TABLE 1.
Summary of the chemical compounds that showed the best biological activity against metacercariae
| Compound plate codea | MMV identifierb | Molecular formulac | Mol wtc (g/mol) | Mean % mortality for MCd | SD for % mortality for MCd | IC50 (μM)e | rf | Activity against other infectious microorganism(s)g |
In silico toxicity featuresh
|
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Acute cytotoxicity (fathead minnow) (mg/liter) | Blood-brain barrier penetration (human) | Carcinogenicity (rodent) | Mutagenicity (S. enterica serovar Typhimurium) | Maximum recommended daily dose (human) (mg/kg bwi /day) | |||||||||
| TCBZ | NA | C14H9Cl3N2OS | 359.7 | 100j | 0j | 15k | NA | Schistosoma | 4.57 | Penetrating | Noncarcinogenic | Nonmutagenic | NA |
| PAA2 | MMV010764 | C14H16N4OS2 | 320.4 | 22 | 38.5 | 24.1 | −0.3 | Plasmodium | NA | NA | Noncarcinogenic | Nonmutagenic | NA |
| PAF4 | MMV676388 | C15H14N4O3S | 330.4 | 29 | 24.7 | 16.9 | 0.8 | Mycobacterium | 254.0 | Penetrating | Carcinogenic | Mutagenic | 2.44 |
| PAF5 | MMV202553 | C15H15N3O2 | 269.3 | 29 | 24.7 | 14.9 | 0.9 | Kinetoplastids | 7.58 | Penetrating | Noncarcinogenic | Mutagenic | 0.993 |
| PAG6 | MMV063404 | C19H24N3OCl | 345.9 | 54 | 7.2 | 5.3 | 1.0 | Mycobacterium | NA | Penetrating | Carcinogenic | Mutagenic | NA |
| PAH6 | MMV676539 | C20H16N2O3 | 332.4 | 17 | 28.9 | 24.7 | −1.0 | Mycobacterium | 25.9 | Penetrating | Carcinogenic | Mutagenic | 4.05 |
| PBD3 | MMV637953 | C51H40N6O23S6 | 1,435.3 | 25 | 9.9 | 21.8 | −0.6 | Trypanosoma and Onchocerca | NA | Penetrating | Noncarcinogenic | Nonmutagenic | NA |
| PBD7 | MMV019838 | C18H10N4OF6 | 412.3 | 26 | 11.6 | 12.4 | 0.0 | Plasmodium | NA | Penetrating | Noncarcinogenic | Mutagenic | NA |
| PBF4 | MMV003270 | C7H5N2OCl | 168.6 | 26 | 25.1 | 8.2 | −0.7 | Ancylostoma | 6.75 | Penetrating | Noncarcinogenic | Nonmutagenic | 15.5 |
| PBF6 | MMV688853 | C19H23N5O2 | 389.9 | 25 | 22.5 | 31.9 | −0.8 | Cryptosporidium | NA | Nonpenetrating | Noncarcinogenic | Mutagenic | NA |
| PBF11 | MMV085210 | C22H24N3O3ClS | 446.0 | 40 | 15.3 | 2.4 | 0.8 | Plasmodium | NA | Penetrating | Noncarcinogenic | Nonmutagenic | 1.64 |
| PBH10 | MMV676380 | C18H15N4O3Cl | 370.8 | 33 | 33.3 | 1.3 | 0.1 | Plasmodium | 132.0 | Penetrating | Noncarcinogenic | Nonmutagenic | 101.0 |
| PCA2 | MMV675997 | C24H29N4O2F | 424.5 | 22 | 38.4 | 18.1 | −0.2 | Kinetoplastids | NA | Penetrating | Noncarcinogenic | Mutagenic | 1.51 |
| PCA6 | MMV688852 | C16H17N5ClF | 333.8 | 29 | 37.4 | 17.2 | −0.7 | Toxoplasma | NA | Penetrating | Noncarcinogenic | Mutagenic | NA |
| PCC2 | MMV688508 | C19H19N2O4F | 358.4 | 26 | 3.7 | 16.9 | −0.5 | Mycobacterium | NA | Penetrating | Noncarcinogenic | Mutagenic | NA |
| PCC5 | MMV687730 | C22H32N4O2 | 384.5 | 28 | 13.4 | 0.4 | −0.5 | Mycobacterium | NA | Penetrating | Carcinogenic | Nonmutagenic | NA |
| PCC6 | MMV687251 | C8H9N3O4S2 | 275.3 | 30 | 12.0 | 0.3 | −0.5 | Mycobacterium | NA | Penetrating | Noncarcinogenic | Nonmutagenic | 13.3 |
| PCC9 | MMV688361 | C21H19N5O | 357.4 | 32 | 11.5 | 17.2 | −0.7 | Kinetoplastids | NA | Penetrating | Carcinogenic | Mutagenic | NA |
