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Molecular modeling optimization of anticoagulant pyridine derivatives.

ABSTRACT: Intravascular clotting remains a major health problem in the United States, the most prominent being deep vein thrombosis, pulmonary embolism and thromboembolic stroke. Previous reports on the use of pyridine derivatives in cardiovascular drug development encourage us to pursue new types of compounds based on a pyridine scaffold. Eleven pyridine derivatives (oximes, semicarbazones, N-oxides) previously synthesized in our laboratories were tested as anticoagulants on pooled normal plasma using the prothrombin time (PT) protocol. The best anticoagulant within the oxime series was compound AF4, within the oxime N-oxide series was compound AF4-N-oxide, and within the semicarbazone series, compound MD1-30Y. We also used a molecular modeling approach to guide our efforts, and found that there was good correlation between coagulation data and computational energy scores. Molecular docking was performed to target the active site of thrombin with the DOCK v5.2 package. The results of molecular modeling indicate that improvement in anticoagulant activities can be expected by functionalization at the three-position of the pyridine ring and by N-oxide formation. Results reported here prove the suitability of DOCK in the lead optimization process.

SUBMITTER: Hernandez Prada JA

PROVIDER: S-EPMC3752647 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Molecular modeling optimization of anticoagulant pyridine derivatives.

Hernandez Prada Jose A JA Madden Sandra L SL Ostrov David A DA Hernandez Maria A MA

Journal of molecular graphics & modelling 20080207 8

Intravascular clotting remains a major health problem in the United States, the most prominent being deep vein thrombosis, pulmonary embolism and thromboembolic stroke. Previous reports on the use of pyridine derivatives in cardiovascular drug development encourage us to pursue new types of compounds based on a pyridine scaffold. Eleven pyridine derivatives (oximes, semicarbazones, N-oxides) previously synthesized in our laboratories were tested as anticoagulants on pooled normal plasma using th ...[more]

PMID: 18372200

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Project description:A new series of conjugated donor-π-acceptor type of 2,6-bis(pyrazolyl)pyridine derivatives (compounds IK-(3-9)) have been synthesized via Horner-Wadsworth-Emmons (HWE) reaction, starting from a common phosphonate precursor and diverse donor aromatic aldehydes and characterized by routine spectral analysis including elemental analysis. Compound IK-2, one of the starting precursors, and molecule IK-3, the first member of the donor-π-acceptor series, are additionally characterized by single-crystal X-ray structure determination. Compounds IK-2 and IK-3 are crystallized in P1̅ (triclinic) and P21/c (monoclinic) space groups, respectively. The absorption maxima in the electronic spectra of the title compounds shift mainly due to intramolecular charge transfer (ICT) between different donor (dibutyl and cyclic pyrrolidine) groups and the acceptor moiety [2,6-bis(pyrazolyl) pyridine]. Solution-state emission spectral studies of all these compounds show large solvent sensitive behavior with significant amounts of Stokes shifts. The large solvent dependence of the emission indicates that the excited state is stabilized in more polar solvents due to the ICT. All chromophores exhibit solid-state fluorescence behavior except compound IK-7. The role of the position and nature of the donor functionalities in the conjugated backbone of overall donor moiety of compounds IK-(3-9), on the electronic absorption properties of the title chromophores has been demonstrated, which has further been corroborated by density functional theory (DFT) and time-dependent DFT (TDDFT) computational studies. The emission spectral results of compounds IK-3, IK-5, and IK-7 have also been supported by the DFT and TDDFT calculations. A fluorescence lifetime study on this series also shows that the excited states are stabilized in more polar solvents. Finally, one of the chromophores (chromophore IK-4) in the title series has been shown to act as a selective molecular sensor (turn-off switch) for the Cu(II) ion.

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Molecular modeling optimization of anticoagulant pyridine derivatives.

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Molecular modeling optimization of anticoagulant pyridine derivatives.

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