
  • 15 Espinoza J, Urzúa A, Sanhueza L, Walter M, Fincheira P, Muñoz P, Mendoza L, Wilkens M. Essential oil, extracts, and sesquiterpenes obtained from the heartwood of Pilgerodendron uviferum act as potential inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. Front Microbiol 2019; 10: 337
  • 16 Cho JY, Kim AR, Jung JH, Chun T, Rhee MH, Yoo ES. Cytotoxic and pro-apoptotic activities of cynaropicrin, a sesquiterpene lactone, on the viability of leukocyte cancer cell lines. Eur J Pharmacol 2004; 492: 85-94
  • 17 Olajide OA, Heiss EH, Schachner D, Wright CW, Vollmar AM, Dirsch VM. Synthetic cryptolepine inhibits DNA binding of NF-κB. Bioorg Med Chem 2007; 15: 43-49
  • 18 Huang GC, Chien TY, Chen LG, Wang CC. Antitumor effects of zerumbone from Zingiber zerumbet in P-388D1 cells in vitro and in vivo . Planta Med 2005; 71: 219-224
  • 19 Burim RV, Canalle R, Lopes JLC, Vichnewski W, Takahashi CS. Genotoxic action of the sesquiterpene lactone centratherin on mammalian cells in vitro and in vivo. Teratog Carcinog Mutagen 2001; 21: 383-393
  • 20 Dougnon G, Ito M. Essential oil from the leaves of Chromolaena odorata, and sesquiterpene caryophyllene oxide induce sedative activity in mice. Pharmaceuticals 2021; 14: 651
  • 21 Ogawa K, Yabe H, Kitayama T, Ito M. Locomotor-reducing activity of sesquiterpenes related to Zingiber zerumbet essential oil and hexahydrozerumbone derivatives. Biol Pharm Bull 2016; 39: 1077-1080
  • 22 Wishart DS. Improving early drug discovery through ADME modelling: An overview. Drugs R D 2007; 8: 349-362
  • 23 Dunkin CM, Pokorny A, Almeida PF, Lee HS. Molecular dynamics studies of transportan 10 (Tp10) interacting with a POPC lipid bilayer. J Phys Chem B 2010; 115: 1188-1198
  • 24 Horn JN, Romo TD, Grossfield A. Simulating the mechanism of antimicrobial lipopeptides with all-atom molecular dynamics. Biochemistry 2013; 52: 5604-5610
  • 25 Duncavage EJ, Abel HJ, Pfeifer JD. In silico proficiency testing for clinical next-generation sequencing. J Mol Diagnostics 2017; 19: 35-42
  • 26 Hartati FK, Djauhari AB, Viol KD. Evaluation of pharmacokinetic properties, toxicity, and bioactive cytotoxic activity of black rice (Oryza sativa L.) as candidates for Diabetes mellitus drugs by in silico . Biointerface Res Appl Chem 2021; 11: 12301-12311
  • 27 Harley BK, Amponsah IK, Ben IO, Adongo DW, Mireku-Gyimah NA, Baah MK, Mensah AY, Fleischer TC. Myrianthus libericus: Possible mechanisms of hypoglycaemic action and in silico prediction of pharmacokinetics and toxicity profile of its bioactive metabolite, friedelan-3-one. Biomed Pharmacother 2021; 137: 111379
  • 28 Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7: 1-13
  • 29 Zafar F, Gupta A, Thangavel K, Khatana K, Sani AA, Ghosal A, Tandon P, Nishat N. Physicochemical and pharmacokinetic analysis of anacardic acid derivatives. ACS Omega 2020; 5: 6021-6030
  • 30 Ogawa K, Miyoshi T, Kitayama T, Ito M. Locomotor-reducing effects and structural characteristics of inhaled zerumbone and tetrahydrozerumbone derivatives. Biol Pharm Bull 2014; 37: 1559-1563
  • 31 Imamura K, Mataga N, Mori K. Coding of odor molecules by mitral/tufted cells in rabbit olfactory bulb. I. Aliphatic compounds. J Neurophysiol 1992; 68: 1986-2002
  • 32 Araneda RC, Kini AD, Firestein S. The molecular receptive range of an odorant receptor. Nat Neurosci 2000; 3: 1248-1255
  • 33 Yang NJ, Hinner MJ. Getting across the cell membrane: An overview for small molecules, peptides, and proteins. Methods Mol Biol 2015; 1266: 29
  • 34 Flores-Sumoza M, Alcázar JJ, Márquez E, Mora JR, Lezama J, Puello E. Classical QSAR and docking simulation of 4-pyridone derivatives for their antimalarial activity. Molecules 2018; 23: 3166
  • 35 Ravichandran V, Jain PK, Mourya VK, Agrawal RK. QSAR study on some arylsulfonamides as anti-HIV agents. Med Chem Res 2007; 16: 342-351
  • 36 Topliss JG, Edwards RP. Chance factors in studies of quantitative structure-activity relationships. J Med Chem 1979; 22: 1238-1244
  • 37 Takemoto H, Yagura T, Ito M. Evaluation of volatile components from spikenard: Valerena-4, 7(11)-diene is a highly active sedative compound. J Nat Med 2009; 63: 380-385
  • 38 Takemoto H, Ito M, Shiraki T, Yagura T, Honda G. Sedative effects of vapor inhalation of agarwood oil and spikenard extract and identification of their active components. J Nat Med 2008; 62: 41-46
  • 39 Wold S, Eriksson L, Clementi S. Statistical validation of QSAR results. Chemom Methods Mol Des 2008; 2: 309-338
  • 40 Ravichandran V, Shalini S, Sundram K, Sokkalingam AD. QSAR study of substituted 1, 3, 4-oxadiazole naphthyridines as HIV-1 integrase inhibitors. Eur J Med Chem 2010; 45: 2791-2797
