C25

Parkinson’s disease (PD) is a persistent neurodegenerative condition marked by rising global rates of disability and mortality, warranting the need for new treatment options. The present investigation evaluated the protective effects of novel glitazones C7 and C25 against rotenone-induced PD in a mouse model.

Molecular docking using Discovery Studio and molecular dynamics simulations were employed to evaluate the binding ability of C7 and C25 to the PGC-1α target protein. Pharmacokinetic evaluations of C7 and C25 were performed against the standard pioglitazone in the rats model, and acute toxicity assessments were conducted following OECD guidelines 423. The neuroprotective effects of C7 were tested in a rotenone-induced mouse model of PD at doses of 10, 20, and 30 mg/kg body weight. Behavioral studies, including locomotor activity, grip strength, and catalepsy, as well as biochemical analyses such as endogenous antioxidant levels and AChE levels, were assessed.

The novel compound C7 demonstrated good binding and simulation at the PGC-1α target protein. The kinetic profile of C7 was found to be good when compared to C25. Both the novel glitazones were safe at 300 mg/kg body weight when tested for oral acute toxicity. The novel compound C7 effectively alleviated symptoms related to rotenone-induced PD, demonstrating its promise as a therapeutic candidate.

In the rotenone-induced mouse model, compound C7 exhibited a promising anti-PD effect by attenuating oxidative stress and increasing muscular activity, which merits further investigations.

Additional research using various induction models, along with further investigation of cellular and molecular markers in larger animal studies, is needed to validate these findings.

Botulinum neurotoxins are the most potent toxins responsible for causing flaccid paralysis of muscles by blocking the release of acetylcholine at the neuromuscular junction. There are no postexposure therapeutics and effective active/passive prophylaxis available for the treatment. Therefore, it is highly desirable to develop a potential antidote to counter botulinum neurotoxicity. In this study, ~800 molecules were mined by a structure similarity search from open databases and docked into the pocket of the catalytic domain of botulinum toxin type E using AutoDock 4.2. Twenty‐four small molecules with the best scoring function were selected and evaluated using in vitro and in vivo assays. Among these, two molecules, NSC1011 and NSC1012, were identified as inhibiting the catalytic activity of BoNT/E, with IC50 values of 31.25 ± 1.0 μM and 55.45 ± 5.2 μM and KD of 5.54E−07 and 6.51E−06 M, respectively. To find inhibitors that can reverse the neurotoxicity more effectively, we have derived and synthesized 12 analogs of NSC1011. These compounds showed higher inhibition than the parent molecules, with IC50 and KD values of 4.375 ± 2.3 µM and 1.61E−08 M (C25.12) and 10.25 ± 3.0 µM and 4.70E‐08 M (C25.9). Compounds C25.9 and C25.12 completely protected mice in premixed doses and led to significant extension in survival of up to 60 h with therapeutic treatment. This study showed that these 8‐HQ derivatives had the potency to inhibit BoNT/E by interacting with the active site. Further studies could lead to the development of undiscovered postexposure therapeutics against this deadly neurotoxin.