Dimethoxyindoles based thiosemicarbazones as multi-target agents; synthesis, crystal interactions, biological activity and molecular modeling.

Alzheimer's disease (AD) is known as one of the most devastating neurodegenerative disease diagnosed for the old-aged people and cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. A range of novel monomeric and dimeric indole based thiosemicarbazone derivatives 17-28 was synthesized in order to target cholinesterases (ChE). Biological importance of the targeted compounds 17-28 was investigated by employing the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes along with three different antioxidant property determination assays, namely DPPH free radical scavenging, ABTS cationic radical decolarization, and CUPRAC cupric reducing antioxidant capacity. The compounds 18 and 19 displayed the best inhibitor activity against BChE with IC50 values of 7.42 and 1.95 µM, respectively. The antioxidant potentials were found to be moderate for DPPH and ABTS assays and the compounds 28 and 18 were the most potent candidates for both antioxidant assays. Cupric reducing capacity was the most promising assay and the compounds 25, 26 and 28 provided better inhibition values than all the standards. Further binding mode and affinity studies performed by molecular docking and molecular dynamics simulations. Accordingly, the compound 19 is the most plausible candidate that can compete with galantamine (GNT), a common pharmaceutics targeting both cholinesterase enzymes.

Discovery and Computational Rationalization of Diminishing Alternation in [n]Dendralenes.

The [n]dendralenes are a family of acyclic hydrocarbons which, by virtue of their ability to rapidly generate structural complexity, have attracted significant recent synthetic attention. [3]Dendralene through [8]dendralene have been previously prepared but no higher member of the family has been reported to date. Here, we describe the first chemical syntheses of the "higher" dendralenes, [9]dendralene through [12]dendralene. We also report a detailed investigation into the spectroscopic properties and chemical reactivity of the complete family of fundamental hydrocarbons, [3]dendralene to [12]dendralene. These studies reveal the first case of diminishing alternation in behavior in a series of related structures. We also report a comprehensive series of computational studies, which trace this dampening oscillatory effect in both spectroscopic measurements and chemical reactivity to conformational preferences.

Synthesis and Diels-Alder Reactivity of Substituted [4]Dendralenes.

The first synthesis of all five possible monomethylated [4]dendralenes has been achieved via two distinct synthetic strategies. The Diels-Alder chemistry of these new dendralenes (as multidienes) with an electron poor dienophile, N-methylmaleimide (NMM), has been studied. Thus, simply upon mixing the dendralene and an excess of dienophile at ambient temperature in a common solvent, sequences of cycloadditions result in the rapid generation of complex multicyclic products. Distinct product distributions are obtained with differently substituted dendralenes, demonstrating that dendralene substitution influences the pathway followed, when a matrix of mechanistic possibilities exists. Dendralene site selectivities are traced to electronic, steric and conformational effects, thereby allowing predictive tools for applications of substituted dendralenes in future synthetic endeavors.