Journal of Medicinal Chemistry 0 Copyright 1965 by the American Chemical Society
YOLKME8, KCMBER 3
APRII 26, 1965
Structure-Activity Relationships i n the Field of Antibacterial Steroid Acids JOSEFFRIED,^ GERALD JY. Iiiiust therefore, be considt:red active. Xniong the dirarhosylic acids only t h r two lrans-acids 5 and 7 shon.ed activity, the two cis-acGds being inactive ai ihc 100-7 level. AI^ interesting r o i l t rast i n activity 11-as shoivi1 between the wcll-l~iio~~-ii keto acid 9 and its 5-deoxo derivative 10. The f o l ~ t i c i . was active at the 2-y level, whereas the latter was iliac,tive at 100 y. T h e preseiicc of aii oxygen fuiivtioil i i t the y- or 6-positioii with respect to the carboxyl group has beeri a characaterist i c , feature of all act,ive csoinpouiids r, a i d , iiideed, it is a charact'ei irriitg steroid antibiotics. as ~ ~ 1 1'I'h(1 .
two> if
May 1965
lack of activity of compound 10 indicates that this may be an essential requirement for antibacterial activity. As we shall see later, a double bond appropriately located may take the place of this oxygen function. The simple alicyclic &keto acid, cyclohexanone-2-(3-propionic acid) (Table 111, 2), was inactive, stressing the necessity for a larger condensed ring system. This latter condition is fulfilled in the ring B seco-acid (Table 111, 3)) which showed activity equal to that of the keto acid 9 (Table 11). TABLE I11 NISCELLAXEOUS ACIDS Structure
CoInpd.
,
MIC,” y/m1.
14
> 100
3
HO
4d
& uo
2-3
COOH
The data presented here although adiiiittedly sketchy indicate that the antibacterial activity of the steroid acids is a phenomenon of limited structural and steric specificity. What appears to be necessary is a rigid, essentially flat niolecule possessing at least, and preferably, one anionic site, which is close to an oxygen function or perhaps also the a-electrons of a double bond. These requirements are fulfilled in the naturally occurring steroid antibiotics, all of which possess an acetoxy group in y-position to the carboxyl group. It should be kept in mind that the most active coinpourids described in this paper possess about 1/50 to 1 ’100th the activity of fusidic acid, indicating that our conclusions regarding the limited structural requireiiieiits for activity will have to be refined when it conies to define i i i u x i m m activity. These more subtle factors, however, niay no longer be related to intrinsic biological activity, that is, the chemical events occurring at the site of action, but may be connected with factors such as transport to the site of action, metabolic inactivation, coniplexing with cell constituents, etc. The attairinieiit of niaxiniuni biological activity represents a sequence of events of such complexity that, to consider our data in a more quantitative sense would be all but nieaningless. Xevertheless, by defining the minilnuin requiremerits for activity, the findings presented in this paper should prove useful in the selection of additional antiniicrobially active compounds from aiiiong known steroids and terpenes, and in the synthesis of new, hopefully more active, representatives of this class. The validity of the above generalizations regarding the relationships of structure and activity among antiniicrobial steroids is dependent upon a coninion mechanism of action for both the naturally occurring antibiotics and the steroidal acids reported in this paper. Such corresporiderice was demonstrated by showing that a strain of 8. uureus made resistant towards fusidic acid was also resistant to the action of two synthetic coiiipounds representative of this work (Table I, 2, and Table 11, 3). Both were inactive at 100 y’1ii1. when tested against that strain.
Ho*cx w 1-2
k+A& .9
5.
281
AXTIBACTERIAL STEROIDACIDS
CtP
>loo
1Iiriimum iiihibitory concentration of steroid acids ill twoJ. Polonsky, fold serial dilution assay against S. u w m s 209P. Bztll. soc. chim. France, I73 (1953); S.Breivis and T. G. Halsall, J . Chem. Soc., 646 (1961); cj”. also ref. 11. c T’. 5’. Korshak, S. L. Sosin, and E. 11.1Iorozova, Zh. Obshch. Khim., 30,907 (1960); Chem. d b s t r . , 5 5 , 376c (1961). d L. F. Fieser and AI. Fieser, “Steroids,” Reinhold Publishing Corp., New York, N. Y., 1959, p. 5 5 ; e Ref. d , p. 61. a
Unexpectedly high activity (1-2 -y/iril.) was shown by cholatrienic acid (Table 111, 4). Other bile acid derivatives such as the fully saturated cholanic acid (Table 111, 5 ) , 3,12-diketocholanic acid, and 3,7,12-triketocholanir acid were inactive. Perhaps, t,he 11,12double bond of cholatrienic acid takes the place of the oxygen function considered necessary for activity, but this is a rat’her tenuous assumption, because of the distance of the double bond from the carboxyl group and because of the fact that the two 12-keto acids tested did not show activity. The triterpenoid asiatic acid (Table 111, l ) , which possesses a double bond in the yposition with respect to the (axial) carboxyl group, may more justifiably be viewed as an analog of the active y- or &hydroxy or keto acids, in which the double bond takes the place of the oxygen function.
0.-7A 0
VI1
IV, R = A c V, R = H VI, O R = =O
0 VI11
Experimental JIelting points were taken on a Thomas-Hoover apparatus and are corrected for stem exposure. Rotations were determined in chloroform. Infrared spectra were t,aken on a Perkin-Elmer 21 spectrometer. The substances listed in Tables 1-111 weye either taken from our collection of steroids or were prepared specifically for the purpose of this paper, Thuse not hitherto described in detail
(',
31.10 H, 1 1 J b
3.4-Secoluoan-4-ol-3-oic Acid (Table I. 7 1.
A susueiisioii 1 ri
