- Email: [email protected]
Chapter 14. Antifungal Agents
Chapter 14. Antifungal Agents
F. E. Pansy, Wm. L. Parker and N. S. Semenuk Sqriibb Institute for Medical Research, New Brunswick, N.J. Reviews - A thorough review of the clinical use of nystatin discusses all available formulations and all indications.’ The use of griseofulvin is similarly reviewed.2 An invaluable review of the treatment of the systemic mycoses gives current data on the mechanisms of antifungal chemotherapy, as well as a summation of the clinical experience with griseofulvin, saramycetin, 5-fluorocytosine, clotrimazole (Bay b5097), and the polyene antibiotic^.^ The three leading antifungal antibiotics, nystatin, amphotericin B, and griseofulvin are also reviewed in a new text. 4 Methods - The detection and preclinical evaluation of new antifungal agents is facilitated by a new test procedure. Single doses of potential agents are administered to infected mice previously X-irradiated. The procedure gives a more uniform “take” of the various infections, and reduces the time of the test p r ~ c e d u r e . ~ Since the therapeutic outcome in the treatment of systemic mycoses with amphotericin B is related t o the serum level achieved, careful monitoring is desirable. A bioassay has been proposed that gives precise and accurate results. Low levels of the drug were detected in th’eserum up to 7 weeks after cessation of therapy.6 Clinical Experience-- Amphotericin B administered intravenously continues t o be a mainstay in the treatment of the systemic mycoses. As experience has been built up, a number of reviews of the action of the drug in various diseases have been published. In chronic pulmonary histoplasmosis, a review of the treatment of 408 patients is presented. In spite of the fact that low doses eradicated the organism in the sputum, a dosage of 35 mg/kg of body weight was required to decrease the case fatality ratio.’ In the progressive disseminated form of the disease a dosage of 25 mg/kg is life-saving but higher dosages are preferred.8 In extracutaneous sporotrichosis, several papers indicate the superiority of amphotericin B over iodides or hydroxystilbamidine i s o e t h i ~ n a t e . In ~,~ a ~review of 1 0 9 patients with chronic pulmonary coccidioidomycosis, it was observed that all patients receiving more than 30 mgfkg of amphotericin B did well, whereas those receiving less did poorly. Less drug was required than was the case with the disseminated form of the disease.ll With systemic North American blastomycosis, 1 4 of 16 cases achieved partial or complete remission with total dosages ranging from 0.39 t o 60 g of drug.12 The case for aspergillosis is not as clear, although, there is an intravenous amphotericin B in pulmon impression that it is of some value. It appears ineffective when patients also have aspergillomas. An interesting procedure is the instillation of a paste containing amphotericin B or nystatin by repeated intracavitary needling for the treatment of patients with aspergillomas. Results are reported as e ~ c e l 1 e n t . l It ~ appears that amphotericin B administered by the intravenous route may not reach the aspergilloma in a therapeutic concentration. Amphotericin B proved effective in disseminated cryptococcosis that followed kidney transplantation, with its concomitant treatment with antibacterial antibiotics and immunosuppressive agents.16 The drug was also effective in several cases of ocular cryptoco~colsis.~~ Administered orally at a dose of 1.5 t o 2 g per day for 9 l2 days, amphotericin B eliminated Candida albicans from the stools of 21 of 22 patients.
‘g4
1%
130
Sect. LTI
-
Chemotherapeutic Agents
Conover, Ed.
The tetraene antifungal antibiotic, pimaricin, has been shown t o be effective when applied topically in experimental C. albicans oculomycosis in rabbits." In human medicine, corneal ulcers caused by Fusarium and Ce halosporium sp. have been treated successfully A short review su ests that pimaricin is no with topically applied pimaricin ointment. more effective than nystatin in the treatment of candidal vaginitis.
$5
The production of levorin, a heptaene antifungal antibiotic, is being studied vigorously in the U.S.S.R.23*24 Toxicity studies in rats showed that there was a strong teratogenic effect when the drug was administered orally in repeated doses of 100 mg/kg. Deaths occurred with single doses of 500 mg/kg or more.25 In the clinic, the drug was administered orally in the treatment of various C. albicans infections of visceral organs. Improvement was reported in cases of candidal pneumonia cholecystitis, and colitis. Levorin was reported as superior to nystatin in these disorders?' although the rationale for employing nystatin, an agent that is not absorbed from the gastrointestinal tract, to treat pneumonia and cholecystitis is not clear. Analogs of griseofulvin prepared by modification of the 5' position proved to be less active than the parent compound in vitro and in vivo. In 3 of 1 4 patients treated with oral griseofulvin, there was rise in erythrocyte protoporphyrin that may have been secondary to hepatic toxicity2' Griseofulvin has been reported as effective in the treatment of Raynaud's disease, a vasospastic disorder. 30 27928
First clinical studies with 5-fluorocytosine have been reported. Doses of 100 mg/kg per day for as long as 87 days were administered orally to ten patients with severe candidosis. Cures or a favorable response were achieved in more than half the cases. No toxic symptoms were ob~erved.~'Sixteen patients with cryptococcal meningitis were treated with 4 to 6 g per day for 30 to 111days. Cures were achieved in half the cases. Toxic symptoms were not serious.32 The drug proved ineffective in experimental coccidioidomycosis in mice.33 Clotrimazole (Bay b5097) will soon be on clinical trial in the U.S.A.34 Clinical studies in Germany demonstrated the compound t o be active by the oral route in single cases of candidal pneumonia and bronchitis, and a s p e r g i l l ~ m a , ~but ~ , ~not ~ in a case of c h r o m ~ m y c o s i s .High ~ ~ doses produced liver hypertrophy in rats. As an inducer of liver oxidative enzymes, clotrimazole is as active as phenobarbital. 38 Miconazole nitrate, 1-[ 2,4dichloro-&( 2,4dichlorobenzyloxy)phenethyl]imidazole,is reported effective both orally and topically in experimental infections of guinea pigs caused by Trichophyton mentagrophytes, T. canis, and C. aibicans. In humans it was very effective in the topical treatment of tinea pedis caused by a variety of Trichophyton sp. 39 Haloprogin (M-1028),2,4,5-trichlorophenyl~-iodopropargyl ether, was active when applied topically in experimental der atophytic infections of guinea pigs. It appeared to be approximately as active as tolnaftate.
