chemistry and biology of hydroxamic acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · a...
TRANSCRIPT
![Page 1: Chemistry and Biology of Hydroxamic Acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · A new important property of aromatic hydroxamic acids and particularly of salicylhydroxamic](https://reader034.vdocuments.us/reader034/viewer/2022052616/60ab8b7dde25ff63c80ead20/html5/thumbnails/1.jpg)
Chemistry and Biology of Hydroxamic Acids
Editor Horst K e h l , K i rksv i l l e , Missouri
63 figures and 29 tables, 1982
S. Karger • Basel • Miinchen • Paris • London • New York • Sydney
![Page 2: Chemistry and Biology of Hydroxamic Acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · A new important property of aromatic hydroxamic acids and particularly of salicylhydroxamic](https://reader034.vdocuments.us/reader034/viewer/2022052616/60ab8b7dde25ff63c80ead20/html5/thumbnails/2.jpg)
14. Salicylhydroxamic Acid and its Derivatives
T. Urbański
Abstract. The action of salicylhydroxamic acid and its halogen derivatives against tuberculosis, fungi, trypanosomae, and the biosynthesis of cholesterol are described. Their hypoglycemic and phospholipid lowering actions are also mentioned.
The author suggested, in 1948, the use of salicylhydroxamic acid I (X = Y = Z = R = H)—called SH—as an antitubercular agent [26]. The suggestion was based on the hypothesis that the hydroxamic group can act as an aminating agent, either as a source of hydroxylamine [14, 25] or through the Lossen degradation, and its effect might, therefore, be similar to that of p-aminosali-cylic acid (PAS), a well-known antitubercular drug. Results with SH on experimental tuberculosis in animals were encouraging. Its acute toxicity was found to be extremely low; the L D 5 0 by oral administration was 3.0 g/kg, but its antitubercular activity in clinical experiments was not significant.
In a search for more potent agents among the derivatives of SH, 5-bro-mosalicylhydroxamic acid I (X = Y = R = H , Z = Br) was prepared [27, 23]. This derivative will be referred to as BSH. Like SH, its toxicity was found to be very low [28]. Mclsaac and Williams [20] explained the low toxicity of these compounds from studies of their metabolism. They found that both SH and BSH are metabolized mainly by direct conjugation with glucuronic acid and sulphuric acid, thus producing I (X = Y = Z = H , R = C 6 H 9 O e or R = SO ; iH) and I (X = Y = H , Z = Br, R = C K H 9 0 6 or SO : !H), respectively.
C O N H O H CONH.,
Y
I II
![Page 3: Chemistry and Biology of Hydroxamic Acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · A new important property of aromatic hydroxamic acids and particularly of salicylhydroxamic](https://reader034.vdocuments.us/reader034/viewer/2022052616/60ab8b7dde25ff63c80ead20/html5/thumbnails/3.jpg)
Urbański 120
In addition, SH and BSH are partly reduced to amides in man, rat, and mouse, yielding II (Z = H , R = C 6 H 9 0 6 or SO;,H) and II (Z = Br, R = C 6 H 9 O e
or SO ; !H), respectively. In rabbits a remarkable difference was found between SH and BSH: the former is not reduced to amide II. Mclsaac and Williams also found that the tuberculostatic activity in vitro of 5-bromosalicylamide II (Z = Br, R = H) is about half that of B S H .
BSH gave positive results in a few hundred clinical cases. Particularly interesting were those that did not respond to the treatment with streptomycine [15].
BSH was made, at this stage, on an industrial scale by reacting ethanolic solution of methyl ester of 5-bromosalicylic acid with a concentrated aqueous solution of hydroxylamine [9].
Further clinical experiments have shown that BSH inhibits the formation of strains of Mycobacterium tuberculosis H 3 7 R v resistant to isoniazid [16,17]. The antitubercular activity of halogenosalicylhydroxamic acids was also reported [4].
Canadian authors [19] found that BSH inhibits the acetylation of isoniazid inactivating this important drug [18]. Such experimental finding opened a new field for the possible application of the BSH. It is well known that acetic ion is the precursor of cholesterol [2] and the biosynthesis of cholesterol in man starts from acetate [29]. Subsequently, Czyaozyk and Urbański anticipated that B S H , while inhibiting the acetylation of isoniazide, might also inhibit the formation of cholesterol in the blood serum. This proved to be correct and in many clinical cases, BSH reduced the cholesterol level significantly [7].
