Novel 1,3,4-Thiadiazole Derivatives as Antibiofilm, Antimicrobial, Efflux Pump Inhibiting Agents and Their ADMET Characterizations

Year 2023, Volume: 10 Issue: 2, 99 - 116, 30.06.2023

Mahmut GÜR Merve ZURNACI Eda ALTINÖZ Nesrin ŞENER Çiğdem ŞAHİN Merve ŞENTURAN İzzet ŞENER Muhammet ÇAVUŞ Ergin Murat ALTUNER

https://doi.org/10.17350/HJSE19030000297

Abstract

In this study, 1,3,4-thiadiazole derivatives were obtained from the reaction of benzophenone-4,4'-dicarboxylic acid and N-substitute-thiosemicarbazide compounds with each other. After the synthesis of the final products, some biological properties of these compounds such as antibiofilm, antimicrobial and efflux pump inhibiting efficiencies were evaluated. According to the MBC/MFC test, all the activities were found to be bacteriostatic, also, especially the biofilm inhibition activity of C1 against K. pneumoniae is noteworthy. In addition, C4 was observed to exhibit efflux pump inhibition activity in E. coli, whereas C2 and C3 in K. pneumoniae. The absorption and emission values of the molecules were obtained and electrochemical studies were performed. In addition; absorption, metabolism, distribution, excretion and toxicity (ADMET) scores were predicted using the pharmacokinetic properties of all 1,3,4-thiadiazole compounds. Finally, the electrochemical stabilities of the synthesized molecules have been analyzed by using cyclic voltammetry in 0.1 M TBAPF6 in DMSO as a supporting electrolyte.

Keywords

Efflux pump inhibition, antibiofilm, antibacterial, ADMET, QSAR

References

• 1. S. Janowska, A. Paneth, M. Wujec, Cytotoxic Properties of 1,3,4-Thiadiazole Derivatives—A Review, Molecules. 25 (2020) 4309.
• 2. R. Ningegowda, N.S. Shivananju, P. Rajendran, Basappa, K.S. Rangappa, A. Chinnathambi, F. Li, R.R. Achar, M.K. Shanmugam, P. Bist, S.A. Alharbi, L.H.K. Lim, G. Sethi, B.S. Priya, A novel 4,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivative inhibits tumor cell invasion and potentiates the apoptotic effect of TNFα by abrogating NF-κB activation cascade, Apoptosis. 22 (2017) 145–157.
• 3. G. Lalita, Chauhan ; Shalini, Journal of drug delivery and therapeutics (jddt), Journal of Drug Delivery & Therapeutics. 9 (2020) 661–668.
• 4. D. Disposition, Op Y Ig Ht S Ht S, 46 (2015) 750–756.
• 5. P.A. Datar, Design and Synthesis of Thiadiazole Derivatives as Antidiabetic Agents, Medicinal Chemistry. 4 (2014).
• 6. S. Thrilochana, P., Sahu, C. N., Hazra, K., and Ramachandran, Synthesis and Biological Evaluation of New Thiadiazole Analogs for Anti-diabetic Activity against Alloxan-Induced Diabetes, J. Pharm. Res. 8 (2014) 1–8.
• 7. A. Cristina, D. Leonte, L. Vlase, L. Bencze, S. Imre, G. Marc, B. Apan, C. Mogoșan, V. Zaharia, Heterocycles 48. Synthesis, Characterization and Biological Evaluation of Imidazo[2,1-b][1,3,4]Thiadiazole Derivatives as Anti-Inflammatory Agents, Molecules. 23 (2018) 2425.
• 8. S. Schenone, C. Brullo, O. Bruno, F. Bondavalli, A. Ranise, W. Filippelli, B. Rinaldi, A. Capuano, G. Falcone, New 1,3,4-thiadiazole derivatives endowed with analgesic and anti-inflammatory activities, Bioorganic & Medicinal Chemistry. 14 (2006) 1698–1705. https://doi.org/10.1016/j.bmc.2005.10.064.
• 9. Ö.D. Can, M.D. Altıntop, Ü.D. Özkay, U.İ. Üçel, B. Doğruer, Z.A. Kaplancıklı, Synthesis of thiadiazole derivatives bearing hydrazone moieties and evaluation of their pharmacological effects on anxiety, depression, and nociception parameters in mice, Archives of Pharmacal Research. 35 (2012) 659–669.
