,J. E'. DI(KIE,M. E. L O O M A ~T. S ,11. FAKLEY, \AI) 1'.11. STKOAL
424
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The Chemistry of Antimycin A. XI. N-Substituted 3-Formamidosalicylic Amides' J. P. DICKIE,11.E:.
LOOMASS,
'r. 11. FARLET,
1\11
I;. 11.S T R O A G
Department of Bzocheinzstry, C-nzaersity o j TVLsconsin, .IJudiso/i
h , Ll-iacoiisiii
Received January %8,1 M S A series of antimycin analogs consisting of substituted amides of Y-for~naniidosalicylicarid was prepared by condensing 3-nitrosalicylic acid with suitable primary amines in the presence of o-phenylene phosphorochloridite, catalytically hydrogenating the nitro groups t o primary amines, and formylating' t,heproducts. The inhibitory power of the analogs was estimated by their effect on reduced coenzyme Q-cytochrome c reductase. The higher members of the homologous n-alkyl amides exhibited up to one-half the activity of antimycin -\,while t>he longer chain 3-nitro intermediates showed appreciable but loTver activit,y. Antibacterial, antiviral, and antifungal screening with the n-alkyl series showed no important activity. The results support the hypothesis that. the localization of activity is centered around the aromatic portion of t>heantimycin molecule and that the remaining dilactone portion probably is important only insofar as it contributes the proper solubility characteristic's t>othe molecule.
It has been demonstrated that the characteristic ability of Antimycin -1 (I)* to inhibit the electrontransport system of higher animals3 is abolished by methylation of the phenolic hydroxyl, removal of the S-formyl group, or by alkaline cleavage of the dilactone which ring.2 However, both antimycin AI and -I3, differ only in bearing n-hexyl or n-butyl side chains, respectively, are about equally active,j and the Sformal group may he replaced by an acetyl with only hlight loss of activity.? ' 12or these reasons, it appeared that the most essential portion of the antimycin structure (I) was the aromatic nucleus and the immediately adjacent substituent groups. The remainder of the structure might conceivably be of little importance other than to provide a certain degree of lipid solubility. -1s a start on the program of synthesizing analogs of antimycin A of a relatively simple structure, attention was therefore turned to substituted amides of 3-formamidosalicylic acid (TI)
g HNCHO
c
a''
qCOOH
0' Pc:I
Et3N, RNH?
OH
I
~
NOz
~ c o N H R
CONHR
OH NHCHO
OH KH2.HCI
aniido derivative< ni Table 11. l'lic inhibitory power of the analogs was estimated by noting their effect on the activity of reduced coenzynie Q-cytochrome c reductase as measured with a slight modification of the procedure described by Hatefi, et ~ 1 . ~
0
~~ $O 0 C CCH3 ~H ~ C11H~: C H , : ~ R
0
OHHsC
Antimycin .A1 K Antimycin A? R
= =
n-hexyl n-butyl
([I CC)( H
F O H NHCHO I1
'I'tiese compounds nere prepared by tlie route shown
the next columm. The intermediate 3-nitro compounds prepared are summarized in Table I and the corresponding 3-formill
(1) Thiu work was supported in p a r t b y grant
