Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease.

New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC: AChE, 0.265-4.

New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS.

Synthesis of cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines and their evaluation as 5-HT6 receptor antagonists.

Synthesis and biological evaluation of 1 ('angular') and 2 ('linear') cycloalkane-annelated 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidines as novel ligands of the 5-HT(6) receptors are disclosed. The new compounds 1 and 2 are highly selective antagonists of the receptor with sub-nanomolar affinities (K(i)<1 nM). In its structure, this new chemotype lacks a basic ionizable side chain, which is considered as the characteristic feature of the 5-HT(6) receptor antagonists pharmacophore model.

Screening for caspase-3 inhibitors: effect of a reducing agent on identified hit chemotypes.

When studying cysteinyl proteases in general and caspases in particular, it is generally accepted that a reaction buffer must contain a reducing agent to prevent essential cysteinyl groups from spontaneous oxidation. Dithiothreitol (DTT) and beta-mercaptoethanol (beta-MCE) are 2 of the most broadly used reducing agents. While screening a library of small molecules against caspase-3, the authors have found that the nature of the reducing agent used, DTT or beta-MCE, dramatically affects screening results and leads to identification of nonoverlapping hits.

Screening for caspase-3 inhibitors: a new class of potent small-molecule inhibitors of caspase-3.

From the authors' 650,000 compound collection, they have selected approximately 15,000 potential small-molecule protease inhibitors, which were subjected to high-throughput screening against caspase-3. The screening yielded a series of hits that belong to 11 different scaffolds. Based on the structure of one of the hits, a new class of the small-molecule inhibitors with a double electrophilic warhead, 8-sulfonyl-pyrrolo[3,4-c]quinoline-1,3-diones (SPQ), was synthesized and tested in follow-up mechanistic and anti-apoptosis assays.