Fast- and slow-acting antimalarials against cultured P. falciparum strains. |
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Bernard MM, Mohanty A, Rajendran V. Title: A Comprehensive Review on Classifying Fast-acting and Slow-acting Antimalarial Agents Based on Time of Action and Target Organelle of Plasmodium sp. Pathog Dis. 2022 May 19:ftac015. doi: 10.1093/femspd/ftac015. Epub ahead of print. PMID: 35588061. |
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Antimalarial agent |
Strain |
Inhibitory conc. |
Stage of max. inhibition |
Mechanism of action |
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Fast acting |
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FOOD VACUOLE |
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1. MCQ (5,5’-dimethyl2,2, bipyridine) |
Pf 3D7 |
0.81 µM |
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[CQ containing Organoruthenium] |
Pf W2 |
1.05 µM |
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FCQ (1,10-phenanthrodine) |
Pf 3D7 |
0.37 µM |
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Pf W2 |
0.87 µM |
Trophozoite 18 h |
Inhibition of hemin polymerization leads to obstruction of ß-hematin formation, subsequently inducing oxidative stress by increased ROS. |
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2. Compound 24 6-chloroarylvinylquinoline |
Pf Dd2 |
10.9 nM |
Late troph. Early schiz.1.5 h |
Accumulation of undegraded hemoglobin by supposedly targeting proteases inside food vacuole. |
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Pf 3D7 |
16.8 nM |
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3. DAQ [CQ analog] |
Pf 3D7 |
46 nM |
Early ring |
12 h Inhibition of ß-hematin formation |
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Pf K1 |
50 nM |
Early ring |
12 h Inhibition of ß-hematin formation |
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4. Marinoquinoline derivative |
Pf 3D7 |
39 nM |
Early ring 8-16 h |
Interference with hemoglobin metabolism and exhibit acetylcholinesterase-inhibiting activity |
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Pf K1 |
41 nM |
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5. Moxiquindole [spirofused tetrahydroisoquinoline –oxindole hybrid] |
Pf NF54 |
0.68 µM |
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Pf 3D7 |
1.86 µM |
Ring and Troph. |
<24 h Rapid induction of parasite vacuolation by interfering with lipid vacuolar dynamics leads to impaired hemoglobin degradation. |
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Pf Dd2 |
1.73 µM |
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6. Chloroquine |
P. knowlesi A1H.1 |
0.010 µM |
Blood stage 24 h Block ß-hematin formation. |
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Cycloguanil |
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0.003 µM |
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JPC-3210 [2-aminomethyl phenol] |
Pf 3D7 |
15 nM |
Trophozoite and schizont |
5 h Inhibition of parasite’s hemoglobin digestion and elevation of regulators of protein translation |
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8. Compound 10 [Tetrazole based series] |
Pf 3D7 |
0.40 µM |
Trophozoite |
<24 h Blocking heme biomineralization. |
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Pf Dd2 |
1.8 µM |
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Pf NF54 |
0.83 µM |
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9. Compound 2 [HEA-Pt analogs] |
Pf 3D7 |
1.14 μM |
Ring and Troph. |
3h Inhibition of Plasmepsin (Plm V). |
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Compound 5 |
Pf 3D7 |
1.14 µM |
Ring and Troph. |
3 h Inhibition of Plasmepsin (Plm V). |
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Pf Dd2 |
1.31 µM |
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6 h Inhibition of plasmepsins (Plm II, IV, V and X). |
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Compound 60 [Pyridylvinylquinoline triazole analog] |
Pf Dd2 |
0.04 μM |
Trophozoite |
6 hInhibition of β-hematin formation by possibly targeting vacuolar proteases. |
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Substituted 15-membered azalides |
Pf 3D7 |
0.006 – 0.020 μM |
3h Interference with heme polymerization |
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Pf W2 |
0.007 – 0.027 μM |
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12. Compound 37 [2,4 disubstitutedImidazopyridine compounds] |
Pf NF54 |
0.023 µM |
Blood stage |
31 h Targeting an alternative digestive vacuole process, decreasing hemozoin content. |
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Pf K1 |
0.041 µM |
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13. Compound 10 [Arylmethylamino steroids] |
Pf NF54 |
2.9 nM |
Blood stage |
24 h Chelate-based quinone methide mechanism involving metal or heme bioactivation. |
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14. Monensin [Monovalent ionophores] |