43
In a review of thiabendazole, 2-(4'-thiazolyl)benzimidazole,a drug used as an anthelminthic, its antifungal properties were discussed. ts usefulness for the treatment of the superficial mycotic infections is being investigatedj' Study of the mode of action of thiabendazole suggested that the prim site of action is inhibition of the terminal electron transport system of the mitochondria.
27
Chap. 14
An tifu n g al A g e n t s
Pansy, Parker, Semenuk
131 -
-
New Antifungal Agents The structure of lomofungh, L, a new phenazine antibiotic, has been determined by degradation studies.43 This antibiotic is active against Gram-positive and Gram-negative bacteria and fungi.
OH
C02Me
C HO
OH
I
I
A detailed account of the determination of the structure of LL-Z1271a has been published.44 The structure and biological properties were summarized in last year's Annual Reports in Medicinal Chemistry (pp. 132-3). A peptide antibiotic, havin good activity in vitro against C. albicans, is produced by a strain of Aspergillus rugulosus.' Acid hydrolysis indicates that aspartic acid, glutamic acid, glycine, alanine, threonine, valine and isoleucine are components. The production, isolation, and chemical and biolo 'cal properties of fumigachlorin, an antibiotic produced by a fungus, have been ~tudied.~&'umigachlorinhas a molecular formula of C I ~ H ~ ~ C I ~and N Ohas ~ , strong activity in vitro against some filamentous fungi. An a tibiotic, inomycin, has been isolated from cultures of Streptomyces griseus var. inornycini4' It is active in vitro against Saccharornyces species and also has antitumor activity. This antibiotic has the approximate molecular formula, C17H27NzO4, and appears t o be closely related to cycloheximide. Two new antifungal polyene antibiotics have been repo'rted; ge i ycin, a pentaene produced by an Actinosporangiurn species48 and tbilimycin, a heptaene.
Ik
Several derivatives of pyrrolnitnn have been obtained by the metabolism of substituted tryptophans by Pseudornonas aureofaciens. For example, tryptophan, substituted at the 5-,6- or 7-position with fluorine, or at the 5- or 7-position with methyl, gave fluorinated and methylated pyrrolnitrins, r e ~ p e c t i v e l y .Several ~~ 3-phenylpyrroles related to pyrrolnitrin were ~ y n t h e s i z e d . Some ~ ~ derivatives that lacked a nitro group on the phenyl ring had stronger antifu.ngal activity and a broader spectrum of activity in vitro than did pyrrolnitrin. A new synthetic antifungal agent, 4,4'-( decamethy1enediimino)diquinaldine acetate salt (1:2) (3,has activity in vitro against Staphylococcus aureus, Streptococcus haernolyticus, C. albicans, T. mentagrophytes and Trichomonas vaginalis. It was effective in the treatment of skin and mucosal infections due to these o r g a n i ~ m s .Anticandidal ~~ properties of derivatives of 0-nitrostyrene have been i n v e ~ t i g a t e d . Of ~ ~ the derivatives examined, 4-bromo-P-met.hy1-0-nitrostyrenehad the best activity. This compound was effective against visceral candidiasis in mice and in the treatment of candidal lesions on rabbit skin. ~~ Chemical and Physical Studies of Antifungal Agents - Structural studies of n y ~ t a t i nhave indicated that the attachment of mycosamine is at C-19.These studies also established the pyranose nature of the mycosamine ring and proved the lactone closure to C-37. Except for
132 -
Sect. I11
- Chemotherapeutic Agents
the stereochemistry, the structure,
3 of
Conover, Ed.
nystatin has been completed by this work. The
-3
O+ ,NH~
$7
total structure of amphotericin B has been established as 4 by chemical studies55 and X-ray crystallography of the N-iodoacetyl d e r i ~ a t i v e Chemical .~~ studies on flavofungin have led to the conclusion that this antibiotic is a mixture of two pentaene macrolides that have the same structures as the components of mycoticin, except possibly, for the configuration of one or more asymmetric centers. The biosynthesis of mycoticin has been studied, using labelled precursor^.^^
(s),
The structure of X-537A an antibiotic related to nigencin and monensin, has been determined by X-ray crystallography. 59*60 The absolute configuration is based on the Cotton effect exhibited by a degradation product.59 The structure of nigericin (polyetherin A) (5 R=OH) has been determined by chemical degradation and spectroscopy6' and by X-ray crystallography of the silver salt.62 The absolute configurati n was determined by anomalous dispersion. The structure of grisorixin, a new antibiotic,68 has been determined
Chap. 14
Antifungal Agents
Pansy, P a r k e r , Semenuk
OH
133 -
134
Sect. III
- Chemotherapeutic Agents
C o n o v e r , Ed.
by X-ray crystallography of the silver salt.64 The structure reported64 is the enantiomer of
S,R=H.
