CHLOROQUINE DIPHOSPHATE CHLOROQUINE PHOSPHATE BDBM50411863 ARALEN
DESETHYLCHLOROQUINE Desethyl chloroquine BDBM50408762
BDBM22985 CHLOROQUINE PHOSPHATE Chlorochin Chloroquine Chloroquine, 17 Aralen med.21724, Compound 8 {4-[(7-chloroquinolin-4-yl)amino]pentyl}diethylamine CHEMBL76
- Stocks, PA; Raynes, KJ; Bray, PG; Park, BK; O'Neill, PM; Ward, SA Novel short chain chloroquine analogues retain activity against chloroquine resistant K1 Plasmodium falciparum. J Med Chem 45: 4975-83 (2002)
- Biot, C; Daher, W; Ndiaye, CM; Melnyk, P; Pradines, B; Chavain, N; Pellet, A; Fraisse, L; Pelinski, L; Jarry, C; Brocard, J; Khalife, J; Forfar-Bares, I; Dive, D Probing the role of the covalent linkage of ferrocene into a chloroquine template. J Med Chem 49: 4707-14 (2006)
- Zishiri, VK; Joshi, MC; Hunter, R; Chibale, K; Smith, PJ; Summers, RL; Martin, RE; Egan, TJ Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT). J Med Chem 54: 6956-68 (2011)
- Deane, KJ; Summers, RL; Lehane, AM; Martin, RE; Barrow, RA Chlorpheniramine Analogues Reverse Chloroquine Resistance in Plasmodium falciparum by Inhibiting PfCRT. ACS Med Chem Lett 5: 576-81 (2014)
- Pérez, BC; Fernandes, I; Mateus, N; Teixeira, C; Gomes, P Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues. Bioorg Med Chem Lett 23: 6769-72 (2013)
- Vippagunta, SR; Dorn, A; Matile, H; Bhattacharjee, AK; Karle, JM; Ellis, WY; Ridley, RG; Vennerstrom, JL Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. J Med Chem 42: 4630-9 (1999)
- Miura, T; Hidaka, K; Azai, Y; Kashimoto, K; Kawasaki, Y; Chen, SE; de Freitas, RF; Freire, E; Kiso, Y Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum. Bioorg Med Chem Lett 24: 1698-701 (2014)
- Solaja, BA; Opsenica, D; Smith, KS; Milhous, WK; Terzić, N; Opsenica, I; Burnett, JC; Nuss, J; Gussio, R; Bavari, S Novel 4-aminoquinolines active against chloroquine-resistant and sensitive P. falciparum strains that also inhibit botulinum serotype A. J Med Chem 51: 4388-91 (2008)
- Relitti, N; Federico, S; Pozzetti, L; Butini, S; Lamponi, S; Taramelli, D; D'Alessandro, S; Martin, RE; Shafik, SH; Summers, RL; Babij, SK; Habluetzel, A; Tapanelli, S; Caldelari, R; Gemma, S; Campiani, G Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity. Eur J Med Chem 215: (2021)
- Chipeleme, A; Gut, J; Rosenthal, PJ; Chibale, K Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum. Bioorg Med Chem 15: 273-82 (2007)
- ChEMBL_769822 (CHEMBL1831816) Inhibition of chloroquine-resistant Plasmodium falciparum Dd2 chloroquine resistance transporter expressed in xenopus laevis oocytes assessed as inhibition of [3H]chloroquine uptake after 1 to 2 hrs
- ChEMBL_877808 (CHEMBL2187303) Inhibition of chloroquine-resistant Plasmodium falciparum Dd2 CRT expressed in Xenopus laevis oocytes assessed as reduction in [3H]-chloroquine uptake after 1.5 to 2 hrs
- ChEMBL_864478 (CHEMBL2176281) Inhibition of chloroquine-resistant Plasmodium falciparum Dd2 CRT expressed in Xenopus laevis oocyte assessed as inhibition of [3H]chloroquine uptake measured from 1 to 2 hrs
- ChEMBL_1364181 (CHEMBL3292896) Inhibition of chloroquine-resistant Plasmodium falciparum Dd2 CRT expressed in Xenopus laevis oocytes plasma membrane assessed as reduction of [3H]-chloroquine transportation after 1 to 2 hrs
- ChEMBL_584109 (CHEMBL1051116) Inhibition of hemozoin formation after 48 hrs in chloroquine-sensitive Plasmodium falciparum NF54
- In Vitro Inhibition Assay In vitro antimalarial assay, antimalarial activity of the compounds was determined in vitro on chloroquine sensitive and resistant strains of plasmodium flaciparum as described earlier.
- ChEMBL_1770954 (CHEMBL4223066) Inhibition of falcipain-2 in chloroquine resistant Plasmodium falciparum RKL9 schizont stage infected in human erythrocytes assessed as reduction in bacterial growth after 24 hrs by Giemsa staining based assay
- ChEMBL_1770953 (CHEMBL4223065) Inhibition of falcipain-2 in chloroquine sensitive Plasmodium falciparum MRC-02 schizont stage infected in human erythrocytes assessed as reduction in bacterial growth after 24 hrs by Giemsa staining based assay
- Growth Inhibition Assay The [3H]-hypoxanthine growth inhibition assay (Desjardins et al., 1979 Antimicrobial Agents Chemother 16: 710-718) was used to evaluate the in vitro antimalarial activity of the compounds. Briefly, synchronised parasite cultures (>90% rings, 6 to 8 h post invasion) in [3H]-RPMI-LPLF complete medium with 1% parasitaemia and 2% haematocrit were exposed to the compounds at ten two-fold concentrations. Chloroquine was used as a reference drug. Uninfected RBCs at 2% haematocrit were used as background controls. Two drug exposure periods were evaluated (48 h and 96 h). For the 48 h exposure period, the plates were incubated in the gas mixture at 37° C. for approximately 20 h (about 24 h post-invasion). To each well, 0.2 uCi of tritiated hypoxanthine (GE Healthcare, Amersham) solution in [3H]RPMI-1640-LPLF was added. The plates were incubated for a further 24 h at 37° C. in the gas Mixture and then frozen at 20° C. For the 96 h exposure period, the plates were incubated.
- Parasite Proliferation Assay This parasite proliferation assay, a modification of published DNA intercalating fluorescent dye-based assay, was adapted to 384-well plate format and measures the increase in parasite DNA content using the DNA intercalating dye SYBR Green. Compound 1 exhibited strong potency in both the in vitro biochemical and parasite proliferation assays, which suggests that this compound is potentially acting against PfCDPK1 in vivo. Several other analogs, compounds 7 and 8, exhibited potent enzymatic activity but were inactive in parasite proliferation assays, whereas some analogs displayed low EC50 values in the parasite proliferation assay but were inactive against the enzyme. The EC50 values of all the compounds may be between four- and five-fold higher in the SYBR Green assay compared to the 3H-hypoxanthine-based assay, which measures incorporation of tritium into DNA, as the optimal fluorescent reading conditions required the use of albumax, a lipid-enriched bovine albumin to which small molecules bind. This binding effectively sequesters the drug, thereby reducing the compound concentration and shifting the EC50 to a higher value. A shift in the EC50 due to albumax was also observed for the reference inhibitors chloroquine and artemisinin, which yielded EC50 values of less than 10 nM with the 3D7 strain in the 3H-hypoxanthine-based assay under low protein condition but showed an EC50 in the same range as the best compound in the parasite proliferation assay (70 nM).