ABSTRACT
Secretory phospholipase A2 (sPLA2) is a key enzyme participating in the inflammatory cascade followed by the action of cyclooxygenase-2 and lipoxygenases. Therefore, inhibitors of sPLA2 could be used as potent anti-inflammatory agents to treat the early phase of inflammation. In this study, we have prepared the fenoprofen and ibuprofen analogs containing 1,3,4-oxadiazole nucleus and tested against Vipera russelli venom's basic sPLA2 (VRV-PL-VIIIa). Among the tested ligands 5(a-t),2-(2-chlorophenyl)-5-(1-(4-phenoxyphenyl) ethyl)-1,3,4-oxadiazole (5m) inhibited the catalytic activity of VRV-PL-VIIIa with an IC50 value of 11.52 µM. Biophysical studies revealed that the 5m quenches the intrinsic fluorescence of VRV-PL-VIIIa, in a concentration dependent manner. Also, the compound 5m affected VRV-PL-VIIIa conformation, which was observed by circular dichroism spectra that recorded the prominent shift in the α-helix peak and the random coil formation of VRV-PL-VIIIa. Further, molecular docking analysis revealed that the compound 5m possess strong hydrophobic interactions at catalytic triad region of the VRV-PL-VIIIa. Evident to in vitro and in silico studies, 5m strongly inhibited the hemolysis of red blood cells. Our in vivo pharmacological studies revealed that the compound 5m inhibited the edematogenic activity of VRV-PL-VIIIa in mouse foot pad. Additionally, the 5m inhibited VRV-PL-VIIIa-induced myotoxicity and lung hemorrhage in mice. Overall, our ADMET results depicted that 5m possess better druggable property. Thus, this study explored the new fenoprofen and ibuprofen analog 5m as the lead-structure that serves as an anti-inflammatory agent.
Subject(s)
Enzyme Inhibitors , Fenoprofen , Group II Phospholipases A2 , Ibuprofen , Oxadiazoles , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fenoprofen/analogs & derivatives , Fenoprofen/chemical synthesis , Fenoprofen/chemistry , Fenoprofen/pharmacology , Group II Phospholipases A2/antagonists & inhibitors , Group II Phospholipases A2/chemistry , Group II Phospholipases A2/toxicity , Hemolysis/drug effects , Ibuprofen/analogs & derivatives , Ibuprofen/chemical synthesis , Ibuprofen/chemistry , Ibuprofen/pharmacology , Male , Mice , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Protein Structure, SecondaryABSTRACT
This paper reports the synthesis and antiproliferative effects of new thiomer-diclofenac and fenoprofen conjugates, hydrophilic, bioadhesive, polymeric prodrugs, as well as antiproliferative effects of diclofenac, fenoprofen and a series of previously described polymer-fenoprofen conjugates on five tumor cell lines. Thiolated and nonthiolated polyaspartamides were the chosen polymeric components. Drug-loading ranged from 5.6 to 22.4%, and the amount of SH groups ranged from 6.9 to 45.6micromol g(-1). Tensile studies demonstrated a clear correlation between the amount of thiol and the mucoadhesive properties of the conjugates. The growth-inhibitory activity of the tested polymer-drug conjugates demonstrates that polyaspartamide-type polymers, especially thiolated polymers, enable inhibition of tumor cell growth with significantly lower doses of the active substance.
Subject(s)
Antineoplastic Agents/chemical synthesis , Diclofenac/analogs & derivatives , Diclofenac/chemical synthesis , Fenoprofen/analogs & derivatives , Fenoprofen/chemical synthesis , Nylons/chemistry , Prodrugs/chemical synthesis , Sulfhydryl Compounds/chemistry , Antineoplastic Agents/pharmacology , Aspartic Acid/analogs & derivatives , Aspartic Acid/chemistry , Cell Line, Tumor , Diclofenac/pharmacology , Drug Carriers , Drug Screening Assays, Antitumor , Fenoprofen/pharmacology , Humans , Prodrugs/pharmacology , Structure-Activity RelationshipABSTRACT
Two types of polymer-drug conjugates were synthesized starting from styrene-maleic acid anhydride copolymer (SMA). Fenoprofen and gemfibrozil were chosen as model drugs because of their short plasma half lives. Both drugs were first converted to their 2-aminoethylamides, which possess free amino groups capable of reacting with SMA anhydride rings. By modifying the degree and type of substitution, lipophilic and hydrophilic conjugates were obtained. Drug loading in the conjugates was between 17 and 47%.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Fenoprofen/analogs & derivatives , Fenoprofen/chemical synthesis , Gemfibrozil/analogs & derivatives , Gemfibrozil/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Chromatography, Thin Layer , Fenoprofen/chemistry , Gemfibrozil/chemistry , Hypolipidemic Agents/chemistry , Maleates/chemistry , Prodrugs , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Spectroscopy, Fourier Transform Infrared , Styrenes/chemistryABSTRACT
A new urea-bonded chiral stationary phase has been developed in our laboratory. This bonded phase has been shown to resolve N-terminal substituted amino acids and the carboxyl derivatized anti-inflammatory drugs. Typical alpha-value for dinitrobenzoyl phenylglycine was 1.7. Values for derivatized ibuprofen, naproxen, and fenoprofen were 2, 1.84, and 1.6, respectively. Further application of these studies to biologically active compounds such as peptides and drugs is in progress.
