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1.
J Biomol Struct Dyn ; 35(10): 2280-2292, 2017 Aug.
Article in English | MEDLINE | ID: mdl-27453381

ABSTRACT

In this study, molecular binding affinity was investigated for Nefopam analogues (NFs), a functionalized benzoxazocine, with human serum albumin (HSA), a major transport protein in the blood. Its binding affinity and concomitant changes in its conformation, binding site and simulations were also studied. Fluorescence data revealed that the fluorescence quenching of HSA upon binding of NFs analogues is based on a static mechanism. The three analogues of NFs binding constants (KA) are in the order of NF3 > NF2 > NF1 with values of 1.53 ± .057 × 104, 2.16 ± .071 × 104 and 3.6 ± .102 × 105 M-1, respectively. Concurrently, thermodynamic parameters indicate that the binding process was spontaneous, and the complexes were stabilized mostly by hydrophobic interactions, except for NF2 has one hydrogen bond stabilizes it along with hydrophobic interactions. Circular dichroism (CD) studies revealed that there is a decrease in α-helix with an increase in ß-sheets and random coils signifying partial unfolding of the protein upon binding of NFs, which might be due to the formation of NFs-HSA complexes. Further, molecular docking studies showed that NF1, NF2 and NF3 bound to subdomains IIIA, IB and IIA through hydrophobic interactions. However, NF1 have additionally formed a single hydrogen bond with LYS 413. Furthermore, molecular simulations unveiled that NFs binding was in support with the structural perturbation observed in CD, which is evident from the root mean square deviation and Rg fluctuations. We hope our insights will provide ample scope for engineering new drugs based on the resemblances with NFs for enhanced efficacy with HSA.


Subject(s)
Analgesics, Non-Narcotic/chemistry , Ibuprofen/chemistry , Lidocaine/chemistry , Nefopam/chemistry , Phenylbutazone/chemistry , Serum Albumin, Human/chemistry , Binding Sites , Binding, Competitive , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Nefopam/analogs & derivatives , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Stability , Solutions , Thermodynamics
2.
J Comb Chem ; 12(6): 855-76, 2010 Nov 08.
Article in English | MEDLINE | ID: mdl-20858004

ABSTRACT

A general, sustainable and practical process for the sequential cascade one-pot synthesis of library of highly substituted push-pull olefins, phenols and 2-methyl-2H-chromenes was reported through multicatalysis cascade (MCC) reactions. Direct sequential one-pot combination of amine- or amino acid-catalyzed cascade Knoevenagel/Michael/aldol condensation/decarboxylation with other reactions like amine- or amino acid-catalyzed cascade Claisen-Schmidt/iso-aromatization, Claisen-Schmidt/isomerization, Claisen-Schmidt/iso-aromatization/isomerization, Michael addition, Claisen-Schmidt/Michael, ruthenium-base-silica-catalyzed ring closing metathesis/base-induced ring-opening/benzylic oxidation/[1,7]-sigmatropic hydrogen shift, or ruthenium-base-heat-catalyzed ring closing metathesis/base-induced ring-opening/[1,7]-sigmatropic hydrogen shift reactions of alkyl acetoacetates, a variety of aldehydes and alkyl halides furnished the highly functionalized push-pull olefins, phenols and 2-methyl-2H-chromenes with high yields. The yields and regioselectivities were good to excellent. Evidence for a new reaction pathway involving in situ formation of novel push-pull dienamines under amine- or amino acid-catalysis is presented along with examples demonstrating the amenability of the process to MCC chemistry.


Subject(s)
Alkenes/chemistry , Benzopyrans/chemistry , Phenols/chemistry , Small Molecule Libraries/chemical synthesis , Catalysis , Crystallography, X-Ray , Molecular Structure , Small Molecule Libraries/chemistry
3.
Org Biomol Chem ; 7(17): 3372-8, 2009 Sep 07.
Article in English | MEDLINE | ID: mdl-19675887

ABSTRACT

An efficient amine-/ruthenium-catalyzed three-step process for the synthesis of Nefopam analogues was achieved through combinations of cascade enamine amination/iso-aromatization/allylation and diene or enyne metathesis as key steps starting from functionalized Hagemann's esters. In this communication, we discovered the application of ruthenium-catalysis on olefins containing free amines without in situ formation of salts.


Subject(s)
Benzoxazoles/chemistry , Nefopam/analogs & derivatives , Nefopam/chemical synthesis , Alkenes/chemistry , Amines/chemistry , Catalysis , Organic Chemistry Phenomena , Ruthenium
5.
J Org Chem ; 72(4): 1458-63, 2007 Feb 16.
Article in English | MEDLINE | ID: mdl-17288390

ABSTRACT

A practical and novel one-pot organocatalytic selective process for the cascade synthesis of highly substituted o-hydroxydiarylamines and o-pyrrolidin-1-yldiarylamines is reported. Direct combination of amine-catalyzed cascade Knoevenagel/Michael/aldol condensation/decarboxylation and cascade enamine amination/isoaromatization of alkyl acetoacetates, aldehydes, and nitrosoarenes furnished the highly functionalized anilines with high yields.

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