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Determination of Acidity Constant (pKa), Lipophilic Partition (LogP) and Distribution Coefficients (LogD) Values of Some 3-(2-Phenylethyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione-5-Acetic Acid Derivatives

Year 2024, Volume: 45 Issue: 4, 673 - 682, 30.12.2024

Gürkan Özen , Erhan Palaska , Emirhan Nemutlu

https://doi.org/10.17776/csj.1538755

Abstract

Invasive fungal infections pose a significant threat to human health, emphasizing the urgent need for new and effective antifungal agents. 3,5-Disubstituted-tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives have shown promising antifungal activity. This study focused on characterizing the physicochemical properties, specifically the acidity constant (pKa), lipophilic partition coefficient (logP), and distribution coefficient (logD), of four 3-(2-phenylethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione-5-acetic acid derivatives (EP1, EP2, EP3, and EP4) with varying α-carbon substituents. pKa values were determined using two independent methods: parallel factor analysis (PARAFAC) of UV spectroscopic data and reversed-phase high-performance liquid chromatography (RP-HPLC). Lipophilicity was assessed by measuring logD values using the shake-flask method with n-octanol, and logP values were calculated based on the determined pKa and logD values. The pKa values determined by both PARAFAC and RP-HPLC showed a good correlation. The α-carbon substituent significantly influenced pKa, with electron-withdrawing substituents resulting in lower pKa values, consistent with inductive effects. The logD-pH profiles exhibited typical bell-shaped curves, with logP values at pH 5.5 ranging from -0.38 to 3.00. EP1, EP2, and EP4 displayed lipophilic characteristics, while EP3 showed higher hydrophilicity. This study provides the first reported pKa, logP, and logD values for these novel thiadiazine derivatives. The findings emphasize the influence of structural modifications on physicochemical properties, which are critical for drug absorption, distribution, and target interaction. These data provide a valuable basis for elucidation of the structure-activity relationship and formulation optimization of these antifungal agents.

Keywords

Acidity constant Lipophilic partition Distribution coefficients PARAFAC HPLC

Thanks

I wish to express my sincere gratitude to the Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, for their invaluable support of this study. Their generous provision of laboratory facilities, materials, and comprehensive assistance were instrumental in the successful completion of this research.

References

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  • [13] E. Dinç, Z.C. Ertekin, N. Ünal, Three-way analysis of pH-UV absorbance dataset for the determination of paracetamol and its pKa value in presence of excipients, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 230 (2020) 118049.
  • [14] E. Dinç, F. Selimoğlu, N. Ünal, Z.C. Ertekin, Simultaneous Determination of the Acid Dissociation Constants of Phenolics by Multivariate Analysis of PH and Ultraviolet-Visible Spectrophotometric Measurements, Analytical Letters, 54(16) (2021) 2624-2637.
  • [15] E. Dinç, N. Ünal, Z.C. Ertekin, Three-way analysis-based pH-UV-Vis spectroscopy for quantifying allura red in an energy drink and determining colorant’s pKa, Journal of Food and Drug Analysis, 29(1) (2021) 76.
  • [16] F. Selimoğlu, N. Ünal, Z.C. Ertekin, E. Dinç, PARAFAC and MCR-ALS approaches to the pKa determination of benzoic acid and its derivatives, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 248 (2021) 119253.
  • [17] Z. Yazan, S. Erden, E. Dinç, A comparative application of two-way and three-way analysis to three-dimensional

