KOTES
November 1961)
1115
TABLE I a - ~ C E T A ~ I I D l t A Z O N I U MTHIOSULF.ZTES
NH2
+
CH2/hNHit
I
szo3-
R Compd
11
yield
Approx
oc
Mp, dec
Formulaa
LD~Q, mdkg
Antiradiation act.-Drug dose, Ing/kgd
30-day survival,
7Oe
13 132-163 CsHiiN303Sn pOnNCaHc 37 178-179 CsHioNiO&* 130 80 20 V O-CH~OCOH, 19 136-137 C9Hi3N30& 110 25 13 19 143-144 CsHiaFN303Sn VI p-FCJL VI1 EtOnCCHz 17 143-144 C6Hi3N30jSnC 750 400 13 N : calcd, a Analyt.ica1 results obtained for C, H, and N were within 3k0.4Yc of the theoretical values unless listed otherwise. Compounds were suspended in a physiological saline solution containing 0.3% 18.3; found, 17.8. c C: calcd, 26.6; found, 26.1. carboxymethylcellulose and 0.1 Tween 80 and administered intraperitoneally to mice, which were subjected t.o lethal radiation of No survival among control mice. 960 R.
I11 IV
c6115
was triturated Kith boiling absolute EtOH and dried to give 2.9 g
(377,) of orange product, mp 178-179" dec.
Acknowledgments.-The authors are indebted to Drs. D. P. Jacobus and T . R. Sweeney for antiradiation data and to 3Ir. P. E. Olson, 3Ir. G. J. Lillquist, and the members of the Analytical Research and Services Laboratory of the 311 Company for microanalytical and spectral analyses.
5-Nitro-8-quinolinols and Their Copper(I1) Complexes. Implications of the Fungal Spore Wall as a Possible Barrier against Potential Antifungal Agents' HERMAN GERSHOK, ~IAYNA W.RAICNEIL, D .\SD YvolvN~HINDS Boyce T h o m p s o n Institute f o r Plant Keseurch, Yonkers, ?;ew Y o r k 10701
Ifcceived A p r d 95,1969
A hypothesis was proposed by Gershon, et a1.,'v3 which suggested that the fungal spore wall acted as a barrier against certain potential antifungal agents. If the geometry and charge distribution of a molecule are not compatible with geometry and distribution of charge around the periphery of the holes in the fungal spore wall, the compound cannot penetrate the wall and cause toxic reactions in the spore. It was deduced from the shapes and dimensions of the Cu(I1) chelates of substituted 8-quinolinols that the holes cannot be circular but may be elliptical or hexagonal. If the hypothesis is sound, and the explanation of the liontoxicity of certain compounds is due to the long axes being greater than the major axes of t,he spore holes, alteration of a secondary axis of the compound should not cause the derivative to become toxic. Bis(ti-nitro-8-quinolinolato)copper(II)was shown to be nontoxic to five fungi, Aspergillus niger, Trichoderma viride, Aspergillus oryxae, Myrothecium verrucaria, and ( 1 ) This work was supported in p a r t by the U. S. Public Health Service, Grant No. AI-05808. (2) H . Gershon. R. Parmegiani, A . Weiner, and R. D'Aaooli, Contrib. Boyce Thompson Inst., 1 8 , 219 (1966). (3) H. Gershon, J . M e d . Chem.. 11, 1094 (1968).
Trichophyton nientagrophytes.2 The explanation was that its long axis was greater than the diameter of the holes in the spore walls and penetration of the spores could not be effected. Consequently, any 7-substituted 5-nitro-8-quinolinol Cu(I1) complexes should also be nontoxic to the same fungi. To test this, the Cu(I1) bischelates of 7-fluoro-, 7-chloro-, 7-bromo-, and 7iodo-5-nitro-8-quinolinol were prepared and screened against the same five fungi. Although the chloro ligand4mas previously preparcd by a Skraup synthesis, the present preparation mas obtained by treatment of 5-nitro-8-quinolinoIj with NaOC1. The bromo6 and iodo7 compounds were also prepared from 5-nitro-8-quinolinol. The respective copper(I1) complexes mere prepared from the ligands by treatment with cupric acetate in aqueous JleOH, or aqueous XeOH containing DNF. The data characterizing the new compounds are contained in Table I. All of the compounds were screened for antifungal activity in shake cultcrz a g r h s t the spores of the five fungi previously mentioned, according to published methods.8 The data of Table I1 show that the 7-substituted ~-1~tro-8-quinolinols possess significant antifungal activity but weaker than that of the parent compound, .j-nitro-8-quinolinol.2 The Cu(I1) bischelates were all inactive. Thus, these results were found to be consist ent with our hypothesis. * It should be mentioned that in certain cases the freshly prepared chelate caused inhibition of mycelial development. On repeated boil-up of the chelate with DNF, the inhibitory effect was eliminated. Upon cooling the D X F solution, a chelate was obtained which was inhibitory. When both the soluble and insoluble chelates were decomposed with H2S and the Cu(I1) removed, followed by recovery of the ligands, gas chromatography of the trimethylsilyl derivatives indicated that both chelates appeared to possess the same component parts. We cannot interpret this observation properly, but a reasonable explanation may be that in the formation of the chelate, a small amount of cis F. X. Wiederkehr and E. Hofstetter, Helu. C h i n . Acta. 86, 468 (1952). V. Petrow a n d B. Sturgeon. J . Chem. Soc., 570 (1954). (6) H. Vogt and P. Jeske, Arch. Pharm., 191, 168 (1958). (4) (5)
(7) K . RIatsumura, J . A m . Chem. Soc.. 49, 810 (1927). ( 8 ) H . Gershon and R. Parmegiani, A p p l . X w w b a o l . , 11, 62 (1963).
