528 Journal ofMedicinal Chemistp, 1974, Vol. f7, N o
;i
Notes Effect of 6-a Substitution i n Penicillins a n d 7-a Substitution in Cephalosporins upon P-Lactam Reactivity Joseph M. Indelicate* and William L. Wilham The Lilly Research Laboratories, Eli Lilly and Cornpan), Indianapolis, Indiana 46206. Received October 23, 1973
Strominger hypothesized that penicillins and cephalosporins may irreversibly acylate bacterial transpeptidase because they have a conformation similar to one possible for D-alanylalanine, the terminal fragment of the peptide with which this enzyme is believed to react.l Consequently, he proposed that 6-a-methylpenicillins and 7-a-methylcephalospprins might show increased antibacterial properties over the corresponding 6-a-H and 7-a-H compounds because of increased structural resemblance to the D-alanylalanine Eragment. The discovery of naturally occurring 7-a-methoxycephalosporins, with their increased gramnegative activity, seemed to support this proposal.2 As a result, many synthetic approaches to these and other 6-0 and 7-a derivatives were developed.?
methoxy, or S-methyl group to a penicillin results in a reduction of both transpeptidase inhibition and antibacterial activity. In contrast, the addition of' a 7-tu-methoxv group to a cephalosporin results in compounds that are better transpeptidase enzyme inhibitors than their unsubstituted counterparts although they do not necessarily possess better antibacterial properties. Our purpose in this study was to examine the effect of 6-a and 7-a substitution in penicillins and cephalosporins. respectively, upon the reactivity of the @-lactamsto determine whether chemical reactivity parallels antibacterial activity . The rates of' base hydrolysis of a series of a-substituted and a-unsubstituted penicillins and cephalosporins are listed in Table I. These results show that 6-tu substitution in penicillins resulted in compounds with less reactive P-lactams than the parent compound. This effect must be steric rather than polar because polar substituent constants rr1 or CJ* would predict the rate of hydrolysis of the 6-a-meihoxypenicillin to be faster and the 6-a-methylpenicillin to be slower than the unsubstituted parent penicillin.
T a b l e I. Pseudo-First-Order Rates of Base Hydrolysis a t pH 10, 35"
___
Side chain (R')
PhOCH1C i=O)
PhCHiC (=O)
6i7)-a substituent iR")
H CHJ OCHi SCH, H OCH, OC,H,
H OMe
___
x
__ 101
-
48
1
08
0 1 0.3
K"1W i sec
6 90 0 0 77 = 0 2 35 __ 0 0 77 T 0 5 08 -t 0
48
02
15 1 17 i 0 22 0 67 -fr n 13
9 70 -z0 65 12 40 0 65 f_
--
K>II 1a-R") I