The total synthesis of racemic cryptosporiopsin, 3, has been r e p ~ r t e d . ~This ’ material is half as active as the naturally occuring dextrorotatory enantiomer.
0
- The mode of action of pyrrolnitrin has been studied by use of monkey kidney cells, rat liver mitochondria and beef heart submitochondrial particles.66 These experiments indicated that pyrrolnitrin and “reduced pyrrolnitrin” (having an amino group in place of the nitro group) inhibit respiration of mitochondria, probably by blocking electron transfer between dehydrogenases and cytochrome components of the respiratory chain.
Biological Studies of Antif’ungal Agents
The basis for the nephrotoxicity of am hotericin B has been studied, using turtle tdy!7 exposure of turtle urinary bladder to bladder as a model system. In one su amphotericin B resulted in changes in the electrophysiological properties of the bladder and in morphological changes in the mucosal cells, The results indicate that the primary effect is on luminal plasma membranes. In another study,68 the impairment of urinary acidification was investigated, using turtle bladder that had been exposed to amphotericin B. The results indicate that this defect is attributable t o increased passive permeability of the luminal membrane and not to failure of active transport.
REFERENCES 1. V. H. Witten, Med. Clin. N. Amer., 5 4 , 1 3 2 9 (1970). 2. L. Goldman, i b i J . , 5 4 , 1 3 3 9 (1970). 3. J. P. Utz, Ed. “Symposium on Treatment of the Systemic Mycoses”, in Mod. Treat., 3 505 (1970). 4. G. Hildick-Smith, In: “Antimicrobial Therapy”, B. M. Kagan, Ed., W. B. Saunders, Philadelphia, p119, (1970). 5. R. S. Gordee and T. R. Matthews, Appl. Microbiol., 20,624 (1970). 6. B. T. Fields, Jr., J . H. Bates, and R. S. Abernathy, Appl. Microbiol., 19,955 (1970). 7. J. D. Parker, G. A. Sarosi, I. L. Doto, R. E. Bailey, and F. E. Tosh, New Engl. J. Med., 283,225 (1970). 8. P. Reddy, D. F. Gorelick, C. A. Brasher, and H. Larsh, Amer. J. Med., 48, 629 (1970). 9. J. D. Parker, G. A. Sarosi, and F. E. Tosh, Arch. Intern. Med., 125,858 (1970).
Chap. 14
Antifungal Agents
Pansy, Parker, Semenuk
135 -
10. P. J. Lynch, J. J. Voorhees, and E. R. Harrell, Ann. Intern. Med., E , 2 3 (1970). 11. G. A. Sarosi, J. D. Parker, I. L. Doto, and F. E. Tosh, New Engl. J. Med., 283. 325 (1970). O J , 653 12. M. H. Klapman, N. P. buperfon, and L. M. Solomon, Arch. Dermatol., l (1970). 13. J. D. Parker, G. A. Sarosi, I. L. Doto, and F. E. Tosh, Amer. Rev. Resp. Dis., 101,551 (1970). 101, 14. P. A. Reddy, C. S. Christianson, C. A. Brasher, H. Larsh, and M. Sutaria, E., 928 (1970) 15. P. Krakbwka, K. Traczyk, J. Walczak, H. Halweg, Z. Elsner, and L. Pawlicka, Tubercle, 51,184 (1970). 16. B. B. Platt, M. G. Rosenblatt, and M. Koppel, Clin. Res., 18,182 (1970). 17. M. E. Cameron and A. Harrison, Med. J. Aust., 1,935 (1970). 18. J. C. Reysseguier, P. Bernades, and S. Bonfils, Therapie, 25,723 (1970). 19. A. B. Richads, Y.M.Clayton, and B. R. Jones, Trans. Ophthalmol. SOC.U.K., 89,847 (1969). 20. D. B. Jones., R. Sexton, and G. Rebell, ibid., 89,781 (1969). 21. E. Newmark, A. C. Ellison, and H. E. Kaufman, Amer. J. Ophthalmol., 69,458 (1970). 22. Anonymous, Drug Ther. Bull., 5 52 (1970). 23. I. I. Belousova, E. B. Lishnevskaya, R. E. Elgart, and I. M. Tereshin, Antibiotiki, 15. 221, (1970). 24. I. I. Belousova, E. B. Lishnevskaya, R. E. Elgart, and I. M. Tereshin, ibid., 15.779 (1970). 15,1089 (1970). 25. N. N. Slonitskaya, 26. E. A. Sadokova, Ter. Ark., 42,87 (1970). Ringdoc Abstract 30699K. 27. T. L. Fields, H. Newman, and R. B. Angier, J. Med. Chem., 13,1242 (1970). 