Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

Abstract

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

“…The active pocket of AChE was surrounded by amino acid residues Leu76, Tyr124, Phe338, Gly122, Trp286, Tyr337, Val 340, Phe297, Leu289, Tyr72, Ser298, Ser125, Arg 296, Ser203, Tyr341, Ala204 and His447. The hydrogen bonds and π-π interactions were noticed by the most potent inhibitor 5b as well as by huprine W as reported previously [45]. The cognate ligand (huprine W) showed two conventional hydrogen bonds with Ser203 (2.33 Å) and Gly122 (2.96 Å) and multiple π-π stacking interactions (4.00, 5.30 The type of interactions between ligands (5b and 5d) and receptor (4BDT) along with the distance and atoms involved in the interactions are presented in 2D interactions in Figure S4 and Table 2.…”

“…The synthesis of quinoline-thiosemicarbazone hybrids 5a-k was achieved using a facile and efficient multistep approach, as illustrated in Scheme 1. Several commercially available (un)substituted anilines were acetylated using orthophosphoric acid and acetic acid to afford acetanilides 2a-f [45]. Subsequent Vilsmeier-Haack formylation using dimethylformamide and phosphoryl chloride provided 2-chloroquinoline-3-carbaldehydes 3a-f [55].…”

“…Subsequent Vilsmeier-Haack formylation using dimethylformamide and phosphoryl chloride provided 2-chloroquinoline-3-carbaldehydes 3a-f [55]. Acid-catalyzed condensation of formylquinolines with commercially available Cognizant of the fact that both quinoline and thiosemicarbazone pharmacophores are promising candidates for the generation of molecular and structural libraries of anticholinesterase inhibitors, and taking inspiration from the tacrine scaffold that features a quinoline ring, we herein utilized a pharmacophore hybridization strategy to design and explore the wider chemical space for new and potent cholinesterase inhibitors with less side effects, extending on our previous efforts in the current area of research [39][40][41][42][43][44][45]. Furthermore, in view of high demand and omnipresence of nitrogen heterocycles in numerous drugs [46][47][48][49], we have introduced an additional morpholine ring of high therapeutic value [50][51][52][53][54] in the target structures to examine the effect on the cholinesterase inhibition (Figure 1).…”

“…Molecules 2021, 26, 6573 3 of 23 explore the wider chemical space for new and potent cholinesterase inhibitors with less side effects, extending on our previous efforts in the current area of research [39][40][41][42][43][44][45]. Furthermore, in view of high demand and omnipresence of nitrogen heterocycles in numerous drugs [46][47][48][49], we have introduced an additional morpholine ring of high therapeutic value [50][51][52][53][54] in the target structures to examine the effect on the cholinesterase inhibition (Figure 1).…”

Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl]-N-arylacetamides: An In Silico and Biochemical Approach

“…In silico screening is an excellent approach for the screening of libraries of compounds in a short time and thus it minimizes the laborious synthetic work [52][53][54][55]. Molecular docking is a widely used method to predict binding interactions between the 3D conformations of various ligands and receptor proteins that helps in optimization and leads toward drug development [56][57][58].…”