Future medicinal chemistry · 2025
Development of 5-phenylnitro bearing furan-based chalcones as a new class of potent MAO-B inhibitors.
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Kalathil Kadeeja Thottungal, Pandey Bishnu Prasad, Peedikayil Arshida Thottile, Abdu Raihan Arikkattel, Sreekumari Rajasree Raghavan, Alfagham Alanoud T, Elgorban Abdallah M, Kumar Sunil, Kim Hoon, Dev Sanal, Mathew Bijo
Аннотация
AIM: The purpose is to synthesize a new class of furan-based chalcone compounds (KD1-KD14) and to investigate their monoamine oxidase (MAO)-A and -B inhibitory activities.
MATERIAL AND METHOD: The 14 chalcones were synthesized using an open mortar and pestle. Lead molecules were screened via inhibitory activity, BBB permeability, and computation studies.
RESULTS: Most of the tested compounds showed promising activity for MAO-B over than MAO-A. Among the molecules, KD1 and KD9 revealed the significant inhibitory potentials toward MAO-B with IC50 values of 0.023 ± 0.004 and 0.015 ± 0.001 µM, respectively, and with high selectivity indices of 723.04 and >2666.66, respectively, over MAO-A. Further, kinetics and reversibility test revealed that both KD1 and KD9 were competitive reversible MAO-B inhibitors with Ki values of 13.5 ± 4.95 and 6.15 ± 0.92 nM, respectively. Additionally, the PAMPA test showed that both KD1 and KD9 compounds permeated the central nervous system. Furthermore, molecular docking and dynamics simulations showed that both the chemicals formed pi-cation and hydrogen bonds with the MAO-B pocket and stabilized the MAO-B over the course of a 100 ns simulation.
CONCLUSION: Our results revealed that KD1 and KD9 are potent selective, reversible, and competitive MAO-B inhibitors.
MATERIAL AND METHOD: The 14 chalcones were synthesized using an open mortar and pestle. Lead molecules were screened via inhibitory activity, BBB permeability, and computation studies.
RESULTS: Most of the tested compounds showed promising activity for MAO-B over than MAO-A. Among the molecules, KD1 and KD9 revealed the significant inhibitory potentials toward MAO-B with IC50 values of 0.023 ± 0.004 and 0.015 ± 0.001 µM, respectively, and with high selectivity indices of 723.04 and >2666.66, respectively, over MAO-A. Further, kinetics and reversibility test revealed that both KD1 and KD9 were competitive reversible MAO-B inhibitors with Ki values of 13.5 ± 4.95 and 6.15 ± 0.92 nM, respectively. Additionally, the PAMPA test showed that both KD1 and KD9 compounds permeated the central nervous system. Furthermore, molecular docking and dynamics simulations showed that both the chemicals formed pi-cation and hydrogen bonds with the MAO-B pocket and stabilized the MAO-B over the course of a 100 ns simulation.
CONCLUSION: Our results revealed that KD1 and KD9 are potent selective, reversible, and competitive MAO-B inhibitors.