28. H. Newman and T. L. Fields, J. Org. Chem., & 3156 (1970). 29. H. Perrot and J. Thivolet, Experientia, 26, 256 (1970). 30. C. R. C. Chizles and E. S. C m i c k , Arch. Dermatol., 101,331 (1970). 31. J. F. Warner, R. F. McGehee, R. J. Duma, S. Shadomy, and J. P. Utz, 10th Intersci. Conf. Antinnicrob. Agents Chemother. Abstr., Chicago, 18-21 Oct., p 28 (1970). 32. J. E. Bennett, E.p,28 (1970). 33. G. W. Lone!;, Amer. Rev. Resp. Dis., 101,128 (1970). 34. J. E. Bennett, Ann. Intern. Med., 73,653 (1970). 35. H. Oberste-.Lehn, I. Baggesen, and M. Plempel, Mykosen, l3,l (1970). 36. H. Schwacke, Deut. Med. Wochenschr., 95,2437 (1970). 95,1100 , (1970). 37. Z. Itani, ibh;t. 38. D. Tettenborn, Arch. Pharmakol. Exp. Pathol. (Naunyn-Schmiedebergs), 266, 468 (1970). 39. J. P. Brugmans, J. M. van Cutsem, and D. C. Thienpont, Arch. Dermatol., 102, 428 (1970). 40. E. F. Harrison, P. Zwadyk, Jr., R. J. Bequette, E. E. Hamlow, P. A. Tavormina, and W. A. Zygmunr,, Appl. Microbiol., 19,746 (1970). 41. H. J. Robinson, R. H. Silber, and 0. E. Graessle, Tex. Rep. Biol. Med., 27, suppl. 2, 537 (1969). 42. P. M. Allen and D. Gottlieb, Appl. Microbiol., 20,919 (1970). 43. C. D. Tiptoii and K. L. Rinehart, Jr., J. Amer. Chem. Soc.,92,1425 (1970). 44. G. A. Ellestad, R. H. Evans, Jr., M. P. Kunstmann, J. E. Lancaster and G. 0. Morton, *-ibid 9 92, 5483 (1970). 45. J. Dasgupta, L. V. Kannan, I. Mehdi, V. C. Vora and M. M. Dhar, Indian J. Biochem., 7,81 (1970). I
w.,
136
Sect. III
-
Chemotherapeutic Agents
Conover, Ed,
46. K. Atsumi, M. Takada, K. Mizuno and T. Ando, J. Antibiot., 3,223 (1970). 47. M. Tyc, Arch. Immun. Ther. Exp. (Warsz.), Is,129 (1970). 48. L. Ya. Severinets, V. M. Efimova, L. 0. Bolshakova, A. I. Karnaushkina, S. N. Soloviev and A. N. Egorenkova, Antibiotiki, % , 5 (1970). 49. Yu. D.Shenin, E. N. Sokolova and Yu. E. Konev, ibid., 15,9 (1970). 19,721 50. R. L. Hamill, R. P. Elander, J. A. Mabe and M. Gorman, Appl. Microbiol., (1970). 51. S. Umio, K. Kariyone, K. Tanaka, T. Kishimoto, H. Nakamura and M. Nishida, Chem. Pharm. Bull. (Tokyo), l8,1414 (1970). 52, A. Doppstadt, H.C. Stark, H. G. Stoll and H.-K. Grubmuller, Arzneimittel-Forschung, 19,1764(1969). 44,55 53. B. E. Bilich, V. M. Cherkasov and I. F. Vladimirtsev, Vestn. Dermatol. Venerol., (1970). 54. C. N. Chong and R. W. Rickards, Tetrahedron Lett., 5145 (1970). 55. E. Borowski, J. Zielifiski, T. Ziminski, L. Falkowski, P. Kdodziejczyk, J. Golik, E. Jereczek and H. Adlercreutz, ibid., 3909 (1970). 56. W. Mechlinski, C. P. Schaffner,Ganis and G. A v i t a b i l e ,H ., 3873 (1970). 57. R. BognC, B. 0. Brown, W. J. S. Lockley, S. Makleit, T. P. Toube, B. C. L. Weedon and K. ZsupBn, 471 (1970). 58. H.H.Wasserman, P. A. Zoretic and P. S. Mariano, Chem. Commun., 1634 (1970). 59. J. W.Westley, R. H. Evans, Jr., T. Williams and A. Stempel, 71 (1970). 60. S. M. Johnson, J. Hemn, S. J. Liu and I. C. Paul, J. Amer. Chem. SOC.,92, 4428 (1970). 61. T.Kubota and S. Matsutani, J. Chem. SOC.C, 695 (1970). 62. M. Shiro and H. Koyama, J. Chem. SOC.B, 243 (1970). 63. P. Gachon, A. Kergomard, H. Veschambre, C. Esteve and T. Staron, Chem. Commun., 1421 (1970). 64. M. Alleaume and D. Hickel, ibid., 1422 (1970). 65. G. M. Stnintz and A. S. Court, Experientia, 26,1054 (1970). 66. D. T. Wong and J. M. Airall, J. Antibiot., 23, 55 (1970). 67. S. Rosen, Exp. Mol. Pathol., l2,297 (1970). 68. P. R. Steinmetz and L. R. Lawson, J. Clin. Invest., 9, 596 (1970).
