ID: ALA303933

Max Phase: Phase

Molecular Formula: C29H32Cl2N6

Molecular Weight: 535.52

Molecule Type: Small molecule

Representations

Synonyms (2): Piperaquine | Piperaquinoline
Synonyms from Alternative Forms(2):

Canonical SMILES:  Clc1ccc2c(N3CCN(CCCN4CCN(c5ccnc6cc(Cl)ccc56)CC4)CC3)ccnc2c1

Standard InChI:  InChI=1S/C29H32Cl2N6/c30-22-2-4-24-26(20-22)32-8-6-28(24)36-16-12-34(13-17-36)10-1-11-35-14-18-37(19-15-35)29-7-9-33-27-21-23(31)3-5-25(27)29/h2-9,20-21H,1,10-19H2

Standard InChI Key:  UCRHFBCYFMIWHC-UHFFFAOYSA-N

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: Yes

Availability: No

Prodrug: No

Properties

Molecular Weight: 535.52

Molecular Weight (Monoisotopic): 534.2066

AlogP: 5.42

#Rotatable Bonds: 6

Polar Surface Area: 38.74

Molecular Species: NEUTRAL

HBA: 6

HBD: 0

#RO5 Violations: 2

HBA (Lipinski): 6

HBD (Lipinski): 0

#RO5 Violations (Lipinski): 2

CX Acidic pKa:

CX Basic pKa: 8.47

CX LogP: 5.27

CX LogD: 3.87

Aromatic Rings: 4

Heavy Atoms: 37

QED Weighted: 0.33

Np Likeness Score: -0.88

References

1. Vennerstrom JL, Ellis WY, Ager AL, Andersen SL, Gerena L, Milhous WK..  (1992)  Bisquinolines. 1. N,N-bis(7-chloroquinolin-4-yl)alkanediamines with potential against chloroquine-resistant malaria.,  35  (11): [PMID:1597862] [10.1021/jm00089a025]

2. Friebolin W, Jannack B, Wenzel N, Furrer J, Oeser T, Sanchez CP, Lanzer M, Yardley V, Becker K, Davioud-Charvet E..  (2008)  Antimalarial dual drugs based on potent inhibitors of glutathione reductase from Plasmodium falciparum.,  51  (5): [PMID:18260613] [10.1021/jm7009292]

3. Fivelman QL, Adagu IS, Warhurst DC..  (2007)  Effects of piperaquine, chloroquine, and amodiaquine on drug uptake and of these in combination with dihydroartemisinin against drug-sensitive and -resistant Plasmodium falciparum strains.,  51  (6): [PMID:17404003] [10.1128/aac.01479-06]

4. Karunajeewa HA, Ilett KF, Mueller I, Siba P, Law I, Page-Sharp M, Lin E, Lammey J, Batty KT, Davis TM..  (2008)  Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria.,  52  (1): [PMID:17967917] [10.1128/aac.00555-07]

5. Moore BR, Batty KT, Andrzejewski C, Jago JD, Page-Sharp M, Ilett KF..  (2008)  Pharmacokinetics and pharmacodynamics of piperaquine in a murine malaria model.,  52  (1): [PMID:17984231] [10.1128/aac.00878-07]

6. Kaur K, Jain M, Reddy RP, Jain R..  (2010)  Quinolines and structurally related heterocycles as antimalarials.,  45  (8): [PMID:20466465] [10.1016/j.ejmech.2010.04.011]

7. Nsobya SL, Kiggundu M, Nanyunja S, Joloba M, Greenhouse B, Rosenthal PJ..  (2010)  In vitro sensitivities of Plasmodium falciparum to different antimalarial drugs in Uganda.,  54  (3): [PMID:20065051] [10.1128/aac.01412-09]

8. Tarning J, Ashley EA, Lindegardh N, Stepniewska K, Phaiphun L, Day NP, McGready R, Ashton M, Nosten F, White NJ..  (2008)  Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand.,  52  (3): [PMID:18180343] [10.1128/aac.00955-07]