• 10. A.B. Samel, N.R. Pai, Synthesis of Novel Aryloxy Propanoyl Thiadiazoles as Potential Antihypertensive Agents, Journal of the Chinese Chemical Society. 57 (2010) 1327–1330.
• 11. G. Serban, Synthetic Compounds with 2-Amino-1,3,4-Thiadiazole Moiety Against Viral Infections, Molecules. 25 (2020) 942.
• 12. Brai, Ronzini, Riva, Botta, Zamperini, Borgini, Trivisani, Garbelli, Pennisi, Boccuto, Saladini, Zazzi, Maga, Botta, Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X, Molecules. 24 (2019) 3988.
• 13. and F.B. Azar Tahghighi, Thiadiazoles: the appropriate pharmacological scaffolds with leishmanicidal and antimalarial activities: a review, Iran J Basic Med Sci. 20 (2017) 613–622.
• 14. S.E. Sadat-Ebrahimi, M. Mirmohammadi, Z.M. Tabatabaei, M.A. Arani, S. Jafari-Ashtiani, M. Hashemian, P. Foroumadi, A. Yahya-Meymandi, S. Moghimi, M.H. Moshafi, P. Norouzi, S.K. Ardestani, A. Foroumadi, Novel 5-(Nitrothiophene-2-yl)-1,3,4-thiadiazole derivatives: Synthesis and antileishmanial activity against promastigote stage of leishmania major, Iranian Journal of Pharmaceutical Research. 18 (2019) 1816–1822.
• 15. H. Muğlu, N. Şener, H.A. Mohammad Emsaed, S. Özkınalı, O.E. Özkan, M. Gür, Synthesis and characterization of 1,3,4-thiadiazole compounds derived from 4-phenoxybutyric acid for antimicrobial activities, Journal of Molecular Structure. 1174 (2018) 151–159.
• 16. M. Gür, S. Yerlikaya, N. Şener, S. Özkınalı, M.C. Baloglu, H. Gökçe, Y.C. Altunoglu, S. Demir, İ. Şener, Antiproliferative-antimicrobial properties and structural analysis of newly synthesized Schiff bases derived from some 1,3,4-thiadiazole compounds, Journal of Molecular Structure. 1219 (2020).
• 17. S. Cascioferro, The Future of Antibiotic: From the Magic Bullet to the Smart Bullet, Journal of Microbial & Biochemical Technology. 06 (2014).
• 18. S. Cascioferro, M.G. Cusimano, D. Schillaci, Antiadhesion agents against Gram-positive pathogens, Future Microbiology. 9 (2014) 1209–1220.
• 19. D. Schillaci, V. Spanò, B. Parrino, A. Carbone, A. Montalbano, P. Barraja, P. Diana, G. Cirrincione, S. Cascioferro, Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms, Journal of Medicinal Chemistry. 60 (2017) 8268–8297.
• 20. A.S. Lynch, G.T. Robertson, Bacterial and Fungal Biofilm Infections, Annual Review of Medicine. 59 (2008) 415–428.
• 21. B. Parrino, P. Diana, G. Cirrincione, S. Cascioferro, Bacterial Biofilm Inhibition in the Development of Effective Anti-Virulence Strategy, The Open Medicinal Chemistry Journal. 12 (2018) 84–87.
• 22. M.V. Raimondi, B. Maggio, D. Raffa, F. Plescia, S. Cascioferro, G. Cancemi, D. Schillaci, M.G. Cusimano, M. Vitale, G. Daidone, Synthesis and anti-staphylococcal activity of new 4-diazopyrazole derivatives, European Journal of Medicinal Chemistry. 58 (2012) 64–71.
• 23. D. Schillaci, S. Petruso, S. Cascioferro, M.V. Raimondi, J.A.J. Haagensen, S. Molin, In vitro anti-Gram-positive and antistaphylococcal biofilm activity of newly halogenated pyrroles related to pyrrolomycins, International Journal of Antimicrobial Agents. 31 (2008) 380–382.
• 24. M. Zurnacı, M. Şenturan, N. Şener, M. Gür, E. Altınöz, İ. Şener, E.M. Altuner, Studies on Antimicrobial, Antibiofilm, Efflux Pump Inhibiting, and ADMET Properties of Newly Synthesized 1,3,4‐Thiadiazole Derivatives**, ChemistrySelect. 6 (2021) 12571–12581.