u.,
w.,
F. E. Pansy, Wm. L. Parker and N. S. Semenuk Sqriibb Institute for Medical Research, New Brunswick, N.J. Reviews - A thorough review of the clinical use of nystatin discusses all available formulations and all indications.’ The use of griseofulvin is similarly reviewed.2 An invaluable review of the treatment of the systemic mycoses gives current data on the mechanisms of antifungal chemotherapy, as well as a summation of the clinical experience with griseofulvin, saramycetin, 5-fluorocytosine, clotrimazole (Bay b5097), and the polyene antibiotic^.^ The three leading antifungal antibiotics, nystatin, amphotericin B, and griseofulvin are also reviewed in a new text. 4 Methods - The detection and preclinical evaluation of new antifungal agents is facilitated by a new test procedure. Single doses of potential agents are administered to infected mice previously X-irradiated. The procedure gives a more uniform “take” of the various infections, and reduces the time of the test p r ~ c e d u r e . ~ Since the therapeutic outcome in the treatment of systemic mycoses with amphotericin B is related t o the serum level achieved, careful monitoring is desirable. A bioassay has been proposed that gives precise and accurate results. Low levels of the drug were detected in th’eserum up to 7 weeks after cessation of therapy.6 Clinical Experience-- Amphotericin B administered intravenously continues t o be a mainstay in the treatment of the systemic mycoses. As experience has been built up, a number of reviews of the action of the drug in various diseases have been published. In chronic pulmonary histoplasmosis, a review of the treatment of 408 patients is presented. In spite of the fact that low doses eradicated the organism in the sputum, a dosage of 35 mg/kg of body weight was required to decrease the case fatality ratio.’ In the progressive disseminated form of the disease a dosage of 25 mg/kg is life-saving but higher dosages are preferred.8 In extracutaneous sporotrichosis, several papers indicate the superiority of amphotericin B over iodides or hydroxystilbamidine i s o e t h i ~ n a t e . In ~,~ a ~review of 1 0 9 patients with chronic pulmonary coccidioidomycosis, it was observed that all patients receiving more than 30 mgfkg of amphotericin B did well, whereas those receiving less did poorly. Less drug was required than was the case with the disseminated form of the disease.ll With systemic North American blastomycosis, 1 4 of 16 cases achieved partial or complete remission with total dosages ranging from 0.39 t o 60 g of drug.12 The case for aspergillosis is not as clear, although, there is an intravenous amphotericin B in pulmon impression that it is of some value. It appears ineffective when patients also have aspergillomas. An interesting procedure is the instillation of a paste containing amphotericin B or nystatin by repeated intracavitary needling for the treatment of patients with aspergillomas. Results are reported as e ~ c e l 1 e n t . l It ~ appears that amphotericin B administered by the intravenous route may not reach the aspergilloma in a therapeutic concentration. Amphotericin B proved effective in disseminated cryptococcosis that followed kidney transplantation, with its concomitant treatment with antibacterial antibiotics and immunosuppressive agents.16 The drug was also effective in several cases of ocular cryptoco~colsis.~~ Administered orally at a dose of 1.5 t o 2 g per day for 9 l2 days, amphotericin B eliminated Candida albicans from the stools of 21 of 22 patients.
‘g4
1%
130
Sect. LTI
-
Chemotherapeutic Agents
Conover, Ed.
The tetraene antifungal antibiotic, pimaricin, has been shown t o be effective when applied topically in experimental C. albicans oculomycosis in rabbits." In human medicine, corneal ulcers caused by Fusarium and Ce halosporium sp. have been treated successfully A short review su ests that pimaricin is no with topically applied pimaricin ointment. more effective than nystatin in the treatment of candidal vaginitis.
$5
The production of levorin, a heptaene antifungal antibiotic, is being studied vigorously in the U.S.S.R.23*24 Toxicity studies in rats showed that there was a strong teratogenic effect when the drug was administered orally in repeated doses of 100 mg/kg. Deaths occurred with single doses of 500 mg/kg or more.25 In the clinic, the drug was administered orally in the treatment of various C. albicans infections of visceral organs. Improvement was reported in cases of candidal pneumonia cholecystitis, and colitis. Levorin was reported as superior to nystatin in these disorders?' although the rationale for employing nystatin, an agent that is not absorbed from the gastrointestinal tract, to treat pneumonia and cholecystitis is not clear. Analogs of griseofulvin prepared by modification of the 5' position proved to be less active than the parent compound in vitro and in vivo. In 3 of 1 4 patients treated with oral griseofulvin, there was rise in erythrocyte protoporphyrin that may have been secondary to hepatic toxicity2' Griseofulvin has been reported as effective in the treatment of Raynaud's disease, a vasospastic disorder. 30 27928
First clinical studies with 5-fluorocytosine have been reported. Doses of 100 mg/kg per day for as long as 87 days were administered orally to ten patients with severe candidosis. Cures or a favorable response were achieved in more than half the cases. No toxic symptoms were ob~erved.~'Sixteen patients with cryptococcal meningitis were treated with 4 to 6 g per day for 30 to 111days. Cures were achieved in half the cases. Toxic symptoms were not serious.32 The drug proved ineffective in experimental coccidioidomycosis in mice.33 Clotrimazole (Bay b5097) will soon be on clinical trial in the U.S.A.34 Clinical studies in Germany demonstrated the compound t o be active by the oral route in single cases of candidal pneumonia and bronchitis, and a s p e r g i l l ~ m a , ~but ~ , ~not ~ in a case of c h r o m ~ m y c o s i s .High ~ ~ doses produced liver hypertrophy in rats. As an inducer of liver oxidative enzymes, clotrimazole is as active as phenobarbital. 38 Miconazole nitrate, 1-[ 2,4dichloro-&( 2,4dichlorobenzyloxy)phenethyl]imidazole,is reported effective both orally and topically in experimental infections of guinea pigs caused by Trichophyton mentagrophytes, T. canis, and C. aibicans. In humans it was very effective in the topical treatment of tinea pedis caused by a variety of Trichophyton sp. 39 Haloprogin (M-1028),2,4,5-trichlorophenyl~-iodopropargyl ether, was active when applied topically in experimental der atophytic infections of guinea pigs. It appeared to be approximately as active as tolnaftate.