Pf 3D7 |
1.0 nM |
Blood stage Gametocytes (IV-V) |
2-4 h Perturbation of the cation gradient in the parasite cytosol and food vacuole. |
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Nigericin |
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9.3 nM |
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Monensin |
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6.1 nM |
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15. Maduramicin |
Pf NF54 |
1.3 nM |
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14.8 nM |
Schizont Gametocyte (Stage III-IV) |
12 h Disruption of Na+ across cellular membranes by targeting PfATP4. |
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gradient |
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16. MMV085071 |
Pf 3D7 |
76.3 nM |
Trophozoite |
4 h Digestive Vacuole disruption and downstream programmed cell death-like mechanism. |
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Pf K1 |
126.6 nM |
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NUCLEUS AND NUCLEAR COMPONENTS |
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L-methionine +Deoxycytidine bisubstrate inhibitors] |
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Compound 70 |
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Pf NF54 |
71 nM |
Early ring |
6 h Inhibition of parasite DNA cytosine methylation by targeting DNMT domain. |
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60 nM |
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BIX-1294 |
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Pf 3D7 |
19 nM |
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TM2-115 [Diaminoquinazoline scaffolds] |
Pf 3D7 |
32 nM |
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BIX-1294 |
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Pf 7G8 |
1.07- 3.84 nM |
Ring Early-late, gametocyte all blood stages |
12, 29 h Inhibition of histone methyltransferase. |
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19. Compound 31 [Thiazole derivatives] |
Pf 3D7 |
0.16 µM |
Blood stage |
24 h Inhibition of Serine/Arginine protein kinase |
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20. GW012X |
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[Nonpeptido-mimetic, Proteasome inhibitor] |
Pf3D7 |
7.9 µM |
ring troph. |
3 h Inhibition of chymotrypsin |
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4.2 µM |
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21. Compound 15 |
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Compound 16 [Arylalkylpolyamino (bis)urea & (bis)thiourea isosteres] |
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Compound 30 |
Pf 3D7 |
88 nM |
Ring and trophozoite |
Blocking nuclear division and DNA replication. Enforce activity by preventing DNA synthesis and nuclear DNA synthesis and nuclear division. |
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PfHB3 |
26 nM |
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22. Quarfloxin |
Pf 3D7 |
0.11 µM |
Ring and trophozoite |
<6 h Deregulated expression of varassociated PQS-containing |
23. Compound 2 [4-aminoquinazolines] |
Pf 3D7 |
0.081 µM |
Blood stage |
24 h Targeting histone lysine methyltransferases, redox and nucleosome proteins and chaperones |
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Pf K1 |
0.144 µM |
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24. Compound 13 [Bischalcones] |
Pf 3D7 |
2.5 µM |
Trophozoite |
18 h Initiate PCD of parasites |
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Pf Dd2 |
3.5 µM |
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GOLGI COMPLEX, ER, RIBOSOMES, PVM |
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25. Torin 2 |
Pf Dd2 |
0.7 nM |
Blood stage |
4 h Alter localization of parasitophorous vacuole membrane (PVM)- resident proteins |
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Pf 3D7 |
1.4 nM |
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26. MMV688533 [Acylguanidine] |
Pf 3D7 |
1.9 nM |
ring to early troph |
24 h Involved in lipid-associated essential components. |
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Pf Dd2 |
3.0 nM |
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Pf K1 |
19 nM |
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Pf FC27 |
9.7 nM |
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27. ICL-M [Isocryptolepine derivative] |
Pf 3D7 |
148.31 nM |
Ring and troph |
4 h Disruption of ribosomal, proteasomal and metabolic pathways. |
PARASITE CYTOSOL |
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28. Artemisinin |
Pf 3D7 |
32 nM |
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Artesunate |
Pf 3D7 |
2 nM |
Blood stage, troph |
1h Contains endoperoxide bond mediating ROS production. DNA damage is mediated by increased ROS production. |
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29. E209 [Tetraoxane based molecule] |
