Facile and Adaptable Synthesis of a Prazosin Analogue Library: Bringing Medicinal Chemistry into the Undergraduate Curriculum

• Published in: Journal of chemical education 2022-03, Vol.99 (3), p.1428-1434
• Main Authors: Milicaj, Jozafina, Dodda, Vasudeva R, Patel, Kaelan R, Aragon, Ingrid Rodriguez, O’Connell, Timothy, Muthyala, Ramaiah, Taylor, Erika A, Sham, Yuk Y
• Format: Article
• Language: English
• Subjects: Advanced Courses; Antihypertensives; Chemical synthesis; Chemistry; College Science; College students; Condensation; Curricula; Curriculum development; Curriculum Research; Design optimization; Laboratory Experiments; Libraries; Mass spectrometry; Medicine; Melting point; Melting points; NMR spectroscopy; Organic Chemistry; Pharmaceutical industry; Pharmacology; Retention; Science Instruction; Spectroscopy; Spectrum analysis; STEM education; Students; Technical education; Undergraduate education; Undergraduate Study
• ISSN: 0021-9584; 1938-1328
• DOI: 10.1021/acs.jchemed.1c00822

Research has shown that the use of practical examples in undergraduate education promotes the retention of historically underrepresented students in STEM majors and lowers achievement gaps within courses. Since many students of color and women aspire toward careers in healthcare and the pharmaceutical industry, efforts to incorporate medicinal chemistry into the organic chemistry and advanced chemistry lab curriculum could potentially help enhance diversity and retention. There is currently a dearth of laboratory experiments that are medically relevant and technically accessible for incorporation into the undergraduate organic chemistry lab curriculum. The theoretical framework for optimization of drug leads and design of chemical libraries used in the exploration of structure–activity relationships is typically introduced in senior-level courses without hands-on laboratory training. In response to this, we have designed a laboratory experiment that translates the typical medicinal chemistry synthesis of a chemical analogue library into a method that can readily be deployed within an undergraduate laboratory setting through the synthesis of the clinically important antihypertensive drug prazosin and its analogues. By the use of commercially available starting materials, a small library of prazosin analogues can be synthesized utilizing nucleophilic aromatic substitution and amide-bond-forming condensation reactions. The experiment introduces a variety of concepts, including (1) retrosynthetic analysis in the design of chemical libraries, (2) methods in extraction and purification, and (3) instrumental analyses via 1H and 13C NMR spectroscopy, mass spectrometry, and melting point determination.