9. Russell B, Chalfein F, Prasetyorini B, Kenangalem E, Piera K, Suwanarusk R, Brockman A, Prayoga P, Sugiarto P, Cheng Q, Tjitra E, Anstey NM, Price RN..  (2008)  Determinants of in vitro drug susceptibility testing of Plasmodium vivax.,  52  (3): [PMID:18180357] [10.1128/aac.01334-07]

10. Okombo J, Kiara SM, Rono J, Mwai L, Pole L, Ohuma E, Borrmann S, Ochola LI, Nzila A..  (2010)  In vitro activities of quinine and other antimalarials and pfnhe polymorphisms in Plasmodium isolates from Kenya.,  54  (8): [PMID:20516285] [10.1128/aac.00325-10]

11. Muangnoicharoen S, Johnson DJ, Looareesuwan S, Krudsood S, Ward SA..  (2009)  Role of known molecular markers of resistance in the antimalarial potency of piperaquine and dihydroartemisinin in vitro.,  53  (4): [PMID:19188388] [10.1128/aac.01656-08]

12. Nguyen DV, Nguyen QP, Nguyen ND, Le TT, Nguyen TD, Dinh DN, Nguyen TX, Bui D, Chavchich M, Edstein MD..  (2009)  Pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam.,  53  (8): [PMID:19528277] [10.1128/aac.01717-08]

13. Mwai L, Kiara SM, Abdirahman A, Pole L, Rippert A, Diriye A, Bull P, Marsh K, Borrmann S, Nzila A..  (2009)  In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1.,  53  (12): [PMID:19770282] [10.1128/aac.00638-09]

14. Briolant S, Henry M, Oeuvray C, Amalvict R, Baret E, Didillon E, Rogier C, Pradines B..  (2010)  Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum.,  54  (9): [PMID:20547801] [10.1128/aac.00183-10]

15. Hasugian AR, Tjitra E, Ratcliff A, Siswantoro H, Kenangalem E, Wuwung RM, Purba HL, Piera KA, Chalfien F, Marfurt J, Penttinen PM, Russell B, Anstey NM, Price RN..  (2009)  In vivo and in vitro efficacy of amodiaquine monotherapy for treatment of infection by chloroquine-resistant Plasmodium vivax.,  53  (3): [PMID:19104023] [10.1128/aac.01511-08]

16. Masseno V, Muriithi S, Nzila A..  (2009)  In vitro chemosensitization of Plasmodium falciparum to antimalarials by verapamil and probenecid.,  53  (7): [PMID:19364853] [10.1128/aac.01689-08]

17. Price RN, Marfurt J, Chalfein F, Kenangalem E, Piera KA, Tjitra E, Anstey NM, Russell B..  (2010)  In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.,  54  (12): [PMID:20876370] [10.1128/aac.00801-10]

18. Siswantoro H, Russell B, Ratcliff A, Prasetyorini B, Chalfein F, Marfurt J, Kenangalem E, Wuwung M, Piera KA, Ebsworth EP, Anstey NM, Tjitra E, Price RN..  (2011)  In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia.,  55  (1): [PMID:20937779] [10.1128/aac.01122-10]

19. Marfurt J, Chalfein F, Prayoga P, Wabiser F, Kenangalem E, Piera KA, Fairlie DP, Tjitra E, Anstey NM, Andrews KT, Price RN..  (2011)  Ex vivo activity of histone deacetylase inhibitors against multidrug-resistant clinical isolates of Plasmodium falciparum and P. vivax.,  55  (3): [PMID:21135175] [10.1128/aac.01220-10]

20. Biamonte MA, Wanner J, Le Roch KG..  (2013)  Recent advances in malaria drug discovery.,  23  (10): [PMID:23587422] [10.1016/j.bmcl.2013.03.067]