Pf 3D7 |
5.1 nM |
Blood stage |
<24 h Intra-parasitic ferrous mediated reductive scission of the endoperoxide bond leading to generation of ROS (Artemisininlike action). |
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30. Plasmodione 3-[4-(trifluoromethyl)benzyl ]-menadione |
Pf 3D7 |
47 nM |
Early ring; early gametocytes+ |
33 h Disturb the redox balance of the parasitized RBC by acting as redox cycles. |
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Pf Dd2 |
59 nM |
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Pf NF54 |
21 nM |
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31. Indole benzamides -12192 |
Pf3D7 |
0.24 µM |
Blood stage |
4 h Inhibition of V type H+-ATPase which disrupts cytosolic pH. |
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Pf 7G8 |
0.41 µM |
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MEROZOITES |
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32. UCF 501 [4-Nitrostyrylquinoline] |
Pf 3D7 |
119 nM |
Early ring and merozoites |
6 h Does not inhibit ß-hematin formation like other quinolones but acts early in the intraerythrocytic stage, including merozoite invasion. |
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Pf Dd2 |
67 nM |
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33. Compound 17 [Thiazole scaffolds] |
Pf 3D7A |
0.18 µM |
Blood stage |
48 h Targeting cyclic GMP-dependent protein kinase (PKG). |
Compound 18 |
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0.19 µM |
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34. Trichostatin |
A D10-PfPHG line |
5 nM |
schizonts and merozoites |
4 h Merozoite invasion inhibition. |
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ACTION UNEXPLORED |
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35. T3/SAR97276 [Choline analog, Bisthiazolium] |
Pf 3D7 |
4 - 5.2 nM |
Ring, troph and Schizont |
1 h, 5 h Blocking the synthesis of phosphatidylcholine by affecting a polyspecific organic cation transporter. |
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36. SC83288 [Amicarbalide derivative] |
Pf NF54 |
5.1 nM |
Trophozoite |
17 h Artemisinin-like action affects different molecular pathways. |
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PfNF54ART |
4.9 nM |
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Pf Dd2 |
3.1 nM |
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37. DDD01034957 [CHEMBL3443358] |
Pf 3D7 |
172 nM |
Blood stage |
24 h Different fast-acting antimalarial activity |
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38. TCMDC-125345 [TCAMS library] TCMDC-124559 |
Pf NF54 0.36 µM |
Gametocytes |
24 h Inhibition of exflagellation and reduction in oocyst intensity (male and female gametes). |
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0.5 µM |
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39. MMV006172 [Acridine and thiazolopyrimidine derivaties] MMV665971 |
Pf 3D7 |
0.14 µM |
Ring |
16 h Different modes of action related to artesunate. |
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0.48 µM |
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40. DC-9237 [Macrocyclic Compound] |
Pf Dd2 |
44 nM |
All blood stages |
6 h Novel mechanism related to macrocyclic inhibitors. |
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41. Compound Ru2 [Half- sandwich Cyclopentadienylruthenium (II) complexes] |
Pf 3D7 |
7.69 nM |
Ring and troph |
3-6 h Cytocidal mode of action by impairing asexual parasite differentiation. |
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42. Compound 46 [Amide Pyrazinyloxy Benzoxaboroles] |
Pf 3D7 |
43 nM |
Blood stage |
30-36 h Possible novel mechanism of action against multiple drug-resistant strain |
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Pf W2 |
33 nM |
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43. DDD01035881 [N-((4-hydroxychroman-4-yl) methyl)-sulphonamide scaffold] |
Pf NF54 |
0.19 µM |
Male gamete |
24 h Prevent the formation of male gametes by inhibiting exflagellation. |
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44. Compound 1 [Pseudoceratidine derivative] |
Pf 3D7 |
1.1 µM |
Early ring |
8-16 h Possibly inhibits de novo fatty acid synthesis pathway. |
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Pf K1 |
1.1 µM |
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45. Compound 54 [2‑Anilino 4‑Amino Substituted Quinazoline series |
Pf 3D7 |
27 nM |
ring, gametocyte (I-III) |
<24 h Target histone lysine methyltransferases, redox proteins, nucleosome proteins and chaperones. |
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Pf W2mef |
57 nM |
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Pf NF54 |
326 nM |
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46. ACT-451840 |
Pf NF54 |
0.4 nM |
All blood stages |
28 hDistinct mode of action by interacting with the Pf multi-drug resistance protein-1(PfMDR-1). |
