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Synthesis, biological activity screening and molecular modeling study of acylaminoacetamide derivatives

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Abstract

In this study, non-rigid analogs of thalidomide have been designed in order to develop potentially active, more effective and safer lead molecules for disorders caused or contributed by inflammation. Five different series of acylaminoacetamide compounds were synthesized, and the biological inhibitory potency of the title compounds has been determined by evaluating their effects on COX-2 isoenzyme expression and PGE2 production in A549 (human lung adenocarcinoma) cell lines. Among the studied series, N-[2-(isopropylamino)-2-oxoethyl]isonicotinamide is the most active inhibitory compound on COX-2 isoenzyme expression, and N-[2-oxo-2-(pyrolydine-1-yl)etyl]isonicotinamide is the most active inhibitory compound on the biosynthesis of PGE2. Molecular docking studies and molecular dynamics simulations were also applied to investigate non-covalent interactions of the most active compounds inside the active side of the crystal structure of murine cyclooxygenase 2 (mCOX-2) isoenzyme.

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Abbreviations

ATCC:

American Type Culture Collection

BCA:

Bicinchoninic acid

COX-1:

Cyclooxygenase-1

COX-2:

Cyclooxygenase-2

COX-3:

Cyclooxygenase-3

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

EDTA:

Ethylenediaminetetraacetic acid

EIA:

Enzyme immunoassay

ESI:

Electrospray ionization

FDA:

United States Food and Drug Administration

GB:

Generalized Born

IL-1β:

Interleukin-1β

mCOX-2:

Murine cyclooxygenase 2

MD:

Molecular dynamics

MM-GBSA:

Molecular mechanics–Generalized Born surface area

MM-PBSA:

Molecular mechanics–Poisson–Boltzmann surface area

NMR:

Nuclear magnetic resonance

PBS:

Phosphate-buffered saline

PGE2 :

Prostaglandin E2

PME:

Particle mesh Ewald

RIPA:

Radioimmunoprecipitation assay

RMSD:

Root-mean-square deviation

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

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Acknowledgments

This study was supported by research grants from Ege University (Project Number: 2009/Ecz/015). We also thank Pharmaceutical Sciences Research Centre (FABAL) of Ege University Faculty of Pharmacy for equipmental support.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, 35100, Izmir, Turkey

    Gunes Coban & Varol Pabuccuoglu

  2. Department of Biochemistry, Faculty of Pharmacy, Ege University, 35100, Izmir, Turkey

    Fadime Aydin Kose & Petek Ballar Kirmizibayrak

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  1. Gunes Coban
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Correspondence to Varol Pabuccuoglu.

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Coban, G., Kose, F.A., Kirmizibayrak, P.B. et al. Synthesis, biological activity screening and molecular modeling study of acylaminoacetamide derivatives. Med Chem Res 24, 3710–3729 (2015). https://doi.org/10.1007/s00044-015-1419-4

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