4-(3-hydroxy-phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester

ID: ALA236789

Chembl Id: CHEMBL236789

Max Phase: Preclinical

Molecular Formula: C14H16N2O3S

Molecular Weight: 292.36

Molecule Type: Small molecule

Names and Identifiers

Synonyms: Monastrol

Canonical SMILES:  CCOC(=O)C1=C(C)NC(=S)NC1c1cccc(O)c1

Standard InChI:  InChI=1S/C14H16N2O3S/c1-3-19-13(18)11-8(2)15-14(20)16-12(11)9-5-4-6-10(17)7-9/h4-7,12,17H,3H2,1-2H3,(H2,15,16,20)

Standard InChI Key:  LOBCDGHHHHGHFA-UHFFFAOYSA-N

Alternative Forms

1. Parent:

   

   ALA236789

   MONASTROL

Molecule Features

Natural Product: Yes

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

Calculated Properties

Molecular Weight: 292.36

Molecular Weight (Monoisotopic): 292.0882

AlogP: 1.75

#Rotatable Bonds: 3

Polar Surface Area: 70.59

Molecular Species: NEUTRAL

HBA: 4

HBD: 3

#RO5 Violations: 0

HBA (Lipinski): 5

HBD (Lipinski): 3

#RO5 Violations (Lipinski): 0

CX Acidic pKa: 9.37

CX Basic pKa:

CX LogP: 1.83

CX LogD: 1.82

Aromatic Rings: 1

Heavy Atoms: 20

QED Weighted: 0.58

Np Likeness Score: -0.86

References

1. Klein E, DeBonis S, Thiede B, Skoufias DA, Kozielski F, Lebeau L..  (2007)  New chemical tools for investigating human mitotic kinesin Eg5.,  15  (19): [PMID:17587586] [10.1016/j.bmc.2007.06.016]

2. Fucini RV, Hanan EJ, Romanowski MJ, Elling RA, Lew W, Barr KJ, Zhu J, Yoburn JC, Liu Y, Fahr BT, Fan J, Lu Y, Pham P, Choong IC, VanderPorten EC, Bui M, Purkey HE, Evanchik MJ, Yang W..  (2008)  Design and synthesis of 2-amino-pyrazolopyridines as Polo-like kinase 1 inhibitors.,  18  (20): [PMID:18793847] [10.1016/j.bmcl.2008.08.095]

3. Kaan HY, Ulaganathan V, Rath O, Prokopcová H, Dallinger D, Kappe CO, Kozielski F..  (2010)  Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol.,  53  (15): [PMID:20597485] [10.1021/jm100421n]

4. Kwok BH, Kapitein LC, Kim JH, Peterman EJ, Schmidt CF, Kapoor TM..  (2006)  Allosteric inhibition of kinesin-5 modulates its processive directional motility.,  2  (9): [PMID:16892050] [10.1038/nchembio812]

5. Diamandis P, Wildenhain J, Clarke ID, Sacher AG, Graham J, Bellows DS, Ling EK, Ward RJ, Jamieson LG, Tyers M, Dirks PB..  (2007)  Chemical genetics reveals a complex functional ground state of neural stem cells.,  3  (5): [PMID:17417631] [10.1038/nchembio873]

6. Fu RG, You QD, Yang L, Wu WT, Jiang C, Xu XL..  (2010)  Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents.,  18  (22): [PMID:20934346] [10.1016/j.bmc.2010.09.020]

7. PubChem BioAssay data set, 

8. PubChem BioAssay data set, 

9. Kamal A, Shaheer Malik M, Bajee S, Azeeza S, Faazil S, Ramakrishna S, Naidu VG, Vishnuwardhan MV..  (2011)  Synthesis and biological evaluation of conformationally flexible as well as restricted dimers of monastrol and related dihydropyrimidones.,  46  (8): [PMID:21620531] [10.1016/j.ejmech.2011.04.048]

10. Rodriguez D, Ramesh C, Henson LH, Wilmeth L, Bryant BK, Kadavakollu S, Hirsch R, Montoya J, Howell PR, George JM, Alexander D, Johnson DL, Arterburn JB, Shuster CB..  (2011)  Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.,  19  (18): [PMID:21855351] [10.1016/j.bmc.2011.07.054]

11. Jiang C, Yang L, Wu WT, Guo QL, You QD..  (2011)  De novo design, synthesis and biological evaluation of 1,4-dihydroquinolin-4-ones and 1,2,3,4-tetrahydroquinazolin-4-ones as potent kinesin spindle protein (KSP) inhibitors.,  19  (18): [PMID:21856161] [10.1016/j.bmc.2011.07.029]

12. PubChem BioAssay data set, 

13. Sashidhara KV, Avula SR, Sharma K, Palnati GR, Bathula SR..  (2013)  Discovery of coumarin-monastrol hybrid as potential antibreast tumor-specific agent.,  60  [PMID:23287057] [10.1016/j.ejmech.2012.11.044]

14. El-Nassan HB..  (2013)  Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents.,  62  [PMID:23434636] [10.1016/j.ejmech.2013.01.031]

15. Unpublished dataset, 

16. Unpublished dataset, 

17. PubChem BioAssay data set, 

18. Yang B, Lamb ML, Zhang T, Hennessy EJ, Grewal G, Sha L, Zambrowski M, Block MH, Dowling JE, Su N, Wu J, Deegan T, Mikule K, Wang W, Kaspera R, Chuaqui C, Chen H..  (2014)  Discovery of potent KIFC1 inhibitors using a method of integrated high-throughput synthesis and screening.,  57  (23): [PMID:25458601] [10.1021/jm501179r]