43
In a review of thiabendazole, 2-(4'-thiazolyl)benzimidazole,a drug used as an anthelminthic, its antifungal properties were discussed. ts usefulness for the treatment of the superficial mycotic infections is being investigatedj' Study of the mode of action of thiabendazole suggested that the prim site of action is inhibition of the terminal electron transport system of the mitochondria.
27
Chap. 14
An tifu n g al A g e n t s
Pansy, Parker, Semenuk
131 -
-
New Antifungal Agents The structure of lomofungh, L, a new phenazine antibiotic, has been determined by degradation studies.43 This antibiotic is active against Gram-positive and Gram-negative bacteria and fungi.
OH
C02Me
C HO
OH
I
I
A detailed account of the determination of the structure of LL-Z1271a has been published.44 The structure and biological properties were summarized in last year's Annual Reports in Medicinal Chemistry (pp. 132-3). A peptide antibiotic, havin good activity in vitro against C. albicans, is produced by a strain of Aspergillus rugulosus.' Acid hydrolysis indicates that aspartic acid, glutamic acid, glycine, alanine, threonine, valine and isoleucine are components. The production, isolation, and chemical and biolo 'cal properties of fumigachlorin, an antibiotic produced by a fungus, have been ~tudied.~&'umigachlorinhas a molecular formula of C I ~ H ~ ~ C I ~and N Ohas ~ , strong activity in vitro against some filamentous fungi. An a tibiotic, inomycin, has been isolated from cultures of Streptomyces griseus var. inornycini4' It is active in vitro against Saccharornyces species and also has antitumor activity. This antibiotic has the approximate molecular formula, C17H27NzO4, and appears t o be closely related to cycloheximide. Two new antifungal polyene antibiotics have been repo'rted; ge i ycin, a pentaene produced by an Actinosporangiurn species48 and tbilimycin, a heptaene.
Ik
Several derivatives of pyrrolnitnn have been obtained by the metabolism of substituted tryptophans by Pseudornonas aureofaciens. For example, tryptophan, substituted at the 5-,6- or 7-position with fluorine, or at the 5- or 7-position with methyl, gave fluorinated and methylated pyrrolnitrins, r e ~ p e c t i v e l y .Several ~~ 3-phenylpyrroles related to pyrrolnitrin were ~ y n t h e s i z e d . Some ~ ~ derivatives that lacked a nitro group on the phenyl ring had stronger antifu.ngal activity and a broader spectrum of activity in vitro than did pyrrolnitrin. A new synthetic antifungal agent, 4,4'-( decamethy1enediimino)diquinaldine acetate salt (1:2) (3,has activity in vitro against Staphylococcus aureus, Streptococcus haernolyticus, C. albicans, T. mentagrophytes and Trichomonas vaginalis. It was effective in the treatment of skin and mucosal infections due to these o r g a n i ~ m s .Anticandidal ~~ properties of derivatives of 0-nitrostyrene have been i n v e ~ t i g a t e d . Of ~ ~ the derivatives examined, 4-bromo-P-met.hy1-0-nitrostyrenehad the best activity. This compound was effective against visceral candidiasis in mice and in the treatment of candidal lesions on rabbit skin. ~~ Chemical and Physical Studies of Antifungal Agents - Structural studies of n y ~ t a t i nhave indicated that the attachment of mycosamine is at C-19.These studies also established the pyranose nature of the mycosamine ring and proved the lactone closure to C-37. Except for
132 -
Sect. I11
- Chemotherapeutic Agents
the stereochemistry, the structure,
3 of
Conover, Ed.
nystatin has been completed by this work. The
-3
O+ ,NH~
$7
total structure of amphotericin B has been established as 4 by chemical studies55 and X-ray crystallography of the N-iodoacetyl d e r i ~ a t i v e Chemical .~~ studies on flavofungin have led to the conclusion that this antibiotic is a mixture of two pentaene macrolides that have the same structures as the components of mycoticin, except possibly, for the configuration of one or more asymmetric centers. The biosynthesis of mycoticin has been studied, using labelled precursor^.^^
(s),
The structure of X-537A an antibiotic related to nigencin and monensin, has been determined by X-ray crystallography. 59*60 The absolute configuration is based on the Cotton effect exhibited by a degradation product.59 The structure of nigericin (polyetherin A) (5 R=OH) has been determined by chemical degradation and spectroscopy6' and by X-ray crystallography of the silver salt.62 The absolute configurati n was determined by anomalous dispersion. The structure of grisorixin, a new antibiotic,68 has been determined
Chap. 14
Antifungal Agents
Pansy, P a r k e r , Semenuk
OH
133 -
134
Sect. III
- Chemotherapeutic Agents
C o n o v e r , Ed.
by X-ray crystallography of the silver salt.64 The structure reported64 is the enantiomer of
S,R=H.
