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Jung, Kong, Koo, Song, Kim, Han, Lee, and Han: Antifungal Effects of New Synthetic Materials, KAF-200522 and KAF-200522-HCl, on in vitro and in vivo Models
Original Article

Lab. Anim. Res. 2010;26(4):353-359.

Published online: 20 January 2010

DOI: https://doi.org/10.5625/lar.2010.26.4.353

Antifungal Effects of New Synthetic Materials, KAF-200522 and KAF-200522-HCl, on in vitro and in vivo Models

Ju Young Jung1, 2, Kwang-Han Kong1, 2, Kyo Hwan Koo2, Si-Whan Song2, Kap-Ho Kim2, Zhong Ze Han2, Yeo Jin Lee2, Jin Soo Han1, ∗

1Institute for the 3Rs & Department of Laboratory Animal Medicine, College of Veterinary Medicine, Institute for the 3Rs & Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Korea

2Preclinical Research Center, Chemon Inc., Yongin, Korea

∗Corresponding author: Jin Soo Han, Institute for the 3Rs & Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea Tel: +82-2-2049-6114 Fax: +82-2-3437-6114 E-mail: labvet@konkuk.ac.kr

Received 11 November 2010       Revised 23 November 2010       Accepted 26 November 2010

Copyright © 2010 Korean Association for Laboratory Animal Science

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

KAF-200522 and its chloride form, KAF-200522-HCl, were invented in Chemon inc. as new triazole antifungal agents with excellent activities in vivo and in vitro against wide range of fungi. As a result of in vitro susceptibility measurements, 80% minimum inhibitory concentrations (MIC80) of both test articles against Candida albican sp. and Aspergillus fumigatus sp. were below 0.0156 µg/mL, which were over 4,100 times lower than those of fluconazole against fluconazole resistant C. albican sp. and A. fumigatus sp., and were over 16 times lower than those of amphotericin B against above same fungi. Additionally, against representative dermatophytes, Trichophyton sp., the MIC80s of both test articles were below 0.0156 µg/mL which were over 64 times lower than those of fluconazole and amphotericin B. As in vivo antifungal activities in A. fumigatus sp. infected mouse models, KAF-200522 treatment group at 600 mg/ kg showed 80% survival rate which was 2 times higher than that of amphotericin B and showed 13.7 days in the mean survival time (MST) which was about 2.1 times higher than that of amphotericin B. But in KAF-200522-HCl treatment groups, all animals were found dead in contrast to 40% survival rate in amphotericin B treatment group, however dose dependent increases in MST was revealed. In conclusion, antifungal activities of KAF-200522 and its mimics, KAF-200522-HCl in vitro and in vivo were confirmed in this study, therefore the potentiality of the present compounds to be developed into new antifungal drug was expected.

Keywords: Antifungal effects, KAF-200522, KAF-200522-HCl, MIC80

References

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Figure 1.
Survival curves for mice infected with A. fumigatus strain (16424, ATCC) and treated with various doses of KAF-200522 for 5 consecutive days by oral administration route. ○, Vehicle (PEG 400) treated control; ●, KAF-200522 at 10 mg/ kg; △, KAF-200522 at 25 mg/kg; ▲, KAF-200522 at 50 mg/kg; □, KAF-200522 at 100 mg/kg, ■, amphotericin B given by i.p at 3 mg/kg.
lar-26-353f1.tif
Figure 2.
Survival curves for mice infected with A. fumigatus strain (16424, ATCC) and treated with various doses of KAF-200522-HCl for 5 consecutive days by oral administration route. ○, Vehicle (0.5% MC) treated control; ●, KAF-200522-HCl at 0.4 mg/kg; △, KAF-200522-HCl at 2 mg/kg; ▲, KAF-200522-HCl at 10 mg/kg; ■, amphotericin B given by i.p at 3 mg/kg.
lar-26-353f2.tif
Table 1.
Physical properties of KAF-200522 and the synthesis proof KAF-200522-HCl from KAF-200522
Name   KAF-20522  
Formulation Molecular weight Melting point   C23H23CIF2N6O2 488.92 129–130oC  
Process of KAF-20522-HCl synthesis
Table 2.
In vitro activities of KAF-200522, KAF-200522-HCl and other antifungal agents against strains causing experimental systemic infections
MIC80 (µg/mL)a)
Test item C. albicans C. krusei A. fumigatus
  ATCC-36082 ATCCMYA-573 ATCC-6258 ATCC-28301
KAF-200522 ≤0.0156 ≤0.0156 0.125 ≤0.0156
KAF-200522-HCl ≤0.0156 ≤0.0156 0.25 ≤0.0156
Amphotericin B 0.125 0.25 0.5 0.25
Fluconazole 0.125 128 32 64

a) MIC80s were determined by the broth microdilution method with RPMI 1640 medium, the inoculums size was 1×108conidia/mL, and incubation was at 35C for 5–7 days.

Table 3.
In vitro activities of KAF-200522 and other antifungal agents against dermatophytes
Test article MIC80 (µg/mL)
Trichophyton mentagrophytes Trichophyton rubrum
KCTC 6085 KCCM 60450
KAF-200522 ≤0.0156 ≤0.0156
Amphotericin B 1 0.5
Fluconazole 2 2
Terbinafin ≤0.0078 ≤0.0078

a) MIC80s were determined by the broth microdilution method with RPMI 1640 medium, the inoculums size was 1×108 conidia/ mL, and incubation was at 35oC for 5–7 days.

Table 4.
Mean survival times (MST) of A. fumigatus -infected ICR mice for 14 days after 5 days repeated oral administrations of KAF-200522 and KAF-200522-HCl
Test article (mg/kg) Vehicle (PEG400) KAF-200522 Amphotericin B
0 10 25 50 100 3
MST (days)±S.E.M 5.8±0.92 6.3±1.06 9.3±1.36 13.0±0.53## 13.7±0.00# 6.5±0.70
Test article mg/kg) Vehicle (0.5 % MC)   KAF-200522-HCl   Amphotericin B
0 0.4   2 10 3
MST (days)±S.E.M 4.7±0.82 4.7±1.21 6.0±2.68 7.3±2.58∗ 9.4±4.88∗

# P<0.01 vs. PEG 400 treated group,

## P<0.001 vs. PEG 400 treated group

∗ P<0.05 vs. 0.5 % MC treated group (The MST data were analyzed by Kaplen-Meier test).

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