TABLE 3.
Antifungal activities of bicyclic guanidines derived from the PS-SCL
| Type of compound | Building blocka
|
C. albicans
|
C. neoformans
|
Hemolysis
|
||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R1 | R2 | R3 | IC50 (μg/ml) | MIC (μg/ml) | IC50 (μg/ml) | MIC (μg/ml) | HD50 (μg/ml) | Indexb
|
||
| C. albicans | C. neoformans | |||||||||
| Selected | 4-tBu-cyclohexanecarboxylic acid | l-chAla | d-chAla | 2.3 ± 0.1 | 3–4 | 5.5 ± 2.9 | 8–16 | 9.6 ± 2.2 | 4.1 | 1.7 |
| 1-Adamantaneacetic acid | l-chAla | d-chGly | 2.4 ± 0.1 | 3–4 | 2.6 ± 0.8 | 4–8 | 5.5 ± 1.4 | 3.5 | 2.1 | |
| 1-Adamantaneacetic acid | d-chAla | l-chGly | 2.5 ± 0.3 | 3–4 | 2.1 ± 0.6 | 3–4 | 4.5 ± 0.2 | 1.8 | 2.1 | |
| 1-Adamantaneacetic acid | l-chAla | d-chAla | 2.9 ± 0.7 | 5–8 | 2.7 ± 1.4 | 4–8 | 6.8 ± 0.7 | 2.3 | 2.5 | |
| 1-Adamantaneacetic acid | d-chAla | l-chAla | 3.0 ± 0.9 | 4–8 | 2.3 ± 0.7 | 4–8 | 4.8 ± 0.5 | 1.6 | 2.1 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chAla | d-chGly | 3.5 ± 1.2 | 5–8 | 2.8 ± 1.4 | 8–16 | 8.0 ± 2.5 | 2.3 | 2.9 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chAla | l-chAla | 4.2 ± 0.2 | 5–8 | 2.2 ± 0.6 | 8–16 | 6.0 ± 1.6 | 1.4 | 2.7 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chAla | l-chAla | 4.4 ± 0.1 | 5–8 | 3.4 ± 1.7 | 8–16 | 6.5 ± 1.0 | 1.5 | 1.9 | |
| 1-Adamantaneacetic acid | l-chAla | l-chAla | 4.4 ± 0.2 | 5–8 | 5.7 ± 3.8 | 8–16 | 10 ± 2.5 | 2.4 | 1.8 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chAla | d-chAla | 4.5 ± 0.1 | 5–8 | 3.7 ± 1.7 | 4–8 | 6.7 ± 1.2 | 1.5 | 1.8 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chAla | l-chGly | 4.6 ± 0.2 | 5–8 | 1.7 ± 0.7 | 2–4 | 5.5 ± 0.8 | 1.2 | 3.2 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chAla | d-chGly | 6.6 ± 0.5 | 8–16 | 4.7 ± 1.7 | 8–16 | 14 ± 2.7 | 2.1 | 3.0 | |
| 1-Adamantaneacetic acid | d-chAla | d-chAla | 7.3 ± 1.7 | 8–16 | 4.1 ± 1.9 | 16–32 | 11 ± 1.2 | 1.5 | 2.7 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chGly | l-chAla | 7.3 ± 1.9 | 8–16 | 2.3 ± 1.2 | 4–8 | 7.3 ± 0.2 | 1.0 | 3.2 | |
| 1-Adamantaneacetic acid | l-chGly | d-chAla | 8.3 ± 0.7 | 10–16 | 2.1 ± 1.3 | 4–8 | 6.6 ± 0.5 | 0.8 | 3.1 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chAla | l-chGly | 8.7 ± 0.3 | 10–16 | 4.1 ± 2.2 | 8–16 | 16 ± 2.5 | 1.8 | 3.9 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chGly | d-chAla | 8.7 ± 0.9 | 10–16 | 2.0 ± 0.7 | 4–8 | 5.4 ± 0.5 | 0.6 | 2.7 | |
| 1-Adamantaneacetic acid | l-chGly | d-chGly | 9.0 ± 0.1 | 10–16 | 2.4 ± 1.5 | 4–8 | 17 ± 2.4 | 1.8 | 7.1 | |
| 1-Adamantaneacetic acid | d-chGly | d-chAla | 9.1 ± 0.1 | 10–16 | 3.7 ± 1.4 | 8–16 | 8.9 ± 0.3 | 1.0 | 2.4 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chGly | l-chAla | 9.2 ± 0.5 | 10–16 | 3.5 ± 1.4 | 8–16 | 18 ± 2.8 | 2.0 | 5.1 | |
| 1-Adamantaneacetic acid | l-chGly | l-chAla | 9.3 ± 0.1 | 10–16 | 3.2 ± 2.0 | 16–32 | 9.7 ± 0.6 | 1.1 | 3.0 | |
| 1-Adamantaneacetic acid | d-chGly | l-chAla | 9.4 ± 0.7 | 10–16 | 3.6 ± 1.7 | 8–16 | 10 ± 1.0 | 1.1 | 2.8 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chGly | d-chAla | 9.7 ± 0.1 | 16–32 | 2.1 ± 0.7 | 8–16 | 23 ± 2.9 | 2.4 | 11 | |