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Pf K1 |
0.3 nM |
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ACT-213615 |
Pf K1 |
0.46 nM |
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1h |
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Pf W2 |
0.42 nM |
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47. Boromycin |
Pf 3D7 |
0.9 nM |
All blood stages |
6 h Low ionophoric activity on potassium channels with a novel primary mode of action |
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Pf Dd2 |
0.6 nM |
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Fast-acting antimalarial agents with their time, stage and mode of action against in vivo |
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Antimalarial agent |
Strain |
Effective dose |
Stage of Max. inhibition |
Time onf actio |
Mechanism of action |
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PLASMA MEMBRANE AND ASSOCIATED TRANSPORTERS |
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1. Albitiazolium |
P.vinckei |
ED50 - 0.22 mg/kg |
Mature stages |
3 h |
Inhibition of de novo PC biosynthesis by blocking the parasite choline carrier and interaction with heme inside the food vacuole. |
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Ring |
6 h |
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2. Methnaridine |
P.berghei |
ED50 - 0.52 mg/kg |
Blood stage |
36 h |
Breakage of parasite immune escape by restoring Tregs and Th1 response
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3. Compound 12 [Triaminopyrimidines] |
Pf 3D70087/N9 mouse |
ED90 - 1.9 mg/kg |
Blood stage |
72 h |
Targets the essential proton pump (V-type H+ -ATPase). |
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4. (+)-SJ733 |
Pf NODSCID mouse (3D70087/N9) |
ED90 - 1.9 mg/kg |
Blood stage |
48 h |
Targets the ATP4 causing a rapid perturbation of Na+ homeostasis |
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5. PA21A092 [Pyrazoleamide compounds] |
Pf NOD/SCID/IL2Rgnull mouse |
ED90 - 2.5 mg/kg |
Blood stage |
48h |
Disruption of Na+ homeostasis. |
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FOOD VACUOLE |
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6. Compound 13 [Trisubstituted pyrimidines] |
Pf SCID mouse |
ED90 - 11.7 mg/kg |
Blood stage |
48 h |
Blocking hemozoin (ßhematin) formation with a distinct profile than CQ. |
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7. Ozonide OZ439 |
P.berghei |
Single Dose - 20 mg/kg |
All blood stages and gametocytes |
Within 7-8 days |
Heme alkylation- relating to heme electron transfer to the peroxide bond. |
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NUCLEUS AND NUCLEAR COMPONENTS |
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8. Compound 1 [Azepanylcarbazole aminoalcohol] |
Pf 3D7 SCID mouse |
ED90 - 3.6 mg/kg |
Schizont |
24 - 48 h |
Inhibition of PfHsp 90 and blocking voltage-dependent potassium ion channel |
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9. 8aA [Carbohybrid based 2-aminopyrimidine analogues] |
P. chabaudi |
ED50 - 0.32 mg/kg |
All blood stages |
12 h |
Block cell cycle progression |
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11aA |
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ED50 - 0.12 mg/kg |
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ACTION UNEXPLORED |
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10. Artemether |
P. berghei |
Single dose – |
Blood stage |
24 h |
Decrease leukocyte sequestration and |
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ANKA |
25mg/kg |
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inflammation during cerebral malaria |
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11. Compound 23 [ Bis-1,2,4- Triazine] |
Pf 3D7 SCID mouse |
ED50 - 1.85 mg/kg |
Blood stage |
Within 72 h |
Fast-killing profile is similar to artesunate and chloroquine. |
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12. Compound 43 [2,6- disubstituted imidazopyridine compounds] |
Pf NOD SCID mouse |
ED90- 4.2 mg/kg |
Within 48 h |
Novel mechanism of action |
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Compound 74 |
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ED90 - 5.6 mg/kg |
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13. Compound 7 N-[3-[(Benzimidazol-2-yl)amino]propyl]amide s |
Pf 3D7 SCID mouse |
Dose -100 mg/kg |
Blood stage |
48 h |
Fast-killing profile is similar to dihydroartemisinin and piperaquine |
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Slow-acting antimalarial agents with their time, stage and mode of action against cultured P. falciparum strains. |
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Antimalarial agent |
Strain |
Inhibitory conc. |
Stage of max inhib |
Time of action |
Mechnism of action |
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APICOPLAST |