The total synthesis of racemic cryptosporiopsin, 3, has been r e p ~ r t e d . ~This ’ material is half as active as the naturally occuring dextrorotatory enantiomer.
0
- The mode of action of pyrrolnitrin has been studied by use of monkey kidney cells, rat liver mitochondria and beef heart submitochondrial particles.66 These experiments indicated that pyrrolnitrin and “reduced pyrrolnitrin” (having an amino group in place of the nitro group) inhibit respiration of mitochondria, probably by blocking electron transfer between dehydrogenases and cytochrome components of the respiratory chain.
Biological Studies of Antif’ungal Agents
The basis for the nephrotoxicity of am hotericin B has been studied, using turtle tdy!7 exposure of turtle urinary bladder to bladder as a model system. In one su amphotericin B resulted in changes in the electrophysiological properties of the bladder and in morphological changes in the mucosal cells, The results indicate that the primary effect is on luminal plasma membranes. In another study,68 the impairment of urinary acidification was investigated, using turtle bladder that had been exposed to amphotericin B. The results indicate that this defect is attributable t o increased passive permeability of the luminal membrane and not to failure of active transport.
REFERENCES 1. V. H. Witten, Med. Clin. N. Amer., 5 4 , 1 3 2 9 (1970). 2. L. Goldman, i b i J . , 5 4 , 1 3 3 9 (1970). 3. J. P. Utz, Ed. “Symposium on Treatment of the Systemic Mycoses”, in Mod. Treat., 3 505 (1970). 4. G. Hildick-Smith, In: “Antimicrobial Therapy”, B. M. Kagan, Ed., W. B. Saunders, Philadelphia, p119, (1970). 5. R. S. Gordee and T. R. Matthews, Appl. Microbiol., 20,624 (1970). 6. B. T. Fields, Jr., J . H. Bates, and R. S. Abernathy, Appl. Microbiol., 19,955 (1970). 7. J. D. Parker, G. A. Sarosi, I. L. Doto, R. E. Bailey, and F. E. Tosh, New Engl. J. Med., 283,225 (1970). 8. P. Reddy, D. F. Gorelick, C. A. Brasher, and H. Larsh, Amer. J. Med., 48, 629 (1970). 9. J. D. Parker, G. A. Sarosi, and F. E. Tosh, Arch. Intern. Med., 125,858 (1970).
Chap. 14
Antifungal Agents
Pansy, Parker, Semenuk
135 -
10. P. J. Lynch, J. J. Voorhees, and E. R. Harrell, Ann. Intern. Med., E , 2 3 (1970). 11. G. A. Sarosi, J. D. Parker, I. L. Doto, and F. E. Tosh, New Engl. J. Med., 283. 325 (1970). O J , 653 12. M. H. Klapman, N. P. buperfon, and L. M. Solomon, Arch. Dermatol., l (1970). 13. J. D. Parker, G. A. Sarosi, I. L. Doto, and F. E. Tosh, Amer. Rev. Resp. Dis., 101,551 (1970). 101, 14. P. A. Reddy, C. S. Christianson, C. A. Brasher, H. Larsh, and M. Sutaria, E., 928 (1970) 15. P. Krakbwka, K. Traczyk, J. Walczak, H. Halweg, Z. Elsner, and L. Pawlicka, Tubercle, 51,184 (1970). 16. B. B. Platt, M. G. Rosenblatt, and M. Koppel, Clin. Res., 18,182 (1970). 17. M. E. Cameron and A. Harrison, Med. J. Aust., 1,935 (1970). 18. J. C. Reysseguier, P. Bernades, and S. Bonfils, Therapie, 25,723 (1970). 19. A. B. Richads, Y.M.Clayton, and B. R. Jones, Trans. Ophthalmol. SOC.U.K., 89,847 (1969). 20. D. B. Jones., R. Sexton, and G. Rebell, ibid., 89,781 (1969). 21. E. Newmark, A. C. Ellison, and H. E. Kaufman, Amer. J. Ophthalmol., 69,458 (1970). 22. Anonymous, Drug Ther. Bull., 5 52 (1970). 23. I. I. Belousova, E. B. Lishnevskaya, R. E. Elgart, and I. M. Tereshin, Antibiotiki, 15. 221, (1970). 24. I. I. Belousova, E. B. Lishnevskaya, R. E. Elgart, and I. M. Tereshin, ibid., 15.779 (1970). 15,1089 (1970). 25. N. N. Slonitskaya, 26. E. A. Sadokova, Ter. Ark., 42,87 (1970). Ringdoc Abstract 30699K. 27. T. L. Fields, H. Newman, and R. B. Angier, J. Med. Chem., 13,1242 (1970). 