Authors : Bennett Yoonjae Cho

Volume/Issue : Volume 10 - 2025, Issue 9 - September

Google Scholar : https://tinyurl.com/3vp7hmvr

Scribd : https://tinyurl.com/y26jwt4h

DOI : https://doi.org/10.38124/ijisrt/25sep789

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Abstract : Modulating blood–brain barrier (BBB) permeability is a crucial aspect of central nervous system (CNS) drug design. One strategy to decrease undesired BBB penetration involves the structural modification of drug molecules through the introduction of sterically bulky substituents. This study aimed to develop and evaluate a synthetic method for the selective introduction of tert-butyl groups onto an aromatic ring via Friedel-Craft alkylation, in order to investigate its potential to reduce BBB permeability. Acetanilide which synthesized from aniline was subjected to Friedel-Craft alkylation under mild conditions using tert-butyl chloride and aluminum chloride as reagents. Structural modification was confirmed via Fourier transform infrared spectrometer and nuclear magnetic resonance spectrometer. The tert-butyl group was successfully introduced, resulting in a substantial increase in molecular steric bulk. This approach may offer utility in the rational design of peripherally acting drugs by minimizing unintended CNS exposure.

Keywords : Medicinal Chemistry, Freidel-Craft Alkylation, BBB Permeability.

References :

1. The Texas Tribune. (2019, May 29). Texas passes law banning sale of cough medicine to minors. https://www.texastribune.org/2019/05/29/texas-passes-law-cough-medicine-dextromethorphan/
2. Ding, Y., & Xue, X. (2024). Medicinal chemistry strategies for the modification of bioactive natural products. Molecules, 29(3), 689.
3. Wu, K., Kwon, S. H., Zhou, X., Fuller, C., Wang, X., Vadgama, J., & Wu, Y. (2024). Overcoming challenges in small-molecule drug bioavailability: A review of key factors and approaches. International Journal of Molecular Sciences, 25(23), 13121.
4. Ferreira, F. J., & Carneiro, A. S. (2025). AI-Driven Drug Discovery: A Comprehensive Review. ACS omega.
5. Talbert, J., Blumenschein, K., Burke, A., Stromberg, A., & Freeman, P. (2012). Pseudoephedrine sales and seizures of clandestine methamphetamine laboratories in Kentucky. JAMA, 308(15), 1524-1526.
6. U.S. Congress. (2005). Combat Methamphetamine Epidemic Act of 2005, Pub. L. No. 109–177, 120 Stat. 256. https://www.fda.gov/drugs/information-drug-class/legal-requirements-sale-and-purchase-drug-products-containing-pseudoephedrine-ephedrine-and
7. Faramarzi, S., Kim, M. T., Volpe, D. A., Cross, K. P., Chakravarti, S., & Stavitskaya, L. (2022). Development of QSAR models to predict blood-brain barrier permeability. Frontiers in Pharmacology, 13, 1040838.
8. Zhang, L., Zhu, H., Oprea, T. I., Golbraikh, A., & Tropsha, A. (2008). QSAR modeling of the blood–brain barrier permeability for diverse organic compounds. Pharmaceutical research, 25(8), 1902-1914.
9. Janicka, M., Sztanke, M., & Sztanke, K. (2020). Predicting the blood-brain barrier permeability of new drug-like compounds via HPLC with various stationary phases. Molecules, 25(3), 487.