A Study of the Biological Pharmacology of IFO, a New Selective and Reversible Monoamine Oxidase-B Inhibitor.

Abstract

propoxy]phenyl]-5-trifluoromethyl-1,2,4-oxadiazole (IFO), design ed to be a novel selective inhibitor of monoamine oxidase (MAO), showed highly selective inhibition for type-B (MAO-B); its IC50 was approximately > 200 pM and 30 nM for type-A (MAO-A) and MAO-B, respectively, in the standard assay using mitochondrial preparations from rat brain or liver. The in vitro MAO-B inhibition by IFO was time-independent, non-competitive and tight-binding; and furthermore, in the presence of sodium cholate its inhibition was not tight-binding and was reversible. Oral administration of IFO (0.5 -100 mg/kg) produced a dose-dependent MAO-B inhibition in mouse brain; its ED50 (p.o., 1 hr) was 1.6 mg/kg, while L-deprenyl inhibited the enzyme with the ED50 of approximately 8.0 mg/kg. The ED50 for MAO-A was > 100 mg/kg for either IFO and L-deprenyl. The MAO inhibitive effect of IFO in mouse liver was the same as that in the brain, but that of L-deprenyl in mouse liver was different from that in the brain as shown by the ED50 values of 35 mg/kg and 0.6 mg/kg for MAO-A and MAO-B, respectively. In mice, IFO increased the striatal concentrations of 2-phenylethylamine (2-PEA) and showed almost the same protective efficacy as L-deprenyl against the lethality and striatal dopamine (DA) depletion induced by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results indicate that IFO appears to be a potent inhibitor of MAO-B in mouse brain.

Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1,2,4‐oxadiazoles

“…[ 26,27 ] Particularly, 3,5‐disubstituted‐1,2,4‐oxadiazoles were reported to have potential anticancer activities and apoptosis against various cancer cell lines. [ 28–32 ] These results established that 3,5‐disubstituted‐1,2,4‐oxadiazoles are potential anticancer motifs. Herein, we designed and synthesized novel benzofuran‐based 3,5‐disubstituted‐1,2,4‐oxadiazole hybrids and evaluated their cytotoxic activities against the HCT116 (colon cancer) and MIA PaCa2 (pancreatic cancer) cell lines.…”

Oxadiazoles

“…They show activity as antirhinoviral agents [297], growth hormone secretagogues [298], anti-inflammatory agents [234], and antitumor agents [183,188,299]. They also inhibit the SH2 domain of tyrosine kinase [300], monoamine oxidase [301], human neutrophil elastase [302], and human DNA topoisomerases. Finally, tropane derivatives of 1,2,4-oxadiazoles display high affinity for the cocaine binding site of the dopamine transporter [303].…”

Design, synthesis, characterization, and antibacterial activity of {5-chloro-2-[(3-substitutedphenyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-(phenyl)-methanones

“…Similar ring systems are present in various biologically interesting compounds such as muscarinic receptor agonists [2], tyrosine kinase inhibitors [3], anti-inflammatory agents [4], selective H 3 receptor antagonists [5], antitumor agents [6], monoamine oxidasea inhibitors [7], anticonvulsant [8], and anti-HIV agents [9]. Synthetic methods generating 1,2,4-oxadiazoles and the chemical properties of these compounds have been reviewed [10].…”