Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase.

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294 µM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519 µM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

Synthesis, in vitro, and in silico studies of new derivatives of diphenylpiperazine scaffold: A key substructure for MAO inhibition.

Fifteen new diphenylpiperazine hybrids were designed, synthesized and in vitro biologically evaluated against hMAOs enzymes via fluorometric method. All of our new compounds displayed strong inhibitory activities against both two isoforms of hMAOs with IC50 range of 0.091-16.32 µM. According to selectivity index values, all hybrids showed higher selectivity against hMAO-A over hMAO-B. Compound 8 exhibited the best hMAO-A inhibition activity (IC50 value = 91 nM, SI = 19.55). With a selectivity index of 31.02 folds over MAO-B, compound 7 was revealed to be the most effective hMAO-A inhibitor. In silico prediction of physicochemical parameters and BBB permeability proved that all of the newly synthesized compounds have favorable pharmacokinetic profiles and acceptable ADME properties and can pass BBB. For clarification and explanation of the biological activity of compounds 7 and 8, molecular docking simulations were carried out. In light of this, 1,4-diphenylpiperazine analogues can be seen as an encouraging lead to develop safe and effective new drugs for treatment of many disorders such as anxiety and depression by inhibition of hMAO-A enzyme.

Biphenylpiperazine Based MAO Inhibitors: Synthesis, Biological Evaluation, Reversibility and Molecular Modeling Studies.

In this study, 21 new 1,4-biphenylpiperazine derivatives were designed, synthesized and evaluated as monoamine oxidase (MAO) inhibitors by in vitro fluorometric method. All these compounds exhibited inhibitory activity against hMAO enzymes, 17 analogues of them showed selectivity towards hMAO-B over hMAO-A enzyme. Compound 20 exhibited the best activity and selectivity towards hMAO-B with IC50 value of 53 nM and selectivity index of 1122 folds over MAO-A, compared to the reference drugs rasagiline (IC50 = 66 nM) and selegiline (IC50 = 40 nM). Kinetic study and reversibility test of the most potent compound (20) revealed that it is reversible and mixed competitive inhibitor (Ki value is 17 nM for the inhibition of hMAO-B). Compound 20 was evaluated against normal NIH/3T3 mouse embryonic fibroblast cell lines and it was found that it is non-cytotoxic at its effective concentration against hMAO-B. Moreover, compound 20 and the most potent compounds have acceptable ADME properties and good pharmacokinetics profiles. Molecular docking simulations were performed for explanation and elucidation for the biological activity of compounds 19 and 20. Accordingly, 1,4- biphenylpiperazine derivatives can be considered as a promising lead to produce more potent and safer MAO inhibitors for management of various neurological disorders.