Synthesis and Anti-Melanoma Activity of Acryloyl Pyridinone Analogues.

A major challenge for clinical management of melanoma is the prevention and treatment of metastatic disease. Drug discovery efforts over the last 10 years have resulted in several drugs that improve the prognosis of metastatic melanoma; however, most patients develop early resistance to these treatments. We designed and synthesized, through a concise synthetic strategy, a series of hybrid olefin-pyridinone compounds that consist of structural motifs from tamoxifen and ilicicolin H. These compounds were tested against a human melanoma cell line and patient-derived melanoma cells that had metastasized to the brain. Three compounds 7 b, 7 c, and 7 g demonstrated promising activity (IC50=0.4-4.3 µM). Cell cycle analysis demonstrated that 7 b and 7 c induce cell cycle arrest predominantly in the G1 phase. Both 7 b and 7c significantly inhibited migration of A375 melanoma cells; greater effects were demonstrated by 7 b. Molecular modelling analysis provides insight into a plausible mechanism of action.

Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study.

COVID-19, an acute viral pneumonia, has emerged as a devastating pandemic. Drug repurposing allows researchers to find different indications of FDA-approved or investigational drugs. In this current study, a sequence of pharmacophore and molecular modeling-based screening against COVID-19 Mpro (PDB: 6LU7) suggested a subset of drugs, from the Drug Bank database, which may have antiviral activity. A total of 44 out of 8823 of the most promising virtual hits from the Drug Bank were subjected to molecular dynamics simulation experiments to explore the strength of their interactions with the SARS-CoV-2 Mpro active site. MD findings point toward three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 Mpro with interactions at His41 and Met49. MD simulations identified an additional interaction with Glu166, which enhanced the binding affinity significantly. Therefore, Glu166 could be an interesting target for structure-based drug design. Quantitative structural-activity relationship analysis was performed on the 44 most promising hits from molecular docking-based virtual screening. Partial least square regression accurately predicted the values of independent drug candidates' binding energy with impressively high accuracy. Finally, the EC50 and CC50 of 10 drug candidates were measured against SARS-CoV-2 in cell culture. Nilotinib and bemcentinib had EC50 values of 2.6 and 1.1 µM, respectively. In summary, the results of our computer-aided drug design provide a roadmap for rational drug design of Mpro inhibitors and the discovery of certified medications as COVID-19 antiviral therapeutics.

Fused Imidazopyrazine-Based Tubulin Polymerization Inhibitors Inhibit Neuroblastoma Cell Function.

Targeting the colchicine binding site on tubulin is a promising approach for cancer treatment to overcome the limitations of current tubulin polymerization inhibitors. New classes of colchicine binding site inhibitors (CBSIs) are continually being uncovered; however, balancing metabolic stability and cellular potency remains an issue that needs to be resolved. Therefore, we designed and synthesized a series of novel fused imidazopyridine and -pyrazine CBSIs and evaluated their cellular activity, metabolic stability, and tubulin-binding properties. Evidence shows that the imidazo[1,2-a]pyrazine series are effective against neuroblastoma cell lines marked by MYCN amplification. Further assessment shows that a combination of an imidazo[1,2-a]pyrazine core with a trimethoxyphenyl ring D results in the highest cellular activity and binding characteristics compared with a dichloromethoxyphenyl or difluoromethoxyphenyl ring D. However, the metabolic stability of compounds with a dichloromethoxyphenyl or difluoromethoxyphenyl ring D is significantly higher than that of those containing a trimethoxyphenyl ring D, suggesting that improved metabolic stability is achieved with a moderate impact on potency.

Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies.

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer's disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aß). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aß aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aß42 (10 µM) as a toxin. Finally, Aß-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aß aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aß-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.