A novel alpha-amylase inhibitor-based spirooxindole-pyrrolidine-clubbed thiochromene-pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol⁻¹ below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular H^…O hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).     

Tolerability safety and effectiveness of enhanced external counterpulsation versus individual shear rate therapy in patients with lower extremity atherosclerotic disease: A prospective pilot clinical trial

Aims

We aimed to investigate the tolerability, safety, and effectiveness of enhanced external counterpulsation therapy (EECP) versus individual shear rate therapy (ISRT) in patients with lower extremity atherosclerotic disease (LEAD).

Methods

Eighteen patients (age: 73.1 ± 6 years) underwent EECP and ISRT, each daily over five consecutive days in a cross-over design with a 1 week resting period in between the two regimens. A quality-of-life questionnaire was used to assess the therapy experience. Oxygen saturation (SO₂), relative hemoglobin amount (rHb) and blood flow (Flow) in the capillary-venous-system (microcirculation) of the skin were monitored continuously during all therapy sessions using the micro-lightguide spectrophotometer, also known as oxygen to see (O2C). The effects of EECP and ISRT on the renal function and skeletal muscles were evaluated using serial blood and urine tests.

Results

EECP therapy had to be terminated early before the end of the 5th session in 10 patients (55.6%) because of discomfort. Four patients (22.2%) experienced signs of critical limb ischaemia under EECP. The total score of the quality-of-life questionnaire was significantly higher (= better tolerated) post-ISRT compared with EECP. Microcirculation monitoring revealed that ISRT significantly increased the SO₂, blood flow and rHb during the therapy. All three parameters remained significantly increased in the observation period after ISRT. The serum levels of creatin kinase and myoglobin increased significantly under EECP.

Conclusions

ISRT significantly improves tolerability, safety, and effectiveness over EECP in patients with LEAD.