To continue this line, a number of halogen substituted derivatives of SH were prepared [8]. All of them caused marked lowering of the cholesterol level. The strongest activity was shown by 3,5-dibromosalicylhydroxamic acid—I (X = Z = Br, Y = R = H)—and the next best by 3-bromo-5-fluorosalicylhydrox-amic acid—I (X = Br, Z = F , Y = R = H). The trihalogen substituted product was less active.
Monosubstituted derivatives were less effective than the disubstituted de-rivaties mentioned above, but 5-chlorosalicylhydroxamic acid—I (X = Y = R = H , Z = C1) was more effective than BSH. Unsubstituted SH proved to be practically inactive.
In another series of studies, salicylhydroxamic acid proved to be of interest as an antifungal agent. When taken orally, it inhibited various types of deep skin mycoses [1]. Particularly striking results were obtained with ring worm in children [5].
Recently it was found [24] that 3,5-dibromosalicylhydroxamic acid has a
![Page 4: Chemistry and Biology of Hydroxamic Acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · A new important property of aromatic hydroxamic acids and particularly of salicylhydroxamic](https://reader034.vdocuments.us/reader034/viewer/2022052616/60ab8b7dde25ff63c80ead20/html5/thumbnails/4.jpg)
Salicylhydroxamic Acid Derivatives 121
strong hypoglycemic action and not only reduces phospholipid concentrations
but as previously reported, lowers blood serum cholesterol levels [8].
A new important property of aromatic hydroxamic acids and particularly
of salicylhydroxamic acid was discovered—that is, their activity against trypa-
nosomae—by Evans and Brown [10]. This particular property was described in
a number of pages [3, 6, 11-13, 21, 22].
Currently the author of this paper was authorized by the Polish Academy
of Sciences to sign an agreement between the London School of Hygiene and
Tropical Medicine and the said Academy in 1979 to collaborate closely to find
new agents effective against trypanosomiasis. So far the following were the
most effective compounds against T. rhodesiensis: 4- and 5-bromo, 5-chloro-,
5-fluoro-, 5-iodo-, 3,5-dibromo-, and 5-methyl derivatives of SH.
It should be pointed out that in all clinical experiments no toxic effects of
SH and BSH were noted.
References
1 Alkiewicz, J. et al.: Fungistatic activity of some hydroxamic acids. Nature 180: 1204-1205(1957).
2 Bloch, К. and Langdon, R . G . : Biosynthesis of squalen. J. Biol. Chem. 200: 129-134 (1953).
3 Brohn, F . H . and Clarkson, А . В . , Jr.: Quantitative effects of salicylhydroxamic acid and glycerol on Trypanosoma brucei glycolysis in vitro and in vivo. Acta Trop. 35: 23-33 (1978).
4 Buu-Hoi. Ng. , Ph.; Dat-Xuong, N . . and Hoang Nam, N. : Tuberculostatiques acids hydroxamiques. C . R. 236: 635-637 (1953).
5 Chęc iński , T . and Dabkowski, R.: Salicylhydroxamic acid in treatment of Scalp mycoses in children. Lancet / : 1352 {i961 ).
6 Clarkson, А . В . , Jr. and Brown, F . H . : Trypanosomiasis: an approach to chemotherapy by the inhibition of carbohydrate catabolism. Science 194: 204-206 (1976).
7 Czyaozyk, A . and Urbański , T . : Influence of 5-bromosalicylhydroxamic acid on serum cholesterol-level. Nature 197: 381-382 ( 1963).
8 Czyaozyk, A . : Ostaszynski, A . ; Plenkiewicz, H . ; et al.: Lowering of cholesterol level in the blood stream of rabbits by halogen substituted salicylhydroxamic acids. Arzneim. Forsch. 22: 465-468 (1972).
9 Eckstein, Z . ; Dominiak, Z . , and Urbański, T . : Preparation of 5-bromosalicylhydroxamic acid in a pilot plant. Przem. Chem. 9: 536-538 (1953).
