Synthesis, biological evaluation, and molecular modeling of nitrile‐containing compounds: Exploring multiple activities as anti‐Alzheimer agents

Abstract

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti‐aggregating properties. Eighty‐three nitrile‐containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ1–42, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ1–42 fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application.

Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa

“…In the modern design of biologically active compounds with specified properties, one of the common approaches is to obtain hybrid molecules that carry in their structure fragments of known pharmacophores, as well as substructures whose ability to interact with specified targets has been studied. This approach makes it possible to create complex molecules that potentially have dual or multiple activities [ 61 , 62 , 63 , 64 , 65 ].…”

From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

“… [17] Other discoveries have found molecules that tackle relevant AD targets such as AChE and its induced β‐amyloid aggregation, butyrylcholinesterase, monoamine oxidase or metal chelation. [ 18 , 19 , 20 ]…”

From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer's Disease using Protein‐Templated Synthesis

“…The first reported trifunctional molecules exhibited acetylcholinesterase (AChE) inhibitory activity together with the reduction of AChE‐induced amyloid‐β aggregation and metal chelating properties [17] . Other discoveries have found molecules that tackle relevant AD targets such as AChE and its induced β‐amyloid aggregation, butyrylcholinesterase, monoamine oxidase or metal chelation [18–20] …”

“…[17] Other discoveries have found molecules that tackle relevant AD targets such as AChE and its induced b-amyloid aggregation, butyrylcholinesterase,m onoamine oxidase or metal chelation. [18][19][20] Ther ational design of MTDs is based in three main strategies:linkage,fusion and incorporation (Figure 1).…”