21. Flannery EL, Fidock DA, Winzeler EA..  (2013)  Using genetic methods to define the targets of compounds with antimalarial activity.,  56  (20): [PMID:23927658] [10.1021/jm400325j]

22. Unpublished dataset, 

23. Ashton TD, Devine SM, Möhrle JJ, Laleu B, Burrows JN, Charman SA, Creek DJ, Sleebs BE..  (2019)  The Development Process for Discovery and Clinical Advancement of Modern Antimalarials.,  62  (23): [PMID:31385706] [10.1021/acs.jmedchem.9b00761]

24. Dodean RA, Kancharla P, Li Y, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Huezo SJ, Rasmussen SA, Stephens MT, Tan JC, Cooper RA, Smilkstein MJ, Pou S, Winter RW, Riscoe MK, Kelly JX..  (2019)  Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials.,  62  (7): [PMID:30852885] [10.1021/acs.jmedchem.8b01961]

25. Xue L, Shi DH, Harjani JR, Huang F, Beveridge JG, Dingjan T, Ban K, Diab S, Duffy S, Lucantoni L, Fletcher S, Chiu FCK, Blundell S, Ellis K, Ralph SA, Wirjanata G, Teguh S, Noviyanti R, Chavchich M, Creek D, Price RN, Marfurt J, Charman SA, Cuellar ME, Strasser JM, Dahlin JL, Walters MA, Edstein MD, Avery VM, Baell JB..  (2019)  3,3'-Disubstituted 5,5'-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity.,  62  (5): [PMID:30715882] [10.1021/acs.jmedchem.8b01799]

26. Kancharla P, Dodean RA, Li Y, Pou S, Pybus B, Melendez V, Read L, Bane CE, Vesely B, Kreishman-Deitrick M, Black C, Li Q, Sciotti RJ, Olmeda R, Luong TL, Gaona H, Potter B, Sousa J, Marcsisin S, Caridha D, Xie L, Vuong C, Zeng Q, Zhang J, Zhang P, Lin H, Butler K, Roncal N, Gaynor-Ohnstad L, Leed SE, Nolan C, Ceja FG, Rasmussen SA, Tumwebaze PK, Rosenthal PJ, Mu J, Bayles BR, Cooper RA, Reynolds KA, Smilkstein MJ, Riscoe MK, Kelly JX..  (2020)  Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials.,  63  (11): [PMID:32390431] [10.1021/acs.jmedchem.0c00539]

27. Tibon NS,Ng CH,Cheong SL.  (2020)  Current progress in antimalarial pharmacotherapy and multi-target drug discovery.,  188  [PMID:31911292] [10.1016/j.ejmech.2019.111983]

28. Bernhard Ellinger, Justus Dick, Vanessa Lage-Rupprecht, Bruce Schultz, Andrea Zaliani, Marcin Namysl, Stephan Gebel, Ole Pless, Jeanette Reinshagen, Christian Ebeling, Alexander Esser, Marc Jacobs, Carsten Claussen, and Martin Hofmann-Apitius.  (2021)  HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators,  [10.6019/CHEMBL4808148]

29. Van de Walle T, Cools L, Mangelinckx S, D'hooghe M..  (2021)  Recent contributions of quinolines to antimalarial and anticancer drug discovery research.,  226  [PMID:34655985] [10.1016/j.ejmech.2021.113865]

30. Puhl AC, Fernandes RS, Godoy AS, Gil LHVG, Oliva G, Ekins S..  (2023)  The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.,  83  [PMID:36940609] [10.1016/j.bmc.2023.117239]

31. Sutherland JJ, Yonchev D, Fekete A, Urban L..  (2023)  A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.,  14  (1): [PMID:37468498] [10.1038/s41467-023-40064-9]

Source

Source(3):

• Scientific Literature
• Clinical Candidates
• Fraunhofer HDAC6