10 Evans, D . A . and Brown, R . C . : The inhibitory effect of aromatic hydroxamic acids on the cyanide-insensitive terminal oxdase of Trypanosoma brucei. Trans. Roy. Soc. Trop. Med. 67: 258 (1973).
![Page 5: Chemistry and Biology of Hydroxamic Acidsbcpw.bg.pw.edu.pl/...hydroxamic_acid_1982_s119.pdf · A new important property of aromatic hydroxamic acids and particularly of salicylhydroxamic](https://reader034.vdocuments.us/reader034/viewer/2022052616/60ab8b7dde25ff63c80ead20/html5/thumbnails/5.jpg)
Urbański 122
11 Evans, D . A . : Brightman, C . J . , and Holland, M . F . : Salicylhydroxamic acid/glycerol in experimantal trypanosomiasis. Lancet / : 769 (1977).
12 Evans, D . A . and Holland, M . F . : Effective treatment of Trypanosoma vivax infections with salicylhydroxamic acid. Trans. Roy. Soc. Trop. Med. 72: 203- 204 (1978).
13 Fairlamb, A . H . ; Opperdoes, F . R . , and Borst, P.: New approach to screening drugs for activity against African trypanosomes. Nature 265: 270-271 (1977).
14 Graebe, C . : Ueber eine directe Bildungsweise aromatischer Amine aus Kohlerwas-serstoffen. Chem. Ber. 34: 1778-1782(1901).
15 Hornung, S., Amazowicz, F.; Parykski, E . , et al.: Evaluation of therapeutic effects of salicylhydroxamic acid derivatives in T B . Gruźlica Tuberculosis 21: 873-910(1953).
16 Hornung, S.; Amazowicz, F.; Broda, Z . , et al.: Action of 5-bromosalicylhydrox-amic acid against drug resistance in tuberculosis. Brit. J. Tuberc. Dis. Chest. 52: 19-25(1958).
17 Hornung, S.; Broda, Z . ; Paryski, E . , et al.: Action of bromosalicylhydroxamic acid on the biological level of 1NH and the emergence of INH-resistant bacilli in combined treatment of Т В . Acta Tuberc. Pneumol. Scand. 42: 233-239 (1962).
18 Johnson, W.J . : Biological acetylation of isoniazid. Nature 174: 744-745 (1954). 19 Johnson, W . J . ; Mankiewicz, E . ; Jasmin, R. , et al.: Inhibition of acetylation of
isoniazid. A m . Rev. Respir. Dis. 84: 872-876 (1961). 20 Mclsaac, W . M . and Williams, R . T . : Studies in detoxication. Biochem. J. 66:
369-375 (1957). 21 Opperdoes, F.R.; Aarsen, P.N.; Vander meer, C , et al.: Trypanosoma brucei: an
evaluation of salicylhydroxamic acid as a trypanocidal drug. Exp. Parasitol. 40: 198-205 (1976).
22 Opperdoes, F .R. ; Borst, P., and Fonck, K.: Potential use of inhibitors of glycerol-3-phosphate oxidase for chemotherapy of African trypanosomiasis. FEBS Lett. 62: 169-176 (1976).
23 Slopek, S.: On the antitubercular properties of 5-bromosalicylhydroxamic acid. Bull. Acad. Pol. Sci. , C l . Ill I: 325-326 ( 1953).
24 Szczepanik, Z . , Thesis, Medical Academy, Warsaw, (1978). 25 Turski, J .F . : Einf'uhrung von Aminogruppen in aromatische Verbindungen. Ger
man Pat. 287756 (1915). 26 Urbański , T . : Salicylhydroxamic acid as an antitubercular agent. Nature 166: 267-
268 (1950). 27 Urbański , T . and Lewenstein, W.: 5-Bromosalicylhydroxamic acid. Roczn. Chem.
26: 565-570 (1952); 27: 314 (1953). 28 Urbański , T . ; Hornung, S.; Slopek, S., et al.: New hydroxamic acids as antitu
bercular agents. Nature 170: 753-755 (1952). 29 Woodward, R . B . and Bloch, К.: The cyclization of squalen in cholesterol synthe
sis. J. A m . Chem. Soc. 75: 2023-2024 ( 1953).