| 1-Adamantaneacetic acid | d-chGly | l-chGly | 9.9 ± 0.1 | 11–16 | 2.5 ± 0.3 | 4–8 | 14 ± 1.9 | 1.4 | 5.6 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chGly | d-chGly | 16.8 ± 1.8 | 18–32 | 3.7 ± 0.9 | 4–8 | 28 ± 1.8 | 1.7 | 7.6 | |
| 1-Adamantaneacetic acid | l-chGly | l-chGly | 18.6 ± 1.2 | 20–32 | 2.2 ± 0.5 | 8–16 | 21 ± 1.3 | 1.1 | 9.5 | |
| 1-Adamantaneacetic acid | d-chGly | d-chGly | 23.1 ± 2.2 | 32–64 | 3.8 ± 0.8 | 8–16 | 45 ± 1.6 | 2.0 | 12 | |
| 1-Adamantaneacetic acid | d-chAla | d-chGly | 23.8 ± 1.1 | 32–64 | 9.9 ± 3.9 | 16–32 | 52 ± 2.3 | 2.2 | 5.2 | |
| 4-tBu-cyclohexanecarboxylic acid | l-chGly | l-chGly | 24.1 ± 7.4 | 32–64 | 3.3 ± 0.8 | 4–8 | 39 ± 1.6 | 1.6 | 12 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chGly | l-chGly | 29.3 ± 7.8 | >64 | 4.5 ± 2.2 | 8–16 | 42 ± 2.4 | 1.4 | 9.3 | |
| 4-tBu-cyclohexanecarboxylic acid | d-chGly | d-chGly | 34.2 ± 9.3 | >64 | 3.6 ± 1.4 | 4–8 | 50 ± 2.4 | 1.4 | 14 | |
| 1-Adamantaneacetic acid | l-chAla | l-chGly | 38.8 ± 2.7 | >64 | 15.0 ± 5.7 | 16–32 | 46 ± 1.3 | 1.2 | 3.1 | |
| Control | ||||||||||
| 1 | 1-Adamantaneacetic acid | d-Leu | l-chGly | 26.6 ± 11 | >64 | 4.5 ± 0.2 | 5–8 | 21 ± 0.2 | 0.8 | 4.7 |
| 2 | 1-Adamantaneacetic acid | d-Leu | d-chGly | 48.6 ± 3.7 | >64 | 9.1 ± 0.1 | 10–16 | >32 | ND | >3.5 |
| 3 | 1-Adamantaneacetic acid | l-Phe | l-Phe | 24.9 ± 3.0 | 32–64 | 6.3 ± 4.2 | 16–32 | 20 ± 1.8 | 0.8 | 3.2 |
| 4 | 4-tBu-cyclohexanecarboxylic acid | l-Phe | l-Phe | 50.6 ± 1.8 | >64 | 2.5 ± 0.3 | 4–8 | 18 ± 2.8 | 0.4 | 7.2 |
| 5 | Acetic acid | l-chAla | l-Phe | >64 | >64 | 41.0 ± 6.4 | 62–125 | >32 | ND | >13 |
| 6 | Acetic acid | d-chAla | l-Phe | >64 | >64 | 37.9 ± 4.2 | 62–125 | >32 | ND | ND |
| 7 | Acetic acid | l-chGly | l-Phe | >64 | >64 | 64.6 ± 11 | >25 | >32 | ND | ND |
| 8 | Acetic acid | d-chGly | l-Phe | >64 | >64 | 38.6 ± 1.7 | 62–125 | >32 | ND | ND |
| 9 | Acetic acid | l-Phe | l-chAla | >64 | >64 | 45.2 ± 0.8 | 62–125 | >32 | ND | ND |
| 10 | Acetic acid | l-Phe | d-chAla | >64 | >64 | 37.7 ± 4.1 | 62–125 | >32 | ND | ND |
| 11 | Acetic acid | l-Phe | l-chGly | >64 | >64 | 72.2 ± 24 | >125 | >32 | ND | ND |
| 12 | Acetic acid | l-Phe | d-chGly | >64 | >64 | 34.5 ± 2.2 | 62–125 | >32 | ND | ND |
| 13 | Butyric acid | l-Phe | l-Phe | >250 | >250 | ND | ND | >32 | ND | ND |
| 14 | 3,4-Dimethoxyphenylacetic acid | l-Phe | l-Phe | >250 | >250 | ND | ND | >32 | ND | ND |
| 15 | Acetic acid | d-Ala | l-Phe | >250 | >250 | ND | ND | >32 | ND | ND |
| 16 | Acetic acid | d-Arg | l-Phe | >250 | >250 | ND | ND | >32 | ND | ND |
| 17 | Acetic acid | l-Phe | Aib | >250 | >250 | ND | ND | >32 | ND | ND |
| 18 | Acetic acid | l-Phe | l-tBu-Gly | >250 | >250 | ND | ND | >32 | ND | ND |
a
t-Bu, t-butyl; l-chAla, l-cyclohexylalanine; d-chAla, d-cyclohexylalanine; l-chGly, l-cyclohexylglycine; d-chGly, d-cyclohexylglycine; d-Leu, d-leucine; l-Phe, l-phenylalanine; Aib, α-aminoisobutyric acid; ND, not determined.
b
Defined as HD50/IC50.