Year 2024, Volume: 45 Issue: 4, 673 - 682, 30.12.2024

Gürkan Özen , Erhan Palaska , Emirhan Nemutlu

https://doi.org/10.17776/csj.1538755

Abstract

References

  • [1] S. Campoy, J.L. Adrio, Antifungals, Biochemical pharmacology, 133 (2017) 86-96.
  • [2] G. Wall, J.L. Lopez-Ribot, Current antimycotics, new prospects, and future approaches to antifungal therapy, Antibiotics, 9(8) (2020) 445.
  • [3] J. Loeffler, D.A. Stevens, Antifungal Drug Resistance, Clinical Infectious Diseases, 36(Supplement_1) (2003) S31-S41.
  • [4] M. Ertan, A. Bilgin, E. Palaska, N. Yulug, Syntheses and antifungal activities of some 3-(2-phenylethyl)-5-substituted-tetrahydro-2H-1, 3, 5-thiadiazine-2-thiones, Arzneimittel-forschung, 42(2) (1992) 160-163.
  • [5] A.N. El‐Shorbagi, New Tetrahydro‐2H‐1, 3, 5‐thiadiazine‐2‐thione Derivatives as Potential Antimicrobial Agents, Archiv der Pharmazie: An International Journal Pharmaceutical and Medicinal Chemistry, 333(9) (2000) 281-286.
  • [6] M. Ertan, S. Sarac, N. Yulug, Synthesis and antimicrobial activities of some new tetrahydro-2H-1, 3, 5-thiadiazine-2-thione derivatives of amoxicillin, Arzneimittel-forschung, 40(7) (1990) 790-795.
  • [7] S. Raheem, R. Khan, X. Pan, R. Ullah, S.A. Halim, A. Khan, A. Al-Harrasi, One pot domino synthesis of new 3, 5-disubstituted-tetrahydro-2H-1, 3, 5-thiadiazine-2-thiones (THTTs) as anti-inflammatory and antinociceptive candidates: A proof from in-vivo to in-vitro and in-silico mechanistic studies, Bioorganic Chemistry, 127 (2022) 105974.
  • [8] H. Ali, R. Khan, X. Pan, F. Shaheen, A. Jabeen, A. Rauf, M. Shah, U. Rashid, Y.S. Al-Awthan, O.S. Bahattab, Synthesis, characterization, anticancer, anti-inflammatory activities, and docking studies of 3, 5-disubstituted thiadiazine-2-thiones, Green Processing and Synthesis, 12(1) (2023) 20228136.
  • [9] D. Katiyar, V. Tiwari, R. Tripathi, A. Srivastava, V. Chaturvedi, R. Srivastava, B. Srivastava, Synthesis and antimycobacterial activity of 3, 5-disubstituted thiadiazine thiones, Bioorganic & medicinal chemistry, 11(20) (2003) 4369-4375.
  • [10] N. Arshad, J. Hashim, M.A. Minhas, J. Aslam, T. Ashraf, S.Z. Hamid, T. Iqbal, S. Javed, New series of 3, 5-disubstituted tetrahydro-2H-1, 3, 5-thiadiazine thione (THTT) derivatives: synthesis and potent antileishmanial activity, Bioorganic & Medicinal Chemistry Letters, 28(19) (2018) 3251-3254.
  • [11] Y. Ishihama, M. Nakamura, T. Miwa, T. Kajima, N. Asakawa, A rapid method for pKa determination of drugs using pressure-assisted capillary electrophoresis with photodiode array detection in drug discovery, Journal of pharmaceutical sciences, 91(4) (2002) 933-942.
  • [12] C. Hansch, A. Leo, Substituent constants for correlation analysis in chemistry and biology, Journal of Quantum Information Science, Vol 1, No 2 ,1979.
  • [13] E. Dinç, Z.C. Ertekin, N. Ünal, Three-way analysis of pH-UV absorbance dataset for the determination of paracetamol and its pKa value in presence of excipients, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 230 (2020) 118049.
  • [14] E. Dinç, F. Selimoğlu, N. Ünal, Z.C. Ertekin, Simultaneous Determination of the Acid Dissociation Constants of Phenolics by Multivariate Analysis of PH and Ultraviolet-Visible Spectrophotometric Measurements, Analytical Letters, 54(16) (2021) 2624-2637.
  • [15] E. Dinç, N. Ünal, Z.C. Ertekin, Three-way analysis-based pH-UV-Vis spectroscopy for quantifying allura red in an energy drink and determining colorant’s pKa, Journal of Food and Drug Analysis, 29(1) (2021) 76.
  • [16] F. Selimoğlu, N. Ünal, Z.C. Ertekin, E. Dinç, PARAFAC and MCR-ALS approaches to the pKa determination of benzoic acid and its derivatives, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 248 (2021) 119253.
  • [17] Z. Yazan, S. Erden, E. Dinç, A comparative application of two-way and three-way analysis to three-dimensional
There are 17 citations in total.

Details

Primary Language English
Subjects Pharmaceutical Analytical Chemistry, Analytical Spectrometry
Journal Section Natural Sciences
Authors

Gürkan Özen 0000-0003-0777-6402

Erhan Palaska 0000-0002-8914-8858

Emirhan Nemutlu 0000-0002-7337-6215

Publication Date December 30, 2024
Submission Date August 26, 2024
Acceptance Date December 11, 2024
Published in Issue Year 2024Volume: 45 Issue: 4

Cite

APA Özen, G., Palaska, E., & Nemutlu, E. (2024). Determination of Acidity Constant (pKa), Lipophilic Partition (LogP) and Distribution Coefficients (LogD) Values of Some 3-(2-Phenylethyl)-Tetrahydro-2H-1,3,5-Thiadiazine-2-Thione-5-Acetic Acid Derivatives. Cumhuriyet Science Journal, 45(4), 673-682. https://doi.org/10.17776/csj.1538755
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