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1. 7-position modified tetracycline derivatives |
Pf W2 |
18 – 53 nM |
Ring |
96 h |
Specific effect on protein synthesis in the apicoplast. |
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2. Doxycycline |
Pf W2 |
0.46 mM |
Troph and early schiz |
96 h |
Disrupt expression of apicoplast genes. |
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3. Azithromycin |
Pf 3D7 |
52.7 nM |
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Pf W2 |
31 nM |
Late troph and early schiz. |
96 h |
Disrupt apicoplast function by interfering with translation. |
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4. Compound 33 [PfClpP protease inhibitor] |
Pf 3D7 |
9.0 mM |
Early-late schizont |
60 h |
Affect apicoplast development and segregation |
5. DC-9236 |
Pf Dd2 |
0.41 nM |
Mature schizont |
48 h |
Target apicoplast during the second life cycle. |
MITOCHONDRIA |
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6. Tetracycline |
Pf W2 |
4.1 mM |
Preerythrocytic stage |
96 h |
Act on dihydroorotate dehydrogenase enzyme by chelating its iron centre. |
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0.8 mM |
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144 h |
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7. Proguanil (PG) |
Pf 3D7 |
0.11 μM |
Blood stage |
96 h |
Target an alternative mechanism responsible for mitochondrial membrane potential. |
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Pf Dd2 |
0.54 μM |
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tert-butyl PG |
Pf 3D7 |
0.05 μM |
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Pf Dd2 |
0.32 μM |
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8. Alstonine [Natural products] |
Pf 3D7 |
0.17 μM |
Blood stage |
96 h |
Not associated with apicoplast and possibly targets mitochondrial electron transport chain. |
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Himbeline |
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0.58 μM |
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9. Compound 10 [Phthalimide Derivatives] |
Pf 3D7 |
4.2 μM |
Late ring or early troph. |
16 - 32 h |
Inhibition of cytochrome bc1 complex |
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Pf K1 |
4.3 μM |
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10. Compound 4 [Cyclopeptides] |
Pf 3D7A |
1.0 nM |
Blood stage |
48 h |
Slow killing profile like atovaquone and pyrimethamine. |
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Compound 6 |
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1.8 nM |
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PARASITE CYTOSOL |
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11. MMV390048 |
Pf NF54 |
28 nM |
Young schizont |
72 h |
Targeting phosphatidylinositol 4-kinase (P14K). |
12. Compound 1 [1-(pyridin-4-yl) pyrrolidin-2-one derivatives] |
Pf NF54 |
0.018 μM |
Schizont |
96 -120 h |
Inhibition of the plasmodium cytoplasmic PRS enzyme. |
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Pf Dd2 |
0.024 μM |
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Pf K1 |
0.020 μM |
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13. MMV642943 [2-aminopyridines] |
Pf NF54 |
66 nM |
Late gametocytes |
72 h |
Target lipid kinases in various stages of P falciparum. |
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MMV642944 |
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52 nM |
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14. Compound 30 [2,8-Disubstituted-1,5-naphthyridines] |
Pf NF54 |
22 nM |
Schizont |
48 h |
Inhibition of Plasmodium phosphatidyl-inositol 4-kinase (PI4K) enzyme. |
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Pf K1 |
19nM |
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FOOD VACUOLE |
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15. Quinoline-triazole Iridium (III) half sandwich complexes |
Pf NF54 |
0.25 μM |
Ring |
>48 h |
Inhibition of β-hematin formation with a different mode of action. |
|
16. Compound 69 [Pyrido (1,2-a) benzimidazoles] |
Pf NF54 |
0.19 μM |
Blood stage |
72 h |
Inhibition of hemozoin formation |
|
|
|
|
Pf K1 |
0.17 μM |
. |
|
|
|
|
|
|
Compound 11 |
Pf NF54 |
0.04 μM |
|
|
|
|
|
|
|
|
|
Pf K1 |
0.03 μM |
|
|
|
|
|
|
|
MICROTUBULES |
|
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|
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|
|
17. Curcumin |
Pf 3D7 |
5 μM |
Trophozoite and Schizont |
48 h |
Alteration of microtubule morphology by binding to the interface of alpha-beta tubulin heterodimer. |
|
18. Tamoxifen |
Pf 3D7 |
8.33 μM |
|
44 h |
Disruption of Pf Apicortin and tubulin interactions. |
|
|
Pf RKL9 |
8.34 μM |
|
|
|
|
|
|
|
19. Carbohybrid 12 |
Pf 3D7 |
5.86 μM |
Trophozoite and Schizont |
72 h |
Binds to α,β-heterodimer of tubulin and affects microtubule dynamics. |
|
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