March 1968
36i
SOTES n B L E 111 THEPHOTOTOXICITY O F & U I ~ O L I ~ E ~ ~ E T H . ~L)I-N-.\LI~YLs S~L~. CHOH-CH-N(R’), I
It
C1
C1
e133
c1 c1 CIIJ
c1
e1
S,.l-CI, 4-OCHs 3,4-(OCH2)2 3,4-C1> 4-C1 H 4-OCTT3 441
It’
Et Kt
Et n-C,FI,; I-opeir tyl n-Bit n-€311
n-13ii
4-c‘1
U-BIl
4-CI
n-Uli n-Uii n-BLi n-Bii n-Bii n-Bu n-Bii n-Bii n-Bii n-Bil ~-C~HIJ n-CeH13
4-C1 4-e1
4-C1 4-F Cl 4-C1( 3-CH3)h e1 2,4-C1> 2,4-C12(3-CH3)” e1 e1 3,4-C12 c1 3-CFd H e1 4-C1 e1 e1 4-C1 ll-c6~ r, 3 3,4-C!2 n-c6l-I*3 c1 4-OcH3 n-C61113 C1 3-CF3 n-CsH1, a From It. R o d e t t , Tirginia Inst,itute for Scientific Research, Richmond, T a . From T. Biel, dldrich Chemical Co., Xilwaitkee, \Vis. c F. Y. Wiselogle, Ed., “Survey of Aritimalarial L h i g d , 1941-1946,” Edwards Bror., Aiiii Arbor, JIich., 1946. d From A. Saggiomo, Research I~istit~iite of Temple University, Philadelphia, Pa. e From E. Atkillson, Arthur D. Lit,tle, Inc., Cambridge, llass. From Walter Reed Army Institute of Research, Washington, D. C. 0 3Iiiiimiim effective phototosic dose. h CH, on 3 pocitioii of B ring. CFs
F
The structures described in Table I11 are analogs of I bearing various di-S-alkyls in the side chain. A11 proved to be more or less phototoxic. Considered as groups, the potency appears to vary inversely with the length of the alkyl group on the nitrogen in the side chain. Albino mice are convenient and sensitive indicators of photosensitivity. Their small size, sparsely haired ears and tail, and uniform response to uv radiation makes it possible to screen many compounds in a short time and with minimum expense. I n our studies, no attempt was made to score the degree of cutaneous response in the irradiated animals. Rather, multiple drug doses were employed to determine the minimum effective dose for potency comparison. Even such a simple comparison is hazardous since the excretion time and tissue level of individual compounds may vary widely. Perhaps a more meaningful comparison could be related t o an index derived from the ratio of maximum tolerated dose to minimum effective dose, Of course, the problem of drug concentration during irradiation is present in all tests whether the agent is administered orally, parenterally, or topically. Certain tentative assumptions have evolved from a study of our prelimiiiary results. (1) Substitution of the 2 position of the yuinolirie nucleus with a furictional group is iiecessary to ensure
the ability of quinoline methaiiols to seiisitize mice to radiation. The phototoxic potency of %substituted compounds varies with diff ererit functional groups in a manner that may suggest an association with their relative electronegativities. ( 2 ) Definite side-chain influence is present in this series of yuinolirieniethanols. hzaarenes and long alkyl substitutions on nitrogen in the side chain tend to reduce the phototoxic potency. (3) A-Ring substitution usually results in an increased phototoxic response with C1 > CH, > OCH,. Additional testing will be required to substantiate this observation. It is probable that the combination of a functional group in the 2 position and a methanol side chain is important in photoserisitizatioii. The 2-phenyl malogs of such aminoyuinolines as chloroquine and primaquine do not elicit a phototoxic reqponse in mice (unpublished data). Likewise, quinine which is a wellknown quinolinemethanol lacking 2 substitution is not a photosensitizer. The parent compound of our series (I) might be viewed as a tricyclic aromatic ring system with coplanar features. It has been hypothesized that all such ring systems have potential photosensitiziiig ahilitj..7 V:irious a~ialogsof I were synthesized
The Iniluencc of the Carbox! 1 Group upxi thc Antibacterial Activit? of Rifam? ciiisl
1i:w I ) o c ~ i tiemoiistr:ited? t1i:rt rifamycin €3 (I), of the products of the met:ibolisni of Strepfomyces //ieditei.,,a/iei,:l is inactive per SP. 111 aqueous media i.ifaniyciii €3 Ullderg(JeS :iii oxidative and hjdrolytic t ratisf(irin~~tioii t o rifaniycin S' which pussesses high :iiitibacterinl activit).. liifam?.cin S is easilj- reduced t o the hJ.droquinorie form, rifamycin ST' (11). which is
It
oiie
iiow eniployod in the therap!. of ~t:ipli.\~lococcal and other gram-positive iiifectioiih. ljiliw!. tract iiifectioris, , alld lepros).." Thc .tlsilctura tin\x4ii €3 aiid rif;iiii>y:iii S\- COI atiselice iii the latter of the glJw)lic: nioiety tmiring a free CLlrb(JXy1$I'OUL).''
I, 1: 11, 1: IIIa. 1: 1 m ; 11
= = = =
CI1 I?: 11:
IVtL, It
=
11;
11:
NQ,,
for tlic 111 rzt1 o :iiitibacterial activity aiitl coiiip:trcd with the malogous rif:iinycin\ without carbox\ 1 group, already described (IIIb aiid IT'b,g Tb. T?b, aiid YIIb,''' VIIIbl'). Biological Results.. - Table I buiiininrizes tlie n i i i i i mum inhibitory c'oncentratiun of the earho\;yrifniii~~iiih ,igairiat sonic typic:tl htraiiis and conipiire~i t I\ it11 that ~ ~ o n ( l i l lrgl f ~ ~ l i l y ~I\~iti ll ~l ~ o u l :i (Ylrboxyl .ctulting data calcarly ronfirni :t tlccwasc. of activity for the rif:imycirii invebtigatetl, n l l c i i wiiil):ircd t o tile c*orresl)onding tlcrivntivcs \ritliout the c:wbo\yl groul). The ratio of activity het\recii derivatli \Ylth 2 i I l d I\ 1thOUt the cal.b(JXYl gr(JL1p I)l'eSeIltb hrge variationi according t o the t j pe of tlerivativci talien iiito corideratioii arid t o the teht iiii(.roorgaiii~ni. l~:irticularly,Staphylococcus c1wcu.s is more seiisitive t o tlie >trricturiil variation here examined. 111 fact, t h r introduction of :I carboxyl group iiiduceb :i dccrcasc of :ictivity froni 1:1000 (T'IIIa: VIIIb) to 1 : 10 (1T':t IVh)
,Ct/ cpiocori us hei/iuly/zc.us i:, 1c's icrisitivc to tli(wx ~tructuralinodificationh : in wine i~istanc'e\ (IVa PS. IT'b and TWa I H. T'IIb) there i5 iio higiiificarit niodificn:ire praction of activit) . Alllthe carboxyrifam~~iris tically inactive agaimt gram-negative bacterin :irid preseiit only liinitect activity oii JIycobacterzzwi tubei culosis; on the contr:trl-. t he parerit conipounds ihov moderate activity on the former :tnd are highly actiw on the latter.