• 25. İ. Şener, Ç. Şahin, S. Demir, N. Şener, M. Gür, A combined experimental and computational study of electrochemical and photophysical properties of new benzophenone derivatives functionalized with N-substituted-phenyl-1,3,4-thiadiazole-2-amine, Journal of Molecular Structure. 1203 (2020).
• 26. P. Cos, A.J. Vlietinck, D. Vanden Berghe, L. Maes, Anti-infective potential of natural products: How to develop a stronger in vitro “proof-of-concept,” Journal of Ethnopharmacology. 106 (2006) 290–302.
• 27. E.M. Altuner, K. Canli, I. Akata, Antimicrobial screening of Calliergonella cuspidata, Dicranum polysetum and Hypnum cupressiforme, Journal of Pure and Applied Microbiology. 8 (2014) 539–545.
• 28. E.M. ALTUNER, T. ÇETER, M. GÜR, K. GÜNEY, B. KIRAN, H.E. AKWIETEN, S.I. SOULMAN, Chemical Composition and Antimicrobial Activities of Cold-Pressed Oils Obtained From Nettle, Radish and Pomegranate Seeds, Kastamonu Üniversitesi Orman Fakültesi Dergisi. 18 (2018) 236–247.
• 29. K. Canli, A. Yetgin, A. Benek, M.E. Bozyel, E.M. Altuner, In Vitro Antimicrobial Activity Screening of Ethanol Extract of Lavandula stoechas and Investigation of Its Biochemical Composition, Advances in Pharmacological Sciences. 2019 (2019).
• 30. B. Karaca, A. Çöleri Cihan, I. Akata, E.M. Altuner, Anti-Biofilm and Antimicrobial Activities of Five Edible and Medicinal Macrofungi Samples on Some Biofilm Producing Multi Drug Resistant Enterococcus Strains, Turkish Journal of Agriculture - Food Science and Technology. 8 (2020) 69. https://doi.org/10.24925/turjaf.v8i1.69-80.2723.
• 31. Z. Xu, Y. Liang, S. Lin, D. Chen, B. Li, L. Li, Y. Deng, Crystal Violet and XTT Assays on Staphylococcus aureus Biofilm Quantification, Current Microbiology. 73 (2016) 474–482.
• 32. L.K. Vestby, T. Møretrø, S. Langsrud, E. Heir, L.L. Nesse, Biofilm forming abilities of Salmonella are correlated with persistence in fish meal- and feed factories, BMC Veterinary Research. 5 (2009) 1–6. https://doi.org/10.1186/1746-6148-5-20.
• 33. M. Martins, I. Couto, M. Viveiros, L. Amaral, in Bacterial Clinical Isolates by Two Simple Methods, Methods. 642 (2010) 143–157.
• 34. E. Altınöz, E.M. Altuner, Responses of some Escherichia coli clinical isolate strains with multiple drug resistance and overexpressed efux pumps against efux pump inhibitors, International Journal of Biology and Chemistry. 13 (2020) 77–87.
• 35. Drug Likeness Tool, (2018). http://www.niper.gov.in/pi_dev_tools/DruLiToWeb/DruLiTo_index.html.
• 36. A. Daina, O. Michielin, V. Zoete, SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Scientific Reports. 7 (2017) 1–13. https://doi.org/10.1038/srep42717.
• 37. C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews. 64 (2012) 4–17.
• 38. A.K. Ghose, V.N. Viswanadhan, J.J. Wendoloski, A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases, Journal of Combinatorial Chemistry. 1 (1999) 55–68. https://doi.org/10.1021/cc9800071.
• 39. D.F. Veber, S.R. Johnson, H.Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple, Molecular properties that influence the oral bioavailability of drug candidates, Journal of Medicinal Chemistry. 45 (2002) 2615–2623.
• 40. W.J. Egan, K.M. Merz, J.J. Baldwin, Prediction of drug absorption using multivariate statistics, Journal of Medicinal Chemistry. 43 (2000) 3867–3877.
• 41. I. Muegge, S.L. Heald, D. Brittelli, Simple selection criteria for drug-like chemical matter, Journal of Medicinal Chemistry. 44 (2001) 1841–1846.
• 42. J. Dong, N.N. Wang, Z.J. Yao, L. Zhang, Y. Cheng, D. Ouyang, A.P. Lu, D.S. Cao, Admetlab: A platform for systematic ADMET evaluation based on a comprehensively collected ADMET database, Journal of Cheminformatics. 10 (2018) 1–11.