  • 41 Ravichandran V, Rajak H, Jain A, Sivadasan S, Varghese CP, Agrawal RK. Validation of QSAR models – strategies and importance. Int J Drug Des Discov 2011; 2: 511-519
  • 42 Golbraikh A, Tropsha A. Beware of q2!. J Mol Graph Model 2002; 20: 269-276
  • 43 Ravichandran V, Rohini K, Harish R, Parasuraman S, Sureshkumar K. Insights into the key structural features of triazolothienopyrimidines as anti-HIV agents using QSAR, molecular docking, and pharmacophore modeling. Struct Chem 2019; 30: 1471-1484
  • 44 Ravichandran V, Rajak H. Qsar studies on neuraminidase inhibitors as anti-influenza agents. Turkish J Pharm Sci 2021; 18: 151-156
  • 45 Roy K, Das RN, Ambure P, Aher RB. Be aware of error measures. Further studies on validation of predictive QSAR models. Chemom Intell Lab Syst 2016; 152: 18-33
  • 46 Li Z, Howell K, Fang Z, Zhang P. Sesquiterpenes in grapes and wines: Occurrence, biosynthesis, functionality, and influence of winemaking processes. Compr Rev Food Sci Food Saf 2020; 19: 247-281
  • 47 Bayala B, Bassole IHN, Scifo R, Gnoula C, Morel L, Lobaccaro JMA, Simpore J. Anticancer activity of essential oils and their chemical components – A review. Am J Cancer Res 2014; 4: 591-607
  • 48 Eggersdorfer M. Terpenes. In: Ullmannʼs Encyclopedia of Industrial Chemistry. New Jersey, U. S.: Wiley Online Library; 2000: 29-45
  • 49 Toropov AA, Leszczynska D, Leszczynski J. Predicting water solubility and octanol water partition coefficient for carbon nanotubes based on the chiral vector. Comput Biol Chem 2007; 31: 127-128
  • 50 Judge V, Narasimhan B, Ahuja M, Sriram D, Yogeeswari P, De Clercq E, Pannecouque C, Balzarini J. Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides. Med Chem Res 2012; 21: 1935-1952
  • 51 Mahajan S, Kamath V, Nayak S, Vaidya S. QSAR analysis of benzophenone derivatives as antimalarial agents. Indian J Pharm Sci 2012; 74: 41
  • 52 Hamzeh-Mivehroud M, Rahmani S, Rashidi MR, Hosseinpour Feizi MA, Dastmalchi S. Structure-based investigation of rat aldehyde oxidase inhibition by flavonoids. Xenobiotica 2013; 43: 661-670
  • 53 Hamzeh-Mivehroud M, Rahmani S, Rashidi MR, Dastmalchi S. Structural features of guinea pig aldehyde oxidase inhibitory activities of flavonoids explored using QSAR and molecular modeling studies. Med Chem Res 2016; 25: 2773-2786
  • 54 Puzyn T, Mostrag A, Falandysz J, Kholod Y, Leszczynski J. Predicting water solubility of congeners: Chloronaphthalenes–A case study. J Hazard Mater 2009; 170: 1014-1022
  • 55 Puzyn T, Rasulev B, Gajewicz A, Hu X, Dasari TP, Michalkova A, Hwang HM, Toropov A, Leszczynska D, Leszczynski J. Using nano-QSAR to predict the cytotoxicity of metal oxide nanoparticles. Nat Nanotechnol 2011; 6: 175-178
  • 56 Zoete V, Daina A, Bovigny C, Michielin O. SwissSimilarity: A web tool for low to ultra high throughput ligand-based virtual screening. J Chem Inf Model 2016; 56: 1399-1404
  • 57 Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2012; 64: 4-17
  • 58 Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45: 2615-2623
  • 59 Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1999; 1: 55-68
  • 60 Santana K, do Nascimento LD, Lima e Lima A, Damasceno V, Nahum C, Braga RC, Lameira J. Applications of virtual screening in bioprospecting: Facts, shifts, and perspectives to explore the chemo-structural diversity of natural products. Front Chem 2021; 9: 155
  • 61 Naylor MR, Bockus AT, Blanco MJ, Lokey RS. Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Curr Opin Chem Biol 2017; 38: 141-147
  • 62 Rossi SM, Doak BC, Backlund M, Poongavanam V, Over B, Ermondi G, Caron G, Matsson P, Kihlberg J. Impact of dynamically exposed polarity on permeability and solubility of chameleonic drugs beyond the rule of 5. J Med Chem 2018; 61: 4189-4202
  • 63 de Oliveira ECL, Santana K, Josino L, Lima e Lima AH, de Souza de Sales Júnior C. Predicting cell-penetrating peptides using machine learning algorithms and navigating in their chemical space. Sci Reports 2021; 11: 7628
  • 64 Doak BC, Over B, Giordanetto F, Kihlberg J. Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates. Chem Biol 2014; 21: 1115-1142
  • 65 Sander T, Freyss J, Von Korff M, Rufener C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J Chem Inf Model 2015; 55: 460-473
  • 66 Li X, Zhang Y, Chen H, Li H, Zhao Y. Insights into the molecular basis of the acute contact toxicity of diverse organic chemicals in the honey bee. J Chem Inf Model 2017; 57: 2948-2957
  • 67 Yap CW. PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints. J Comput Chem 2011; 32: 1466-1474
  • 68 Abdullahi M, Shallangwa GA, Uzairu A. In silico QSAR and molecular docking simulation of some novel aryl sulfonamide derivatives as inhibitors of H5N1 influenza A virus subtype. Beni-Suef Univ J Basic Appl Sci 2020; 9: 2