Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity

Abstract

The journal implements double-blind peer review practiced by specially invited international editorial board members. Objective: To synthesize chalcone derivatives and investigate their antimalarial activity toward chloroquine-sensitive Plasmodium falciparum 3D7 (Pf3D7) strain; to develop quantitative structureactivity relationships (QSAR) model to estimate IC 50 values for biological activity of antimalarial and compared to experimental measurement; and to determine the binding interactions of the most active compounds with targeting P. falciparum dihydrofolate reductase-thymidylate synthase using molecular docking simulation. Methods: Seven chalcone derivatives have been synthesized from substituted acetophenone and substituted benzaldehyde in ethanol with the presence of bases catalysis at reflux condition. The QSAR analysis was conducted by using Gaussian 09 software to predict IC 50 value for antimalarial activity. The in vitro test was evaluated against the chloroquine-sensitive Pf3D7 strain. Finally, the docking studies were performed with the CDOCKER protocol under the receptor-ligand interaction section in Discovery Studio® 3.1 (Accelrys, Inc., San Diego, USA). Results: Among the synthesized chalcone, a prenylated chalcone 5c and an allylated chalcones 10a showed the best IC 50 values of 1.08 and 1.73 μg/mL respectively against Pf3D7 strain (1.37 and 2.33 μg/mL based on QSAR analysis). Comparison between the prediction of IC 50 value generated from the QSAR and the outcome from an in vitro assay showed a similar result as seen from the r 2 value (r 2 = 0.99). The most active compound 5c was employed in the docking simulation to determine the potential binding interactions with active sites of P. falciparum dihydrofolate reductase-thymidylate synthase (protein data bank ID: 1J3I). The docking simulation study showed 5c bind well with Ala16, Ser108, Ile164, Trp48, and Phe58 which are the crucial interactions that could possibly interrupt the sequential catalysis reactions in the thymidylate cycle and subsequently prevent deoxythymidine monophosphate production and DNA synthesis. The formed binding interaction (H-bond) toward residues of Ala16, Ser108, and Ile164 also indicate the activity of 5c against chloroquine-resistance P. falciparum strain. Conclusions: We have successfully determined the effects of some chalcone derivatives on antimalarial activity against the chloroquine-sensitive Pf3D7 strain. Compound 5c and 10a were described a good antiplasmodial compounds. Interestingly, these in vitro results relevance with IC 50 predicted QSAR studies. Moreover, molecular docking simulation provided insight into the binding modes of 5c into the anti-folate resistance from malarial P. falciparum.

Crystal structure and Hirshfeld surface analysis of (E)-1-(3,5-dichloro-2-hydroxyphenyl)-3-(5-methylfuran-2-yl)prop-2-en-1-one

“…They belong to the flavonoid family, which are basically found in fruits and vegetables (Hijova 2006). Chalcones occupy an important place in the pharmaceutical industry since their derivatives serve as the core structures for many organic compounds possessing various biological activities such as antibacterial (Vibhute & Baseer, 2003), anti-microbial (Prasad et al, 2006), antiinflammatory (Lee et al, 2006), anti-hyperglycemic (Satyanarayana et al, 2004), anti-malarial (Syahri et al, 2017) and anti-oxidant (Cheng et al, 2008). Chalcones also exhibit some non-linear optical (NLO) properties and also find applications in laser technologies such as optical communications, data storage and signal processing because of the , unsaturated functionality (Shobha et al, 2017).…”

Evaluation of antimicrobial, antibiofilm and carbonic anhydrase inhibition profiles of 1,3‐bis‐chalcone derivatives

“…The chalcones, that have this structural feature, are among the important compounds that we frequently encounter in the literature in terms of both their useful synthetic properties and biological activity they exhibit . They have a broad spectrum of biological activity such as antimicrobial, antifungal, anticancer, anti‐inflammatory, analgesic, antioxidant, antileishmanial and antimalarial activities. In addition, many heterocyclic and polyfunctional compounds such as pyrazole, pyrimidine, pyridine, pyridone, quinoline and isoxazole derivatives can be synthesized easily starting from chalcones.…”

Design of 2-Phenylamino Benzothiopyrano [4,3-D] Pyrimidines Compound as an Anticancer

“…Molecular docking was carried out to Human poly (ADPribose) polymerase-1 (HsPARP-1) (protein anticancer target) which retrieved from Protein Data Bank with the code of sensitive protein of 3L3M (2.5 Å). The docking procedure was conducted according to the previous work [22,23]…”