• 43. F. Cheng, W. Li, Y. Zhou, J. Shen, Z. Wu, G. Liu, P.W. Lee, Y. Tang, AdmetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties, Journal of Chemical Information and Modeling. 52 (2012) 3099–3105.
• 44. H. Yang, C. Lou, L. Sun, J. Li, Y. Cai, Z. Wang, W. Li, G. Liu, Y. Tang, AdmetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties, Bioinformatics. 35 (2019) 1067–1069.
• 45. N.K. Lee SK, Chang GS, Lee IH, Chung JE, Sung KY, The PreADME: Pc-Based program for batch prediction of ADME properties, EuroQSAR. 9 (2004) 5–10.
• 46. S. Lee, I.H. Lee, H. joong Kim, G.S. Chang, J.E. Chung, K.T. No, The PreADME Approach: Web-based program for rapid prediction of physico-chemical, drug absorption and drug-like properties, Euro QSAR 2002 - Designing Drugs and Crop Protectants: Processes Problems and Solutions. (2002) 418–420.
• 47. P.A. Datar, 2D-QSAR Study of Indolylpyrimidines Derivative as Antibacterial against Pseudomonas aeruginosa and Staphylococcus aureus : A Comparative Approach , Journal of Computational Medicine. 2014 (2014) 1–9.
• 48. Core R Team, A language and environment for statistical computing, Https://Www.R-Project.Org/. (2016). https://www.r-project.org/.
• 49. N. Şener, M. Gür, M.S. Çavuş, M. Zurnaci, İ. Şener, Synthesis, Characterization, and Theoretical Calculation of New Azo Dyes Derived from [1,5‐ a ]Pyrimidine‐5‐one Having Solvatochromic Properties, Journal of Heterocyclic Chemistry. 56 (2019) 1101–1110.
• 50. E.E. Langdon-Jones, A.J. Hallett, J.D. Routledge, D.A. Crole, B.D. Ward, J.A. Platts, S.J.A. Pope, Using Substituted Cyclometalated Quinoxaline Ligands To Finely Tune the Luminescence Properties of Iridium(III) Complexes, Inorganic Chemistry. 52 (2013) 448–456. https://doi.org/10.1021/ic301853t.
• 51. A. Jabłońska-Wawrzycka, P. Rogala, G. Czerwonka, S. Michałkiewicz, M. Hodorowicz, P. Kowalczyk, Ruthenium(IV) Complexes as Potential Inhibitors of Bacterial Biofilm Formation, Molecules. 25 (2020) 4938.
• 52. S.T. Sultana, J.T. Babauta, H. Beyenal, Electrochemical biofilm control: a review, Biofouling. 31 (2015) 745–758.
• 53. N. Samsonoff, Photosynthetic-Plasmonic-Voltaics: Plasmonically Excited Biofilms for Electricity Production, in: Master of Applied Science Graduate Department of Mechanical and Industrial Engineering, 2013: p. 100. https://tspace.library.utoronto.ca/handle/1807/42922%5Cnhttp://hdl.handle.net/1807/42922.
• 54. L. Nie, Y. Li, S. Chen, K. Li, Y. Huang, Y. Zhu, Z. Sun, J. Zhang, Y. He, M. Cui, S. Wei, F. Qiu, C. Zhong, W. Liu, Biofilm Nanofiber-Coated Separators for Dendrite-Free Lithium Metal Anode and Ultrahigh-Rate Lithium Batteries, ACS Applied Materials and Interfaces. 11 (2019) 32373–32380.
• 55. T. Önkol, D. Doǧruer, L. Uzun, S. Adak, S. Özkan, M.F. Sahin, Synthesis and antimicrobial activity of new 1,2,4-triazole and 1,3,4-thiadiazole derivatives, Journal of Enzyme Inhibition and Medicinal Chemistry. 23 (2008) 277–284. .
• 56. M.P. and A.P. Otilia Pintilie, Lenuta Profire, Valeriu Sunel, Synthesis and Antimicrobial Activity of Some New 1,3,4-Thiadiazole and 1,2,4-Triazole Compounds Having a D,L-Methionine Moiety, Molecules. 12 (2007) 103–113.
