2-{4-[(2-Amino-4-oxo-1,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-pentanedioic acid (PDDF)

ID: ALA389051

Cas Number: 76849-19-9

PubChem CID: 135438608

Product Number: P669303, Order Now?

Max Phase: Preclinical

Molecular Formula: C24H23N5O6

Molecular Weight: 477.48

Molecule Type: Small molecule

Names and Identifiers

Synonyms: TCMDC-131823 | CB-3717 | TCMDC-131823

Canonical SMILES:  C#CCN(Cc1ccc2[nH]c(N)nc(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Standard InChI:  InChI=1S/C24H23N5O6/c1-2-11-29(13-14-3-8-18-17(12-14)22(33)28-24(25)27-18)16-6-4-15(5-7-16)21(32)26-19(23(34)35)9-10-20(30)31/h1,3-8,12,19H,9-11,13H2,(H,26,32)(H,30,31)(H,34,35)(H3,25,27,28,33)/t19-/m0/s1

Standard InChI Key:  LTKHPMDRMUCUEB-IBGZPJMESA-N

Molfile:  

     RDKit          2D

 35 37  0  0  0  0  0  0  0  0999 V2000
   -4.3479   -1.7807    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -5.0624   -1.3682    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.7769   -1.7807    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -5.0624   -0.5432    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -4.3479   -0.1307    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.3479    0.6943    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -3.6335   -0.5432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.9190   -0.1307    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2045   -0.5432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2045   -1.3682    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.9190   -1.7807    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.6335   -1.3682    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.4900   -0.1307    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.7756   -0.5432    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.3678    0.6943    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.3678   -0.1307    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.6534   -0.5432    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.0611   -0.1307    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.0611    0.6943    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.6534    1.1068    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.0823    1.1068    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.0823    1.9318    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    2.7968    0.6943    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.5113    1.1068    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2257    0.6943    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.9402    1.1068    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.6547    0.6943    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.3691    1.1068    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    5.6547   -0.1307    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.5113    1.9318    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2257    2.3443    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    2.7968    2.3443    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -0.7756   -1.3682    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.4900   -1.7807    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2045   -2.1932    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  2  1  1  0
 12  1  1  0
  2  3  1  0
  2  4  2  0
  5  4  1  0
  5  6  2  0
  5  7  1  0
  7  8  2  0
  7 12  1  0
  8  9  1  0
  9 10  2  0
  9 13  1  0
 10 11  1  0
 11 12  2  0
 13 14  1  0
 18 14  1  0
 33 14  1  0
 15 16  2  0
 15 20  1  0
 21 15  1  0
 16 17  1  0
 17 18  2  0
 18 19  1  0
 19 20  2  0
 21 22  2  0
 21 23  1  0
 24 23  1  6
 24 25  1  0
 24 30  1  0
 25 26  1  0
 27 26  1  0
 27 28  2  0
 27 29  1  0
 30 31  2  0
 30 32  1  0
 33 34  1  0
 34 35  3  0
M  END

Alternative Forms

1. Parent:

   

   ALA389051

   10-Propargyl-5,8-dideazafolic acid

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

Calculated Properties

Molecular Weight: 477.48

Molecular Weight (Monoisotopic): 477.1648

AlogP: 1.19

#Rotatable Bonds: 10

Polar Surface Area: 178.71

Molecular Species: ACID

HBA: 7

HBD: 5

#RO5 Violations: ┄

HBA (Lipinski): 11

HBD (Lipinski): 6

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 3.24

CX Basic pKa: 3.54

CX LogP: 1.15

CX LogD: -4.72

Aromatic Rings: 3

Heavy Atoms: 35

QED Weighted: 0.27

Np Likeness Score: -0.62

References

1. Gangjee A, Vidwans A, Elzein E, McGuire JJ, Queener SF, Kisliuk RL..  (2001)  Synthesis, antifolate, and antitumor activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines.,  44  (12): [PMID:11384244] [10.1021/jm0100382]

2. Gangjee A, Mavandadi F, Kisliuk RL, Queener SF..  (1999)  Synthesis of classical and a nonclassical 2-amino-4-oxo-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thymidylate synthase.,  42  (12): [PMID:10377234] [10.1021/jm980586o]

3. Warner P, Barker AJ, Jackman AL, Burrows KD, Roberts N, Bishop JA, O'Connor BM, Hughes LR..  (1992)  Quinoline antifolate thymidylate synthase inhibitors: variation of the C2- and C4-substituents.,  35  (15): [PMID:1495009] [10.1021/jm00093a007]

