“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, and their structures and syntheses have been tabulated in a review by Fang et al. in 2019 [1]. However, the beneficial effects of the chlorine substituent have not yet been discussed to the same extent as other small groups like methyl [2] or fluorine [3]. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold. Following the literature terminology of the “magic methyl effect” in drugs, the term “magic chloro effect” has been coined [4]. Although reports of 500-fold or 1000-fold potency improvements are often serendipitous discoveries that can be considered “magical” rather than planned, attempts to explain an unexpectedly significant chloro effect can be an important exercise. In this presentation, the effect of chlorine substitution on dipole moments, acidity, and lipophilicity, as well as hydrogen and halogen bonding, will be discussed in the context of ligand–protein binding and potency improvements. Furthermore, chlorine substituents can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo. Although there are case-by-case variations, a chlorine atom is able to combine the beneficial effects of a methyl group (e.g., lipophilicity, van der Waals interactions, steric effect) and a fluorine atom (e.g., electronegativity / electron-withdrawing ability, metabolic stability, increased acidity). Suggestions will be made regarding when (and when not to) include chlorine substituents in a preclinical molecule. Although the chlorine effect might be more beneficial for early preclinical studies, it can be argued that the chlorine effect can be useful at all stages of preclinical work, and understanding this effect better could lead to lessons that accelerate the cycle of drug discovery.



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[2] Fang, W.-Y.; Ravindar, L.; Rakesh, K. P.; Manukumar, H. M.; Shantharam, C. S.; Alharbi, N. S.; Qin, H.-L. Synthetic Approaches and Pharmaceutical Applications of Chloro-containing Molecules for Drug Discovery: A Critical Review. Eur. J. Med. Chem. 2019, 173, 117–153.

[3] Schönherr, H.; Cernak, T. Profound Methyl Effects in Drug Discovery and a Call for New C–H Methylation Reactions. Angew. Chem. Int. Ed. 2013, 52, 12256–12267.

[4] Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315–8359.

[5] Chiodi, D.; Ishihara, Y. “Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery. J. Med. Chem. 2023, 66, 5305–5331.