• 57. M.R. Zamani, K.; Faghifi, K.; Tefighi, I.; Sharlatzadeh, Synthesis and Antimicrobial Activity of Some Pyridyl and Naphthyl Substituted 1 , 2 , 4-Triazole and, Turkish Journal of Chemistry. 28 (2004) 95–100.
• 58. H. Richet, P.E. Fournier, Nosocomial Infections Caused by Acinetobacter baumannii A Major Threat Worldwide , Infection Control & Hospital Epidemiology. 27 (2006) 645–646. https://doi.org/10.1086/505900.
• 59. J.V. and the S.G. for the S. of J. Rodrı´guez-Ban˜o, S. Martı´, S. Soto, F. Ferna´ndez-Cuenca, J. M. Cisneros4, J. Pacho´n, A. Pascual, L. Martı´nez- Martı´nez5, C. McQueary6, L. A. Actis, Biofilm formation in Acinetobacter baumannii: associated features and clinical implications, Clinical Microbiology and Infection. 14 (2008) 276–278.
• 60. P. the G. de E. de I.H. (GEIH) Jesús Rodríguez-Baño, MD, PhD; Jose M. Cisneros, MD, PhD; Felipe Fernández-Cuenca, MD, PhD; Anna Ribera, MD; Jordi Vila, MD, PhD; Alvaro Pascual, MD, PhD; Luis Martínez-Martínez, MD, PhD; Germán Bou, MD, PhD; Jerónimo Pachón, MD, Clinical features and epidemiology of Acinetobacter baumanni colonization and infection in Spanish hospitals, 25 (2004) 819–824.
• 61. J. Rodríguez-Baño, Á. Pascual, J. Gálvez, M.Á. Muniain, M.J. Ríos, L. Martínez-Martínez, R. Pérez-Cano, E.J. Perea, Bacteriemias por Acinetobacter baumannii: Características clínicas y pronósticas, Enfermedades Infecciosas y Microbiologia Clinica. 21 (2003) 242–247.
• 62. J.K. Hatt, P.N. Rather, Role of bacterial biofilms in urinary tract infections, Current Topics in Microbiology and Immunology. 322 (2008) 163–192.
• 63. D. López, H. Vlamakis, R. Kolter, Biofilms., Cold Spring Harbor Perspectives in Biology. 2 (2010).
• 64. M.A. Jabra-Rizk, W.A. Falkler, T.F. Meiller, Fungal Biofilms and Drug Resistance, Emerging Infectious Diseases. 10 (2004) 14–19.
• 65. S. Cascioferro, B. Parrino, G.L. Petri, M.G. Cusimano, D. Schillaci, V. Di Sarno, S. Musella, E. Giovannetti, G. Cirrincione, P. Diana, 2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazole derivatives as potent staphylococcal biofilm inhibitors, European Journal of Medicinal Chemistry. 167 (2019) 200–210.
• 66. M.J. Minvielle, C.A. Bunders, C. Melander, Indole-triazole conjugates are selective inhibitors and inducers of bacterial biofilms, MedChemComm. 4 (2013) 916–919.
• 67. G. Markou, D. Georgakakis, Cultivation of filamentous cyanobacteria (blue-green algae) in agro-industrial wastes and wastewaters: A review, Applied Energy. 88 (2011) 3389–3401.
• 68. A. Rahman, S. Agrawal, T. Nawaz, S. Pan, T. Selvaratnam, A review of algae-based produced water treatment for biomass and biofuel production, Water (Switzerland). 12 (2020) 1–27.
• 69. M.A. Webber, L.J.V. Piddock, The importance of efflux pumps in bacterial antibiotic resistance, Journal of Antimicrobial Chemotherapy. 51 (2003) 9–11.
• 70. S. Pogrebnoi, C. Chiriţă, V. Valica, F. Macaev, M.C. Chifiriuc, C. Kamerzan, L. Uncu, A. Uncu, S. Negreş, F.E. Ionică, F. Nicolescu, I.M. Marandiuc, E. Ştefănescu, Studies on the antimycobacterial action of a novel compound of the thiadiazole class, 2-(Propyl-thio)-5H-[1,3,4]-thiadiazole[2,3-B]-quinazoline-5-one, Farmacia. 65 (2017) 69–74.
• 71. B. Zeng, H. Wang, L. Zou, A. Zhang, X. Yang, Z. Guan, Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump, Bioscience, Biotechnology and Biochemistry. 74 (2010) 2237–2241.
