ACS Medicinal Chemistry Letters
Letter
Notes
activity with moderate to high enhancement in bleeding time.
Substitution of the alkyl groups at both of the nitrogens with
benzyl/substituted benzyl groups offered compounds (8g, 8h,
8i, and 8j) with improved antithrombotic activity. Both of these
observations are supported by the docking studies. Simulta-
neous substitution of both of the nitrogens with benzyl/
substituted benzyl group yields compounds having much better
interactions with the enzyme in both of the vital binding
pockets S1 and S4. 4-Methoxybenzyl substituent (8g) at amide
nitrogen with a benzyl group (R1) at amine nitrogen is
responsible for an increase in the antithrombotic activity with a
negligible effect on PT. Replacement of 4-methoxyphenyl with
halo-substituted phenyl ring maintained the antithrombotic
activity in the resulting compounds (8h, 8i, and 8j), but it led
to increase in the bleeding time also. Among the halo
derivatives, the fluoro derivative (8j) offered the best biological
activity profile. For the purpose of comparative study,
compound 8l18 having benzyl substituents at both of the
nitrogens was synthesized and biologically evaluated. In the
docking studies also, it was observed that a lipophilic
substituent at 4-position of amidic benzyl ring was essential
for lipophilic interaction in the S4 pocket of the enzyme with
the ligand. It seems substitution of benzyl/substituted benzyl in
place of alkyl/cycloalkyl groups at amidic “N” (8a, 8b, 8s, 8t,
8u, 8v, and 8x) has a more profound impact on antithrombotic
activity than the substitution of benzyl group on amino “N”
(8e, 8f, and 8k). It is interesting to note that the newly reported
compound 8g did not cause an increase in bleeding time or PT
at variance with aspirin or warfarin at antithrombotic doses,
while maintaining almost the same antithrombotic activity as
warfarin. These observations point out that derivative 8g has
the potential to provide a better therapeutic window over
warfarin and aspirin.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Director and the SAIF-Division of Panjab
University for their help.
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In summary, a series of novel 2-aminobenzamide derivatives
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Docking studies have been performed with fXa to establish a
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ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic procedures, analytical data, procedures for pharmaco-
logical activities, details of toxicity studies, and intermolecular
interactions in docking studies. This material is available free of
(11) Sobieraj-Teague, M.; O'Donnell, M.; Eikelboom, J. New
Anticoagulants for Atrial Fibrillation. Semin. Thromb. Hemostasis
2009, 35, 515−524.
AUTHOR INFORMATION
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Cyclic Guanidines. Tetrahedron Lett. 2012, 53, 2954−2958.
(13) DiMinno, G.; Silver, M. J. Mouse Antithrombotic Assay: a
Simple Method for the Evaluation of Antithrombotic Agents in vivo.
Potentiation of Antithrombotic Activity by Ethyl alcohol. J. Pharmacol.
Exp. Ther. 1983, 225, 57−60.
Corresponding Author
*Tel: +91-265-2434187. Fax: +91-265-2418927. E-mail:
Author Contributions
The manuscript was written through contributions of all
authors.
(14) Dejana, E.; Callioni, A.; Quintana, A.; Giovanni, G. Bleeding
Time in Laboratory Animals. IIA Comparison of Different Assay
Conditions in Rats. Thromb. Res. 1979, 15, 191−197.
Funding
A.V. thanks AICTE, New Delhi, for NDF-fellowship.
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dx.doi.org/10.1021/ml300217f | ACS Med. Chem. Lett. 2013, 4, 32−36