28. H. Newman and T. L. Fields, J. Org. Chem., & 3156 (1970). 29. H. Perrot and J. Thivolet, Experientia, 26, 256 (1970). 30. C. R. C. Chizles and E. S. C m i c k , Arch. Dermatol., 101,331 (1970). 31. J. F. Warner, R. F. McGehee, R. J. Duma, S. Shadomy, and J. P. Utz, 10th Intersci. Conf. Antinnicrob. Agents Chemother. Abstr., Chicago, 18-21 Oct., p 28 (1970). 32. J. E. Bennett, E.p,28 (1970). 33. G. W. Lone!;, Amer. Rev. Resp. Dis., 101,128 (1970). 34. J. E. Bennett, Ann. Intern. Med., 73,653 (1970). 35. H. Oberste-.Lehn, I. Baggesen, and M. Plempel, Mykosen, l3,l (1970). 36. H. Schwacke, Deut. Med. Wochenschr., 95,2437 (1970). 95,1100 , (1970). 37. Z. Itani, ibh;t. 38. D. Tettenborn, Arch. Pharmakol. Exp. Pathol. (Naunyn-Schmiedebergs), 266, 468 (1970). 39. J. P. Brugmans, J. M. van Cutsem, and D. C. Thienpont, Arch. Dermatol., 102, 428 (1970). 40. E. F. Harrison, P. Zwadyk, Jr., R. J. Bequette, E. E. Hamlow, P. A. Tavormina, and W. A. Zygmunr,, Appl. Microbiol., 19,746 (1970). 41. H. J. Robinson, R. H. Silber, and 0. E. Graessle, Tex. Rep. Biol. Med., 27, suppl. 2, 537 (1969). 42. P. M. Allen and D. Gottlieb, Appl. Microbiol., 20,919 (1970). 43. C. D. Tiptoii and K. L. Rinehart, Jr., J. Amer. Chem. Soc.,92,1425 (1970). 44. G. A. Ellestad, R. H. Evans, Jr., M. P. Kunstmann, J. E. Lancaster and G. 0. Morton, *-ibid 9 92, 5483 (1970). 45. J. Dasgupta, L. V. Kannan, I. Mehdi, V. C. Vora and M. M. Dhar, Indian J. Biochem., 7,81 (1970). I
w.,
136
Sect. III
-
Chemotherapeutic Agents
Conover, Ed,
46. K. Atsumi, M. Takada, K. Mizuno and T. Ando, J. Antibiot., 3,223 (1970). 47. M. Tyc, Arch. Immun. Ther. Exp. (Warsz.), Is,129 (1970). 48. L. Ya. Severinets, V. M. Efimova, L. 0. Bolshakova, A. I. Karnaushkina, S. N. Soloviev and A. N. Egorenkova, Antibiotiki, % , 5 (1970). 49. Yu. D.Shenin, E. N. Sokolova and Yu. E. Konev, ibid., 15,9 (1970). 19,721 50. R. L. Hamill, R. P. Elander, J. A. Mabe and M. Gorman, Appl. Microbiol., (1970). 51. S. Umio, K. Kariyone, K. Tanaka, T. Kishimoto, H. Nakamura and M. Nishida, Chem. Pharm. Bull. (Tokyo), l8,1414 (1970). 52, A. Doppstadt, H.C. Stark, H. G. Stoll and H.-K. Grubmuller, Arzneimittel-Forschung, 19,1764(1969). 44,55 53. B. E. Bilich, V. M. Cherkasov and I. F. Vladimirtsev, Vestn. Dermatol. Venerol., (1970). 54. C. N. Chong and R. W. Rickards, Tetrahedron Lett., 5145 (1970). 55. E. Borowski, J. Zielifiski, T. Ziminski, L. Falkowski, P. Kdodziejczyk, J. Golik, E. Jereczek and H. Adlercreutz, ibid., 3909 (1970). 56. W. Mechlinski, C. P. Schaffner,Ganis and G. A v i t a b i l e ,H ., 3873 (1970). 57. R. BognC, B. 0. Brown, W. J. S. Lockley, S. Makleit, T. P. Toube, B. C. L. Weedon and K. ZsupBn, 471 (1970). 58. H.H.Wasserman, P. A. Zoretic and P. S. Mariano, Chem. Commun., 1634 (1970). 59. J. W.Westley, R. H. Evans, Jr., T. Williams and A. Stempel, 71 (1970). 60. S. M. Johnson, J. Hemn, S. J. Liu and I. C. Paul, J. Amer. Chem. SOC.,92, 4428 (1970). 61. T.Kubota and S. Matsutani, J. Chem. SOC.C, 695 (1970). 62. M. Shiro and H. Koyama, J. Chem. SOC.B, 243 (1970). 63. P. Gachon, A. Kergomard, H. Veschambre, C. Esteve and T. Staron, Chem. Commun., 1421 (1970). 64. M. Alleaume and D. Hickel, ibid., 1422 (1970). 65. G. M. Stnintz and A. S. Court, Experientia, 26,1054 (1970). 66. D. T. Wong and J. M. Airall, J. Antibiot., 23, 55 (1970). 67. S. Rosen, Exp. Mol. Pathol., l2,297 (1970). 68. P. R. Steinmetz and L. R. Lawson, J. Clin. Invest., 9, 596 (1970).
u.,
w.,