19. Treptow TG, Figueiró F, Jandrey EH, Battastini AM, Salbego CG, Hoppe JB, Taborda PS, Rosa SB, Piovesan LA, Montes D'Oca Cda R, Russowsky D, Montes D'Oca MG..  (2015)  Novel hybrid DHPM-fatty acids: synthesis and activity against glioma cell growth in vitro.,  95  [PMID:25863023] [10.1016/j.ejmech.2015.03.062]

20. Labrière C, Talapatra SK, Thoret S, Bougeret C, Kozielski F, Guillou C..  (2016)  New MKLP-2 inhibitors in the paprotrain series: Design, synthesis and biological evaluations.,  24  (4): [PMID:26778612] [10.1016/j.bmc.2015.12.042]

21. Pfeffer TJ, Sasse F, Schmidt CF, Lakämper S, Kirschning A, Scholz T..  (2016)  The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function.,  112  [PMID:26896705] [10.1016/j.ejmech.2016.02.022]

22. Rashid U, Sultana R, Shaheen N, Hassan SF, Yaqoob F, Ahmad MJ, Iftikhar F, Sultana N, Asghar S, Yasinzai M, Ansari FL, Qureshi NA..  (2016)  Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents.,  115  [PMID:27017551] [10.1016/j.ejmech.2016.03.022]

23. Matos LHS, Masson FT, Simeoni LA, Homem-de-Mello M..  (2018)  Biological activity of dihydropyrimidinone (DHPM) derivatives: A systematic review.,  143  [PMID:29133039] [10.1016/j.ejmech.2017.10.073]

24. Barbosa FAR, Siminski T, Canto RFS, Almeida GM, Mota NSRS, Ourique F, Pedrosa RC, Braga AL..  (2018)  Novel pyrimidinic selenourea induces DNA damage, cell cycle arrest, and apoptosis in human breast carcinoma.,  155  [PMID:29908443] [10.1016/j.ejmech.2018.06.026]

25.  (2016)  7  (11): [10.1039/C6MD00425C]

26. Ragab FAF, Abou-Seri SM, Abdel-Aziz SA, Alfayomy AM, Aboelmagd M..  (2017)  Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety.,  138  [PMID:28667871] [10.1016/j.ejmech.2017.06.026]

27. Damgaard M, Al-Khawaja A, Nittegaard-Nielsen M, Petersen RF, Wellendorph P, Frølund B..  (2017)  Monastrol, a 3,4-dihydropyrimidin-2(1H)-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α1β2δ GABAA receptors.,  138  [PMID:28683403] [10.1016/j.ejmech.2017.06.024]

28. Gonçalves IL, Rockenbach L, das Neves GM, Göethel G, Nascimento F, Porto Kagami L, Figueiró F, Oliveira de Azambuja G, de Fraga Dias A, Amaro A, de Souza LM, da Rocha Pitta I, Avila DS, Kawano DF, Garcia SC, Battastini AMO, Eifler-Lima VL..  (2018)  Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.,  9  (6): [PMID:30108989] [10.1039/C8MD00095F]

29. De Oliveira FS, De Oliveira PM, Farias LM, Brinkerhoff RC, Sobrinho RCMA, Treptow TM, Montes D'Oca CR, Marinho MAG, Hort MA, Horn AP, Russowsky D, Montes D'Oca MG..  (2018)  Synthesis and antitumoral activity of novel analogues monastrol-fatty acids against glioma cells.,  9  (8): [PMID:30151081] [10.1039/C8MD00169C]

30. Vendrusculo V, de Souza VP, M Fontoura LA, M D'Oca MG, Banzato TP, Monteiro PA, Pilli RA, de Carvalho JE, Russowsky D..  (2018)  Synthesis of novel perillyl-dihydropyrimidinone hybrids designed for antiproliferative activity.,  9  (9): [PMID:30288229] [10.1039/C8MD00270C]

31. Tawfik HO, El-Moselhy TF, El-Din NS, El-Hamamsy MH..  (2019)  Design, synthesis, and bioactivity of dihydropyrimidine derivatives as kinesin spindle protein inhibitors.,  27  (23): [PMID:31648875] [10.1016/j.bmc.2019.115126]

32. González-Hernández E, Aparicio R, Garayoa M, Montero MJ, Sevilla MÁ, Pérez-Melero C..  (2019)  Dihydropyrimidine-2-thiones as Eg5 inhibitors and L-type calcium channel blockers: potential antitumour dual agents.,  10  (9): [PMID:31673316] [10.1039/C9MD00108E]

33. Kurisawa N, Yukawa M, Koshino H, Onodera T, Toda T, Kimura KI..  (2020)  Kolavenic acid analog restores growth in HSET-overproducing fission yeast cells and multipolar mitosis in MDA-MB-231 human cells.,  28  (1): [PMID:31753800] [10.1016/j.bmc.2019.115154]

34. Wu L,Ma X,Yang X,Zhang C.  (2020)  Synthesis and biological evaluation of β-lapachone-monastrol hybrids as potential anticancer agents.,  203  [PMID:32682198] [10.1016/j.ejmech.2020.112594]

35. 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]

Source

Source(4):

• Scientific Literature
• PubChem BioAssays
• Gene Expression Atlas Compounds
• Fraunhofer HDAC6