Synthesis and Biological Evaluation of Dantrolene‐Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases

Abstract

Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC 50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/ acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series.

Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor

“…DOX, with clinical neuroprotective activity, binds PAC1-R-EC1 similarly to PACAP (30)(31)(32)(33)(34)(35)(36)(37), while hydrazide, without clinical neuroprotective activity, binds similarly to PACAP (20)(21)(22)(23)(24)(25)(26)(27) [9], indicating that PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) (GKRYKQRVKNK) plays an important role in the regulation of the activity of PACAP/PAC1-R, a finding which has also been recently recognized by other groups [10,11]. Moreover, some hydrazide and hydrazone analogs have been found to have significant neuroprotective effects, including phenyl hydrazide J147 [12], L-carnosine hydrazide [13], dantrolene-like hydrazide, and hydrazone analogues [14], etc., which are predicted to bind to the site at PAC1-R-EC1 overlapped by PACAP (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). These findings support the conclusion that the binding of PAC1-R-EC1 by PACAP…”

Visible light-driven C–H arylation of heteroarenes with aryl diazonium salts in water catalyzed by a Z-scheme CuInS2/K-C3N4 heterojunction

“…The utility of this protocol was highlighted through the synthesis of bioactive dantrolene ( 4 ), which is a drug for treating malignant hyperthermia. 39 The reaction of furfural with 4-nitrobenzenediazonium tetrafluoroborate salt provided the corresponding arylated product 3a , which further condensed with 1-aminohydantoin hydrochloride to obtain dantrolene with an overall yield of 61% (Scheme 1).…”

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo

“…The exploration of novel AChE-I and their hybrids with other enzyme inhibitors (e.g., MAO A and B), − as well as potent and selective ligands of the cannabinoid receptors, − has long been a major activity of our research groups. Consequently, the aim of this work was the design, synthesis, and physicochemical/pharmacological profiling at the preclinical level of new dual-acting molecules that can inhibit the enzyme AChE and modulate the CB2R.…”