Synthesis and Molecular Docking Study of 1-(3-Chloropropyl)-3,5-Bis((E)-4-Methoxybenzylidene)Piperidin-4-One as Dengue Virus Type 2 (DEN2) NS2B/NS3 Protease Inhibitor Candidate

Abstract

Curcumin is a secondary metabolite compound that has diverse biological activities. However, it is easily hydrolyzed at physiological pH due to the presence of the β-diketone group. Therefore, the replacement of the β-diketone group with mono ketone is expected to overcome this issue. We hereby report the synthesis of mono ketone curcumin derivatives from piperidone by two-steps reactions. The synthesis of curcumin derivate 3 was carried out by Claisen-Schmidt condensation between 4-piperidone and 4-methoxybenzaldehyde using alkaline catalyst. The synthesized curcumin derivate 3 was then reacted with the 1-bromo-3-chloropropane to produce curcumin derivate 5, 1-(3-chloropropyl)-3.5-bis((E)-4-methoxybenzylidene)piperidin-4-one, with 72% yield. The calculated docking scores, the curcumin derivate 5 possessed a better affinity for receptors than the standard panduratin A. The curcumin derivate 5 has a lower docking score of -6.40 kcal/mol compared to panduratin A with value of -5.18 kcal/mol and also had strong binding interactions to DEN2 NS2B/NS3 protease. Thus, this compound is promising candidate as a new anti-dengue agent.

Curcumin as a natural potential drug candidate against important zoonotic viruses and prions: A narrative review

“…With an unidentified mechanism that may entail interactions with NS4A and NS4B, NS1 protein seems to be crucial for viral replication (Chen et al, 2018). Most of the in silico and in vitro studies demonstrated that NS2B/NS3 as well as NS5 and NS1 proteins are targeted by curcumin (Ariza et al, 2014; Habibi et al, 2020; Lim et al, 2020; Lima et al, 2017). Other studies suggest that the cytoskeleton arrangement, the ubiquitin‐proteasome system, and the apoptotic process are altered by curcumin in DENV‐infected cells (Chen et al, 2013; Halim et al, 2021; Padilla‐S et al, 2014).…”

“…Most of the in silico and in vitro studies demonstrated that NS2B/ NS3 as well as NS5 and NS1 proteins are targeted by curcumin (Ariza et al, 2014;Habibi et al, 2020;Lim et al, 2020;Lima et al, 2017).…”

Diarylpentanoids, the privileged scaffolds in antimalarial and anti‐infectives drug discovery: A review

“…In search of potential drug candidates against protein than the positive control panduratin A (−5.18 kcal/mol). [171] This diarylpentanoid derivative also forms hydrophobic and hydrophilic interactions with the important catalytic triad of dengue virus protease enzyme; Ser135, His51, and Asp75, which are mainly involved in antidengue activity. [171] Therefore, the compound can be regarded a viable candidate for a new agent to inhibit dengue virus type 2 and should be experimentally validated to confirm the predicted efficacy.…”

“…In search of potential drug candidates against dengue, Habibi et al developed a new series of diarylpentanoid derivatives and found in silico 1‐(3‐chloropropyl)−3,5‐bis[( E )−4‐methoxybenzylidene]piperidin‐4‐one (compound 53 ) with significant potential anti‐dengue activity as this compound has a higher binding energy (−6.40 kcal/mol) toward dengue type 2 NS2B/NS3 protease protein than the positive control panduratin A (−5.18 kcal/mol). [ 171 ] This diarylpentanoid derivative also forms hydrophobic and hydrophilic interactions with the important catalytic triad of dengue virus protease enzyme; Ser135, His51, and Asp75, which are mainly involved in anti‐dengue activity. [ 171 ] Therefore, the compound can be regarded a viable candidate for a new agent to inhibit dengue virus type 2 and should be experimentally validated to confirm the predicted efficacy.…”

Molecular Docking and Pharmacophore Analysis of Compounds from Ginger (Zingiber officinale) as Inhibitor for Dengue DEN2 NS2B/NS3 Serine Protease

“…To replicate, the DENV-2 virus requires a protein complex protease (NS3) and its cofactor (NS2B), namely the NS2B/NS3 serine protease. The NS3 protein (which is assisted by NS2B as a cofactor) is a protein that has a vital role in the process of proteolytic and viral replication (Habibi et al, 2020).…”