2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023 (567-570)
АУТОР(И) / AUTHOR(S): Mihajlo J. Krunić, Jelena Z. Penjišević, Slađana Kostić-Rajačić, Vladimir B. Šukalović, Deana B. Andrić, Ivana I. Jevtić
Е-АДРЕСА / E-MAIL: jelena.penjisevic@ihtm.bg.ac.rs
DOI: 10.46793/ICCBI23.567K
САЖЕТАК / ABSTRACT:
Two new tacrine/pyrazole conjugates were designed, synthesized, and pharmacologically evaluated for their inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A scalable and cost-efficient synthetic route was developed, and key reaction steps for the synthesis of compounds 4a,b were nucleophilic substitution of α-aroylketene dithioacetals with tacrine intermediates, followed by cyclocondensation of respective N,S-acetals with hydrazine hydrate. The preliminary pharmacological evaluation revealed high inhibitory activities of 4a,b toward AChE (180 and 259 nM, respectively) and BuChE (51 and 95 nM, respectively) as compared with known inhibitor, tacrine. Overall, both compounds were more efficient BuChE inhibitors while 4a, with a shorter linker connecting tacrine and phenylpyrazole moieties, showed higher inhibitory activity toward both enzymes. Molecular docking analysis strongly corroborated pharmacological results since both compounds interacted favorably with target enzymes. Calculated pharmacokinetic properties (absorption, distribution, metabolism, and excretion (ADME) showed that 4a,b obey Lipinski’s rule of druglikeness and are promising lead compounds for the development of new drug candidates.
КЉУЧНЕ РЕЧИ / KEYWORDS:
Alzheimer’s disease, acetylcholinesterase, butyrylcholinesterase, tacrine, pyrazol
ЛИТЕРАТУРА / REFERENCES:
- https://www.who.int/news-room/fact-sheets/detail/dementia
- D. Munoz-Torrero, Acetylcholinesterase Inhibitors as Disease-Modifying Therapies for Alzheimers Disease, Current Medicinal Chemistry, 15 (2008) 2433-2455.
- P. Wexler, Tacrine, Encyclopedia of Toxicology, 3rd Ed. Academic Press, 2014, pp 466-467.
- P. Dhanalakshmi, S. Thimmarayaperumal, S. Shanmugam, Metal catalyst free one-pot synthesis of 2-arylbenzimidazoles from a-aroylketenedithioacetals, RSC Advances 4 (2014) 12028-12036.
- S. Kuettel, A. Zambon, M. Kaiser, R. Brun, L. Scapozza, R. Perozzo, Synthesis and Evaluation of Antiparasitic Activities of New 4-[5-(4-Phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Derivatives, Journal of Medicinal Chemistry 50 (2007) 5833-5839.
- M.J. Krunić, J.Z. Penjišević, R.V. Suručić, S.Šegan, S.V. Kostić-Rajačić, I.I. Jevtić, Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors, Journal of Molecular Structure, Volume 1276 (2023) 134809.