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  • Fast- and slow-acting antimalarials against cultured P. falciparum strains
Fast- and slow-acting antimalarials against cultured P. falciparum strains.
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.
Antimalarial agent Strain Inhibitory conc. Stage of max. inhibition Mechanism of action
Fast acting
FOOD VACUOLE
1. MCQ (5,5’-dimethyl2,2, bipyridine) Pf 3D7 0.81 µM
[CQ containing Organoruthenium] Pf W2 1.05 µM
FCQ (1,10-phenanthrodine) Pf 3D7 0.37 µM
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.
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.
Pf 3D7 16.8 nM
3. DAQ [CQ analog] Pf 3D7 46 nM Early ring 12 h Inhibition of ß-hematin formation
Pf K1 50 nM Early ring 12 h Inhibition of ß-hematin formation
4. Marinoquinoline derivative Pf 3D7 39 nM Early ring 8-16 h Interference with hemoglobin metabolism and exhibit acetylcholinesterase-inhibiting activity
Pf K1 41 nM
5. Moxiquindole [spirofused tetrahydroisoquinoline –oxindole hybrid] Pf NF54 0.68 µM
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.
Pf Dd2 1.73 µM
6. Chloroquine P. knowlesi A1H.1 0.010 µM Blood stage 24 h Block ß-hematin formation.
Cycloguanil 0.003 µM
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
8. Compound 10 [Tetrazole based series] Pf 3D7 0.40 µM Trophozoite <24 h Blocking heme biomineralization.
Pf Dd2 1.8 µM
Pf NF54 0.83 µM
9. Compound 2 [HEA-Pt analogs] Pf 3D7 1.14 μM Ring and Troph. 3h Inhibition of Plasmepsin (Plm V).
Compound 5 Pf 3D7 1.14 µM Ring and Troph. 3 h Inhibition of Plasmepsin (Plm V).
Pf Dd2 1.31 µM 6 h Inhibition of plasmepsins (Plm II, IV, V and X).
Compound 60 [Pyridylvinylquinoline triazole analog] Pf Dd2  0.04 μM Trophozoite 6 hInhibition of β-hematin formation by possibly targeting vacuolar proteases.
Substituted 15-membered azalides Pf 3D7 0.006 – 0.020 μM 3h Interference with heme polymerization
Pf W2 0.007 – 0.027 μM
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.
Pf K1 0.041 µM
13. Compound 10 [Arylmethylamino steroids] Pf NF54 2.9 nM Blood stage 24 h Chelate-based quinone methide mechanism involving metal or heme bioactivation.
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.
Nigericin 9.3 nM
Monensin 6.1 nM
15. Maduramicin  Pf NF54 1.3 nM
14.8 nM Schizont Gametocyte (Stage III-IV) 12 h Disruption of Na+ across cellular membranes by targeting PfATP4. gradient
16. MMV085071 Pf 3D7 76.3 nM Trophozoite  4 h Digestive Vacuole disruption and downstream programmed cell death-like mechanism.
Pf K1 126.6 nM
NUCLEUS AND NUCLEAR COMPONENTS
L-methionine +Deoxycytidine bisubstrate inhibitors]
Compound 70
Pf NF54 71 nM Early ring 6 h Inhibition of parasite DNA cytosine methylation by targeting DNMT domain.
60 nM
BIX-1294 Pf 3D7 19 nM
TM2-115 [Diaminoquinazoline scaffolds] Pf 3D7 32 nM
BIX-1294 Pf 7G8 1.07- 3.84 nM Ring Early-late, gametocyte all blood stages 12, 29 h Inhibition of histone methyltransferase.
19. Compound 31 [Thiazole derivatives] Pf 3D7 0.16 µM Blood stage  24 h Inhibition of Serine/Arginine protein kinase
20. GW012X
[Nonpeptido-mimetic, Proteasome inhibitor] Pf3D7 7.9 µM ring troph. 3 h Inhibition of chymotrypsin
4.2 µM
21. Compound 15
Compound 16 [Arylalkylpolyamino (bis)urea & (bis)thiourea isosteres]
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.
PfHB3 26 nM
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
Pf K1 0.144 µM
24. Compound 13 [Bischalcones] Pf 3D7 2.5 µM Trophozoite 18 h Initiate PCD of parasites
Pf Dd2 3.5 µM
GOLGI COMPLEX, ER, RIBOSOMES, PVM
25. Torin 2 Pf Dd2 0.7 nM Blood stage 4 h Alter localization of parasitophorous vacuole membrane (PVM)- resident proteins
Pf 3D7 1.4 nM
26. MMV688533 [Acylguanidine] Pf 3D7 1.9 nM ring to early troph 24 h Involved in lipid-associated essential components.
Pf Dd2 3.0 nM
Pf K1 19 nM
Pf FC27 9.7 nM
27. ICL-M [Isocryptolepine derivative] Pf 3D7  148.31 nM Ring and troph 4 h Disruption of ribosomal, proteasomal and metabolic pathways.
PARASITE CYTOSOL
28. Artemisinin Pf 3D7 32 nM
Artesunate Pf 3D7 2 nM Blood stage, troph 1h Contains endoperoxide bond mediating ROS production. DNA damage is mediated by increased ROS production.
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).
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.
