ID: ALA404431

Max Phase: Phase

Molecular Formula: C22H36N2O4

Molecular Weight: 392.54

Molecule Type: Small molecule

Representations

Synonyms (2): Oz277 | OZ-277
Synonyms from Alternative Forms(2):

Canonical SMILES:  CC(C)(N)CNC(=O)C[C@H]1CC[C@]2(CC1)OO[C@]1(O2)C2CC3CC(C2)CC1C3

Standard InChI:  InChI=1S/C22H36N2O4/c1-20(2,23)13-24-19(25)12-14-3-5-21(6-4-14)26-22(28-27-21)17-8-15-7-16(10-17)11-18(22)9-15/h14-18H,3-13,23H2,1-2H3,(H,24,25)/t14-,15?,16?,17?,18?,21+,22-

Standard InChI Key:  VXYZBLXGCYNIHP-CAGINOIPSA-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: No

Availability: No

Prodrug: No

Properties

Molecular Weight: 392.54

Molecular Weight (Monoisotopic): 392.2675

AlogP: 3.25

#Rotatable Bonds: 4

Polar Surface Area: 82.81

Molecular Species: BASE

HBA: 5

HBD: 2

#RO5 Violations: 0

HBA (Lipinski): 6

HBD (Lipinski): 3

#RO5 Violations (Lipinski): 0

CX Acidic pKa:

CX Basic pKa: 9.63

CX LogP: 3.11

CX LogD: 0.94

Aromatic Rings: 0

Heavy Atoms: 28

QED Weighted: 0.72

Np Likeness Score: 0.92

References

1. Zhou L, Alker A, Ruf A, Wang X, Chiu FC, Morizzi J, Charman SA, Charman WN, Scheurer C, Wittlin S, Dong Y, Hunziker D, Vennerstrom JL..  (2008)  Characterization of the two major CYP450 metabolites of ozonide (1,2,4-trioxolane) OZ277.,  18  (5): [PMID:18262417] [10.1016/j.bmcl.2008.01.087]

2. Rosenthal AS, Chen X, Liu JO, West DC, Hergenrother PJ, Shapiro TA, Posner GH..  (2009)  Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells.,  52  (4): [PMID:19186946] [10.1021/jm801484v]

3. Kaiser M, Wittlin S, Nehrbass-Stuedli A, Dong Y, Wang X, Hemphill A, Matile H, Brun R, Vennerstrom JL..  (2007)  Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160).,  51  (8): [PMID:17562801] [10.1128/aac.00225-07]

4. Rubio BK, Tenney K, Ang KH, Abdulla M, Arkin M, McKerrow JH, Crews P..  (2009)  The marine sponge Diacarnus bismarckensis as a source of peroxiterpene inhibitors of Trypanosoma brucei, the causative agent of sleeping sickness.,  72  (2): [PMID:19159277] [10.1021/np800711a]

5. Wang X, Creek DJ, Schiaffo CE, Dong Y, Chollet J, Scheurer C, Wittlin S, Charman SA, Dussault PH, Wood JK, Vennerstrom JL..  (2009)  Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity.,  19  (16): [PMID:19616946] [10.1016/j.bmcl.2009.07.013]

6. Martyn DC, Beletsky G, Cortese JF, Tyndall E, Liu H, Fitzgerald MM, O'Shea TJ, Liang B, Clardy J..  (2009)  Synthesis and in vitro DMPK profiling of a 1,2-dioxolane-based library with activity against Plasmodium falciparum.,  19  (19): [PMID:19699641] [10.1016/j.bmcl.2009.08.024]

7. Creek DJ, Charman WN, Chiu FC, Prankerd RJ, Dong Y, Vennerstrom JL, Charman SA..  (2008)  Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials.,  52  (4): [PMID:18268087] [10.1128/aac.01033-07]

8. Creek DJ, Ryan E, Charman WN, Chiu FC, Prankerd RJ, Vennerstrom JL, Charman SA..  (2009)  Stability of peroxide antimalarials in the presence of human hemoglobin.,  53  (8): [PMID:19487440] [10.1128/aac.00363-09]

9. Fügi MA, Wittlin S, Dong Y, Vennerstrom JL..  (2010)  Probing the antimalarial mechanism of artemisinin and OZ277 (arterolane) with nonperoxidic isosteres and nitroxyl radicals.,  54  (3): [PMID:20028825] [10.1128/aac.01305-09]

10. Bousejra-El Garah F, Wong MH, Amewu RK, Muangnoicharoen S, Maggs JL, Stigliani JL, Park BK, Chadwick J, Ward SA, O'Neill PM..  (2011)  Comparison of the reactivity of antimalarial 1,2,4,5-tetraoxanes with 1,2,4-trioxolanes in the presence of ferrous iron salts, heme, and ferrous iron salts/phosphatidylcholine.,  54  (19): [PMID:21888440] [10.1021/jm200768h]

11. Hartwig CL, Lauterwasser EM, Mahajan SS, Hoke JM, Cooper RA, Renslo AR..  (2011)  Investigating the antimalarial action of 1,2,4-trioxolanes with fluorescent chemical probes.,  54  (23): [PMID:22023506] [10.1021/jm2012003]

12. Wang X, Dong Y, Wittlin S, Charman SA, Chiu FC, Chollet J, Katneni K, Mannila J, Morizzi J, Ryan E, Scheurer C, Steuten J, Santo Tomas J, Snyder C, Vennerstrom JL..  (2013)  Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres.,  56  (6): [PMID:23489135] [10.1021/jm400004u]

13. 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]

14. 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]

15. Blank BR, Gut J, Rosenthal PJ, Renslo AR..  (2017)  Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane.,  60  (14): [PMID:28692297] [10.1021/acs.jmedchem.7b00699]

16. Unpublished dataset, 

17. Fernández-Álvaro E, Hong WD, Nixon GL, O'Neill PM, Calderón F..  (2016)  Antimalarial Chemotherapy: Natural Product Inspired Development of Preclinical and Clinical Candidates with Diverse Mechanisms of Action.,  59  (12): [PMID:26791529] [10.1021/acs.jmedchem.5b01485]

18. Woodley CM, Nixon GL, Basilico N, Parapini S, Hong WD, Ward SA, Biagini GA, Leung SC, Taramelli D, Onuma K, Hasebe T, O'Neill PM..  (2021)  Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205.,  12  (7.0): [PMID:34267877] [10.1021/acsmedchemlett.1c00031]

19. Patel OPS, Beteck RM, Legoabe LJ..  (2021)  Exploration of artemisinin derivatives and synthetic peroxides in antimalarial drug discovery research.,  213  [PMID:33508479] [10.1016/j.ejmech.2021.113193]

Source

Source(2):

• Scientific Literature
• Clinical Candidates