QUATERNARY AMMONIUM COMPOUNDS IN MEDICINAL CHEMISTRY. I *

INTEREST in the biological activity of quaternary ammonium salts stems from the elegant work of Crum Brown and Fraser (1868-9), who were the first to record the curariform activity of methiodides of alkaloids such as strychnine, brucine, and atropine. Apart from a few scattered papers, the pharmacological activity of quaternary ammonium salts received little attention for many years. Hunt, Renshaw and their associates, working over a period of some 35 years from 1904 to 1939, published a very large number of papers dealing with the effects of these compounds on the autonomic nervous system ; they established three basic types of activity, muscarinic, nicotinic and curariform. References to this work are listed in full in Craig’s excellent review, “Curariform activity and chemical structure” (1948). Concurrently with these studies, quaternary ammonium compounds were emerging into greater prominence by virtue of their activity against micro-organisms. Their germicidal activity was first recognised in 1916, when Jacobs and his colleagues (Jacobs, 1916; Jacobs, Heidelberger and Amoss, 1916 ; Jacobs, Heidelberger and Bull, 1916) investigated the relation between chemical structure and bactericidal activity of quaternary salts of the hexamethylenetetramine series. The synthesis of the sapamines (acylaminoethyltrialkylammonium salts) by Hartmann and Kagi (1 928) is representative of the work that led to the recognition of the exceptional virtues of this class of high molecular weight quaternary ammonium salts (the so called “invert soaps”) ; the development of these compounds as germicides paralleled the study of their properties as surface-active agents and as textile chemicals. Nevertheless the potentiality of quaternary agents was not fully realised, and their widespread use was not established, until Domagk (1935) examined certain compounds and only found notable germicidal activity when at least one of the four radicals had a carbon chain of length CB to C18. The most important compound to emerge from this work was Zephirol (Zephiran, benzalkonium chloride), which has the structure RN+.(Me,).CH2.Ph C1where R is a saturated straight alkyl chain containing from 12 to 18 carbon atoms. Initially quaternary ammonium germicides were considered to be primarily suited for surgical and medical usage, but later an increasing application to public health and sanitation became a major factor in their commercial development and exploitation. An important stage in the