| PCC10 | MMV689029 | C26H26N4O4S | 490.6 | 33 | 19.1 | 10.5 | 0.8 | Kinetoplastids | NA | Penetrating | Carcinogenic | Mutagenic | 11.9 |
| PCD11 | MMV1030799 | C20H18N4O | 330.4 | 28 | 11.7 | 1.5 | −0.3 | Plasmodium | 6.62 | Nonpenetrating | Carcinogenic | Mutagenic | NA |
| PCE5 | MMV687146 | C19H26N2O | 298.4 | 21 | 25.8 | 15.6 | 0.6 | Mycobacterium | NA | Penetrating | Noncarcinogenic | Mutagenic | NA |
| PCE6 | MMV687696 | C29H28N4O2ClF3 | 557.0 | 26 | 20.6 | 18.2 | −0.7 | Mycobacterium | NA | Nonpenetrating | Carcinogenic | Mutagenic | NA |
| PCE7 | MMV687170 | C17H13N4O2Cl | 340.8 | 34 | 25.3 | 13.1 | 0.0 | Mycobacterium | NA | Penetrating | Carcinogenic | Mutagenic | NA |
| PCE8 | MMV690102 | C22H23N7O2 | 417.5 | 38 | 15.6 | 2.1 | 0.7 | Kinetoplastids | NA | Penetrating | Noncarcinogenic | Mutagenic | 3.27 |
| PCE11 | MMV1029203 | C20H17N5OS | 375.5 | 33 | 29.7 | 7.1 | −0.4 | Plasmodium | 100.0 | Penetrating | Carcinogenic | Mutagenic | NA |
| PCF2 | MMV676053 | C18H16N3O3Cl | 357.8 | 38 | 12.5 | 1.9 | 0.6 | Cryptosporidium | 194.0 | Penetrating | Noncarcinogenic | Mutagenic | 0.991 |
| PCF3 | MMV688179 | C18H16N6OCl2 | 476.2 | 35 | 32.0 | 3.1 | −0.1 | Kinetoplastids | 4.62 | Penetrating | Carcinogenic | Mutagenic | 1.41 |
| PCF4 | MMV023969 | C24H24N4OS | 453.0 | 48 | 21.8 | 1.5 | 0.3 | Mycobacterium | NA | NA | Carcinogenic | Mutagenic | NA |
| PCF5 | MMV687138 | C19H17NO3S | 339.4 | 26 | 11.6 | 14.7 | −0.2 | Mycobacterium | 524.0 | Penetrating | Noncarcinogenic | Mutagenic | 89.7 |
| PCF11 | MMV688921 | C23H18N3O5Cl | 451.9 | 31 | 43.0 | 2.4 | −0.4 | Aedes aegypti- chikungunya virus | NA | Penetrating | Carcinogenic | Mutagenic | NA |
| PCG9 | MMV688891 | C18H11NO4BrF3 | 442.2 | 25 | 10.9 | 25.7 | −0.5 | Mycobacterium | NA | Penetrating | Carcinogenic | Mutagenic | 1.25 |
| PDH11 | MMV688980 | C16H18N3O2FS | 335.4 | 33 | 38.2 | 21.2 | 0.2 | Plasmodium | NA | Penetrating | Carcinogenic | Mutagenic | NA |
| PEC8 | MMV687765 | C25H26N6O | 463 | 28 | 25.5 | 20.6 | −0.8 | Mycobacterium | NA | Penetrating | Noncarcinogenic | Mutagenic | NA |
| PEG9 | MMV084864 | C17H12N6O | 316.3 | 40 | 18.7 | 17.3 | 0.8 | Plasmodium | 14.2 | Penetrating | Noncarcinogenic | Mutagenic | NA |
Coordinates used to identify the compounds in each plate. TCBZ, triclabendazole.
Identification codes assigned by the Medicines for Malaria Venture (MMV). NA, not applicable.
Molecular formulas and molecular weights were obtained from www.mmv.org. For TCBZ, these values were obtained from ChEMBL (https://www.ebi.ac.uk/chembl/).
Measured at 72 h after drug exposure for the metacercaria (MC) stage. Results are the mean and standard deviation for triplicate experiments at a concentration of 33 μM.
Compounds were serially diluted and tested in culture. Results are the means from triplicate experiments. Fasciolicidal activity values were determined with CompuSyn software.
r, correlation coefficient.
Activity shown against other agents causing infectious diseases, obtained from www.mmv.org.
Predictions were obtained using the lazar program (https://lazar.in-silico.de/predict). NA, not available.
bw, body weight.
Data represent the mean and standard deviation for 10 individual experiments performed in 5 plates.
Data were obtained from https://drugs.ncats.io.