• 72. E. Nikaido, I. Shirosaka, A. Yamaguchi, K. Nishino, Regulation of the AcrAB multidrug efflux pump in Salmonella enterica serovar Typhimurium in response to indole and paraquat, Microbiology. 157 (2011) 648–655.
• 73. C. Molina-Santiago, A. Daddaoua, S. Fillet, E. Duque, J.L. Ramos, Interspecies signalling: Pseudomonas putida efflux pump TtgGHI is activated by indole to increase antibiotic resistance, Environmental Microbiology. 16 (2014) 1267–1281.
• 74. P. Artursson, Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorbtive (Caco‐2) cells, Journal of Pharmaceutical Sciences. 79 (1990) 476–482.
• 75. N.A. Kratochwil, W. Huber, F. Müller, M. Kansy, P.R. Gerber, Predicting plasma protein binding of drugs: A new approach, Biochemical Pharmacology. 64 (2002) 1355–1374.
• 76. C. Palleria, A. Di Paolo, C. Giofrè, C. Caglioti, G. Leuzzi, A. Siniscalchi, G. Sarro, L. Gallelli, Pharmacokinetic drug-drug interaction and their implication in clinical management, Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences. 18 (2013) 601–610.
• 77. P. Sonkusre, Specificity of Biogenic Selenium Nanoparticles for Prostate Cancer Therapy With Reduced Risk of Toxicity: An in vitro and in vivo Study, Frontiers in Oncology. 9 (2020) 1–11.
• 78. M.F. Fromm, Importance of P-glycoprotein at blood-tissue barriers, Trends in Pharmacological Sciences. 25 (2004) 423–429.
• 79. M. Elmeliegy, M. Vourvahis, C. Guo, D.D. Wang, Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies, Clinical Pharmacokinetics. 59 (2020) 699–714.
• 80. W.M. Pardridge, Blood-brain barrier delivery, Drug Discovery Today. 12 (2007) 54–61.
• 81. C.W. Fong, Permeability of the Blood–Brain Barrier: Molecular Mechanism of Transport of Drugs and Physiologically Important Compounds, Journal of Membrane Biology. 248 (2015) 651–669.
• 82. P.A. Nielsen, O. Andersson, S.H. Hansen, K.B. Simonsen, G. Andersson, Models for predicting blood-brain barrier permeation, Drug Discovery Today. 16 (2011) 472–475.
• 83. M. Muehlbacher, G.M. Spitzer, K.R. Liedl, J. Kornhuber, Qualitative prediction of blood-brain barrier permeability on a large and refined dataset, Journal of Computer-Aided Molecular Design. 25 (2011) 1095–1106.
• 84. G.R. Wilkinson, D.G. Shand, A physiological approach to hepatic drug clearance, Clinical Pharmacology & Therapeutics. 18 (1975) 377–390.
• 85. M. Ye, S. Nagar, K. Korzekwa, A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding, Biopharmaceutics & Drug Disposition. 37 (2016) 123–141.
• 86. F. Guengerich,Peter, Cytochromes P450, Drugs, and Diseases, Molecular Interventions. 3 (2003) 194–204.
• 87. U.M. Zanger, M. Schwab, Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation, Pharmacology and Therapeutics. 138 (2013) 103–141.
• 88. E.H. Kerns, L. Di, Drug-like Properties: Concepts, Structure Design and Methods, Drug-like Properties: Concepts, Structure Design and Methods. (2008).
• 89. Y. Xu, Z. Dai, F. Chen, S. Gao, J. Pei, L. Lai, Deep Learning for Drug-Induced Liver Injury, Journal of Chemical Information and Modeling. 55 (2015) 2085–2093.
• 90. S. Wang, Y. Li, J. Wang, L. Chen, L. Zhang, H. Yu, T. Hou, ADMET evaluation in drug discovery. 12. Development of binary classification models for prediction of hERG potassium channel blockage, Molecular Pharmaceutics. 9 (2012) 996–1010.
• 91. E. Zeiger, The test that changed the world: The Ames test and the regulation of chemicals, Mutation Research - Genetic Toxicology and Environmental Mutagenesis. 841 (2019) 43–48.
• 92. Y. Fujita, H. Honda, M. Yamane, T. Morita, T. Matsuda, O. Morita, A decision tree-based integrated testing strategy for tailor-made carcinogenicity evaluation of test substances using genotoxicity test results and chemical spaces, Mutagenesis. 34 (2019) 3–16.