Synthesis of 2,4-Bis(trifluoromethyl)benzaldehyde Hybrid Thiosemicarbazones as Prolyl Oligopeptidase Inhibitors for Neurodegenerative Disorders and their In-silico Analysis.

Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia. The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 μM). Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 μM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 μM) indicated competitive inhibition of the aforementioned enzyme. Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

Pasha AR ，Ullah S ，Halim SA ，Khan A ，Hussain J ，F EA ，Naseer MM ，Eltantawy W ，Al-Harrasi A ，Shafiq Z ... -  《-》

Morpholine-tethered Novel Hydrazones as Promising Non-peptidic Prolyl Oligopeptidase (POP) Inhibitors: Synthesis In Vitro and In Silico Studies.

Khalid U ，Fatima N ，Ullah S ，Halim SA ，Khan A ，Mali SN ，El-Kott AF ，AlShehri MA ，Kashtoh H ，Al-Harrasi A ，Shafiq Z ... -  《-》

Identification of novel prolyl oligopeptidase inhibitors from resin of Boswella papyrifera (Del.) Hochst. and their mechanism: Virtual and biochemical studies.

Prolyl endopeptidase or prolyl oligopeptidase (PEP or POP) is highly expressed in brain, and associated with autism spectrum disorders, dementia, aging and various psychological disorders, such as schizophrenia, mania, and neurodegeneration. To design highly potent and novel POP inhibitors, structure-based virtual screening was carried out using pharmacophore modeling and molecular docking studies. The docking based active compounds [incensole (1), incensole acetate (2), incensone (3), incensfuran (4), and epi-incensole acetate (5)] were selected and their dynamic behavior was studied through molecular dynamic simulation. Later, the top-ranked [predicted active, (1-5)] and lower-ranked [predicted in-active, (6-10)] compounds were tested by in-vitro assay. The in-vitro results showed that all top-ranked compounds (1-5) found significantly active against POP enzyme with IC50 values in range of 3.1 ± 0.45 to 24.4 ± 1.16 μM, while lower-ranked (6-10) were inactive, indicated accuracy of docking results. Kinetics studies on all active compounds 1-5 were carried out to investigate their mode of inhibition and dissociation constants Ki. All compounds showed competitive behaviors with Ki values in the range of 0.92-8.12 μM. The study resulted in the identification of five (1-5) diterpene based molecules from natural sources that significantly inhibit the activity of POP by competitive mode of inhibition.

Khan A ，Waqas M ，Khan M ，Halim SA ，Rehman NU ，Al-Harrasi A ... -  《-》

Substrate-like novel inhibitors of prolyl specific oligo peptidase for neurodegenerative disorders.

Khan M ，Halim SA ，Waqas M ，Golmohammadi F ，Balalaie S ，Csuk R ，Uddin J ，Khan A ，Al-Harrasi A ... -  《-》

Synthesis, biological evaluation, and molecular modelling of substituted thiazolyl thiourea derivatives: A new class of prolyl oligopeptidase inhibitors.

Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC50 value of 16.47 ± 0.54 μM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.

Naseem S ，Oneto A ，Ullah S ，Fatima S ，Mali SN ，Jawarkar RD ，Khan A ，Alharthy RD ，Kashtoh H ，Al-Harrasi A ，Shafiq Z ，Boshta NM ... -  《-》