Retargeting azithromycin analogues to have dual-modality antimalarial activity

Burns, Amy L.; Sleebs, Brad E.; Siddiqui, Ghizal; De Paoli, Amanda E.; Anderson, Dovile; Liffner, Benjamin; Harvey, Richard; Beeson, James G.; Creek, Darren J.; Goodman, Christopher D.; McFadden, Geoffrey I.; Wilson, Danny W.

doi:10.1186/s12915-020-00859-4

Table 1 In vitro efficacy of antimalarials and azithromycin analogues against Plasmodium spp. parasites

From: Retargeting azithromycin analogues to have dual-modality antimalarial activity

cmpnd	R³ class	R⁴ class	R⁵ class	In-cycle (44 hr) growth D10-PfPHG IC₅₀ (μM^a, ±SEM)	In-cycle (44 hr) growth DD2 IC₅₀ (μM^b, ±SEM)	Invasion inhibition D10-PfPHG IC₅₀ (μM^c, ±SEM)	In-cycle (24 hr) growth PkYH1 IC₅₀ (μM^d, ±SEM)
AZR	Me	Me	H	11.31 (0.49)	15.6 (2.1)	10 (1.4)	16 (1.8)
CQ				0.052 (0.006)	0.31 (0.31)	ND	0.017 (0.005)
QN				0.39 (0.07)	ND	ND	ND
DHA				0.0008 (0.0001)	ND	ND	0.0024 (0.001)
1	Chloroquinoline	Me	H	0.019 (0.004)	0.082 (0.02)	ND	0.2 (0.005)
56	Me	Chloroquinoline	H	0.011 (0.002)	0.093 (0.02)	3.2 (0.39)	0.031 (0.008)
59	Me	Chloroquinoline	H	0.073 (0.02)	0.049 (0.005)	ND	ND
66	Me	Me	Chloroquinoline	0.007 (0.001)	0.043 (0.002)	ND	0.012 (0.002)
69	Me	Me	Chloroquinoline	0.031 (0.004)	ND	ND	ND
70	Me	Me	Chloroquinoline	0.05 (0.006)	ND	ND	ND
72	Me	Me	Chloroquinoline	0.27 (0.01)	0.065 (0.004)	1.7 (0.02)	0.15 (0.06)
8	Quinoline	Me	H	0.41 (0.02)	0.52 (0.1)	4.4 (1.2)	0.15 (0.01)
10	Quinoline	Me	H	0.48 (0.04)	0.748 (0.1)	ND	0.1 (0.005)
58	Me	Quinoline	H	0.048 (0.004)	0.056 (0.01)	ND	0.071 (0.013)
71	Me	Me	Quinoline	0.053 (0.005)	0.16 (0.02)	ND	0.041 (0.005)
73	Me	Me	Quinoline	0.31 (0.02)	0.48 (0.2)	ND	0.248 (0.07)
3	Naphthalene	Me	H	0.183 (0.02)	0.32 (0.07)	1.8 (0.5)	0.095 (0.02)
4	Naphthalene	Me	H	0.19 (0.01)	ND	2.0 (0.2)	ND
15	Naphthalene	Me	H	0.67 (0.07)	0.4 (0.1)	3.6 (0.4)	0.32 (0.12)
5	Substituted phenyl thiourea	Me	H	0.2 (0.01)	0.4 (0.05)	1.61 (0.02)	0.082 (0.02)
6	Substituted phenyl thiourea	Me	H	0.28 (0.05)	0.27 (0.07)	ND	0.16 (0.03)
9	Substituted phenyl thiourea	Me	H	0.44 (0.07)	0.24 (0.04)	ND	0.016 (0.005)
17	Substituted phenyl thiourea	Me	H	0.7 (0.05)	0.54 (0.06)	ND	0.36 (0.01)

^a Drug treatment of intracellular growth, from rings to late schizonts, with no rupture cycle for D10-PfPHG (P. falciparum, 0–44 hrs). Data represents the mean of 3 or more experiments
^b Drug treatment of intracellular growth, from rings to late schizonts, with no rupture cycle for DD2 (P. falciparum, 0–44 hrs). Data represents the mean of 3 or more experiments
^c Drug treatment of D10-PfPHG merozoites prior to addition of RBCs. Parasitemia was measured by flow cytometry ~ 30 min post invasion. Data represents the mean of 2 (for compounds 4 and 5) or 3 experiments
^d Drug treatment of intracellular growth, from rings to late schizonts, with no rupture cycle for P. knowlesi YH1 (P. knowlesi, 0–24 h). Data represents the mean of 2 or more experiments

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ISSN: 1741-7007

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