Pf Dd2 59 nM
Pf NF54 21 nM
31. Indole benzamides -12192 Pf3D7 0.24 µM Blood stage 4 h Inhibition of V type H+-ATPase which disrupts cytosolic pH.
Pf 7G8 0.41 µM
MEROZOITES
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.
Pf Dd2 67 nM
33. Compound 17 [Thiazole scaffolds]  Pf 3D7A 0.18 µM  Blood stage 48 h Targeting cyclic GMP-dependent protein kinase (PKG).
Compound 18 0.19 µM
34. Trichostatin A D10-PfPHG line 5 nM schizonts and merozoites 4 h Merozoite invasion inhibition.
ACTION UNEXPLORED
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.
36. SC83288 [Amicarbalide derivative] Pf NF54 5.1 nM Trophozoite 17 h Artemisinin-like action affects different molecular pathways.
PfNF54ART 4.9 nM
Pf Dd2 3.1 nM
37. DDD01034957 [CHEMBL3443358] Pf 3D7 172 nM Blood stage  24 h Different fast-acting antimalarial activity
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).
0.5 µM
39. MMV006172 [Acridine and thiazolopyrimidine derivaties] MMV665971 Pf 3D7 0.14 µM Ring 16 h Different modes of action related to artesunate.
0.48 µM
40. DC-9237 [Macrocyclic Compound] Pf Dd2 44 nM All blood stages 6 h Novel mechanism related to macrocyclic inhibitors.
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.
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
Pf W2 33 nM
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.
44. Compound 1 [Pseudoceratidine derivative] Pf 3D7 1.1 µM Early ring 8-16 h Possibly inhibits de novo fatty acid synthesis pathway.
Pf K1 1.1 µM
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.
Pf W2mef 57 nM
Pf NF54 326 nM
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).
Pf K1 0.3 nM
ACT-213615 Pf K1 0.46 nM 1h
Pf W2 0.42 nM
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
Pf Dd2 0.6 nM
Fast-acting antimalarial agents with their time, stage and mode of action against in vivo
Antimalarial agent Strain Effective dose Stage of Max. inhibition Time onf actio Mechanism of action
PLASMA MEMBRANE AND ASSOCIATED TRANSPORTERS
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.
Ring 6 h
2. Methnaridine P.berghei ED50 - 0.52 mg/kg Blood stage 36 h Breakage of parasite immune escape by restoring Tregs and Th1 response
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).
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
5. PA21A092 [Pyrazoleamide compounds] Pf NOD/SCID/IL2Rgnull mouse ED90 - 2.5 mg/kg Blood stage 48h Disruption of Na+ homeostasis.
FOOD VACUOLE
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.
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.
NUCLEUS AND NUCLEAR COMPONENTS
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
9. 8aA [Carbohybrid based 2-aminopyrimidine analogues] P. chabaudi ED50 - 0.32 mg/kg All blood stages 12 h Block cell cycle progression
11aA ED50 - 0.12 mg/kg
ACTION UNEXPLORED
10. Artemether  P. berghei  Single dose –  Blood stage  24 h Decrease leukocyte sequestration and
ANKA 25mg/kg inflammation during cerebral malaria
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.
12. Compound 43 [2,6- disubstituted imidazopyridine compounds] Pf NOD SCID mouse ED90- 4.2 mg/kg Within 48 h Novel mechanism of action
Compound 74 ED90 - 5.6 mg/kg
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
Slow-acting antimalarial agents with their time, stage and mode of action against cultured P. falciparum strains.
Antimalarial agent Strain Inhibitory conc. Stage of max inhib Time of action Mechnism of action
APICOPLAST
1. 7-position modified tetracycline derivatives Pf W2 18 – 53 nM Ring 96 h Specific effect on protein synthesis in the apicoplast.
2. Doxycycline  Pf W2  0.46 mM Troph and early schiz 96 h Disrupt expression of apicoplast genes.
3. Azithromycin Pf 3D7 52.7 nM
Pf W2 31 nM Late troph and early schiz. 96 h Disrupt apicoplast function by interfering with translation.
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
6. Tetracycline  Pf W2 4.1 mM Preerythrocytic stage 96 h Act on dihydroorotate dehydrogenase enzyme by chelating its iron centre.
0.8 mM 144 h
7. Proguanil (PG) Pf 3D7 0.11 μM Blood stage 96 h Target an alternative mechanism responsible for mitochondrial membrane potential.
Pf Dd2 0.54 μM
tert-butyl PG Pf 3D7 0.05 μM
Pf Dd2 0.32 μM
8. Alstonine [Natural products] Pf 3D7 0.17 μM Blood stage  96 h  Not associated with apicoplast and possibly targets mitochondrial electron transport chain.
Himbeline 0.58 μM
9. Compound 10 [Phthalimide Derivatives] Pf 3D7 4.2 μM Late ring or early troph. 16 - 32 h Inhibition of cytochrome bc1 complex
Pf K1 4.3 μM
10. Compound 4 [Cyclopeptides] Pf 3D7A 1.0 nM Blood stage 48 h Slow killing profile like atovaquone and pyrimethamine.
Compound 6 1.8 nM
PARASITE CYTOSOL
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.
Pf Dd2 0.024 μM
Pf K1 0.020 μM
13. MMV642943 [2-aminopyridines] Pf NF54 66 nM Late gametocytes 72 h Target lipid kinases in various stages of P falciparum.
MMV642944 52 nM
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.
Pf K1 19nM
FOOD VACUOLE
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
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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