Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson's disease: Synthesis, biochemistry, and molecular dynamics study.

Oximes are the promising structural scaffold for inhibiting monoamine oxidase (MAO)-B. Eight chalcone-based oxime derivatives were synthesized by microwave-assisted technique, and their ability to inhibit human MAO (hMAO) enzymes were tested. All compounds showed higher inhibitory activity of hMAO-B than hMAO-A. In the CHBO subseries, CHBO4 most potently inhibited hMAO-B with an IC50 value of 0.031 µM, followed by CHBO3 (IC50 = 0.075 µM). In the CHFO subseries, CHFO4 showed the highest inhibition of hMAO-B with an IC50 value of 0.147 µM. Compound CHBO4 had the highest selectivity index (SI) value of 1290.3. However, CHBO3 and CHFO4 showed relatively low SI values of 27.7 and 19.2, respectively. The -Br substituent in the CHBO subseries at the para-position in the B-ring showed higher hMAO-B inhibition than the -F substituent in the CHFO subseries. In both series, hMAO-B inhibition increased with the substituents at para-position in A-ring (-F > -Br > -Cl > -H in order). Compound CHBO4 (-F in A-ring and -Br in B-ring) was 12.6-times potent than the substituents-reversed compound CHFO3 (-Br in A-ring and -F in B-ring; IC50 = 0.391 µM). In the kinetic study, Ki values of CHBO4 and CHFO4 for hMAO-B were 0.010 ± 0.005 and 0.040 ± 0.007 µM, respectively, with competitive inhibitions. Reversibility experiments showed that CHBO4 and CHFO4 were reversible hMAO-B inhibitors. In the cytotoxicity test using the Vero cells by the MTT technique, CHBO4 had low toxicity with an IC50 value of 128.8 µg/mL. In H2O2-induced cells, CHBO4 significantly reduced cell damage by scavenging reactive oxygen species (ROS). Molecular docking and dynamics showed the stable binding mode of the lead molecule CHBO4 on the active site of hMAO-B. These results suggest that CHBO4 is a potent reversible, competitive, and selective hMAO-B inhibitor and can be used as a treatment agent for neurological disorders.

A New Potent and Selective Monoamine Oxidase-B Inhibitor with Extended Conjugation in a Chalcone Framework: 1-[4-(Morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one.

The general blueprint for the design of monoamine oxidase-B (MAO-B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1-[4-(morpholin-4-yl)phenyl]-5-phenylpenta-2,4-dien-1-one (MO10) was prepared by the condensation of 4'-morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO-A and MAO-B. Interestingly, MO10 showed a remarkable inhibition against MAO-B with an IC50 value of 0.044 µM along with a selectivity index of 366.13. The IC50 value was better than that of lazabemide (IC50 value of 0.063 µM), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO-B, with a Ki value of 0.0080 µM. The observation of recovery of MAO-B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC50 value of 195.44 µg/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood-brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO-B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work.

Drug discovery and development are long and financially taxing processes. On an average it takes 12-15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.