4. Hughes LR, Jackman AL, Oldfield J, Smith RC, Burrows KD, Marsham PR, Bishop JA, Jones TR, O'Connor BM, Calvert AH..  (1990)  Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C2 position.,  33  (11): [PMID:2231606] [10.1021/jm00173a024]

5. Jackman AL, Marsham PR, Thornton TJ, Bishop JA, O'Connor BM, Hughes LR, Calvert AH, Jones TR..  (1990)  Quinazoline antifolate thymidylate synthase inhibitors: 2'-fluoro-N10-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C2 position.,  33  (11): [PMID:2231607] [10.1021/jm00173a025]

6. Pendergast W, Dickerson SH, Johnson JV, Dev IK, Ferone R, Duch DS, Smith GK..  (1993)  Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives.,  36  (22): [PMID:8230138] [10.1021/jm00074a030]

7. Marsham PR, Wardleworth JM, Boyle FT, Hennequin LF, Kimbell R, Brown M, Jackman AL..  (1999)  Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors.,  42  (19): [PMID:10508430] [10.1021/jm9803727]

8. Gangjee A, Yu J, McGuire JJ, Cody V, Galitsky N, Kisliuk RL, Queener SF..  (2000)  Design, synthesis, and X-ray crystal structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent.,  43  (21): [PMID:11052789] [10.1021/jm000200l]

9. Pogolotti AL, Danenberg PV, Santi DV..  (1986)  Kinetics and mechanism of interaction of 10-propargyl-5,8-dideazafolate with thymidylate synthase.,  29  (4): [PMID:3754285] [10.1021/jm00154a009]

10. Gangjee A, Yu J, Kisliuk RL, Haile WH, Sobrero G, McGuire JJ..  (2003)  Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents.,  46  (4): [PMID:12570380] [10.1021/jm0203534]

11. Brixner DI, Ueda T, Cheng YC, Hynes JB, Broom AD..  (1987)  Folate analogues as inhibitors of thymidylate synthase.,  30  (4): [PMID:3470522] [10.1021/jm00387a016]

12. Gangjee A, Jain HD, Phan J, Lin X, Song X, McGuire JJ, Kisliuk RL..  (2006)  Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents: design, synthesis, and biological evaluation of classical and nonclassical pyrrolo[2,3-d]pyrimidine antifolates(1).,  49  (3): [PMID:16451071] [10.1021/jm058276a]

13. Costi MP, Gelain A, Barlocco D, Ghelli S, Soragni F, Reniero F, Rossi T, Ruberto A, Guillou C, Cavazzuti A, Casolari C, Ferrari S..  (2006)  Antibacterial agent discovery using thymidylate synthase biolibrary screening.,  49  (20): [PMID:17004711] [10.1021/jm051187d]

14. Gangjee A, Jain HD, McGuire JJ, Kisliuk RL..  (2004)  Benzoyl ring halogenated classical 2-amino-6-methyl-3,4-dihydro-4-oxo-5-substituted thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine antifolates as inhibitors of thymidylate synthase and as antitumor agents.,  47  (27): [PMID:15615522] [10.1021/jm040144e]

15. Gangjee A, Zeng Y, McGuire JJ, Mehraein F, Kisliuk RL..  (2004)  Synthesis of classical, three-carbon-bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.,  47  (27): [PMID:15615538] [10.1021/jm040123k]

16. Gangjee A, Li W, Yang J, Kisliuk RL..  (2008)  Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.,  51  (1): [PMID:18072727] [10.1021/jm701052u]

17. Gangjee A, Li W, Kisliuk RL, Cody V, Pace J, Piraino J, Makin J..  (2009)  Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents.,  52  (15): [PMID:19719239] [10.1021/jm900490a]

18. Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF..  (2010)  Thousands of chemical starting points for antimalarial lead identification.,  465  (7296): [PMID:20485427] [10.1038/nature09107]

19. Srivastava V, Gupta SP, Siddiqi MI, Mishra BN..  (2010)  3D-QSAR studies on quinazoline antifolate thymidylate synthase inhibitors by CoMFA and CoMSIA models.,  45  (4): [PMID:20153089] [10.1016/j.ejmech.2009.12.065]

20. Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A..  (2011)  Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.,  19  (11): [PMID:21550809] [10.1016/j.bmc.2011.03.067]

21. St. Jude Leishmania screening dataset.,  [10.6019/CHEMBL3433997]

22. Huang M, Huang J, Zheng Y, Sun Q..  (2019)  Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism.,  178  [PMID:31195169] [10.1016/j.ejmech.2019.05.078]

Source

Source(3):

• Scientific Literature
• GSK Malaria Screening
• St Jude Leishmania Screening