Docking simulation, synthesis and biological evaluation of novel pyridazinone containing thymol as potential antimicrobial agents

Oliveria decumbens is an Iranian endemic plant used extensively in traditional medicine. Recently, some studies have been performed on biological effects of Oliveria essential oil (OEO). However, to our knowledge, the anticancer activity of OEO has not been reported. Based on our GC/MS analysis, the basic ingredients of OEO are thymol, carvacrol, p-cymene and γ-terpinene. Therefore, we used OEO and its main component, thymol, to explore their effects on cell growth inhibition and anticancer activity. Despite having a limited effect on L929 normal cells, OEO/thymol induced cytotoxicity in MDA-MB231 breast cancer monolayers (2D) and to a lesser extent in MDA-MB231 spheroids (3D). Flow cytometry, caspase-3 activity assay in treated monolayers/spheroids and also fluorescence staining and DNA fragmentation in treated monolayers demonstrated apoptotic death mode. Indeed, OEO/thymol increased the Reactive Oxygen Species (ROS) level leading to mitochondrial membrane potential (MMP, ΔΨm) loss, caspase-3 activation and DNA damage caused S-phase cell cycle arrest. Furthermore, immunoblotting studies revealed the activation of intrinsic and maybe extrinsic apoptosis pathways by OEO/thymol. Additionally, in-vitro experiments, indicated that OEO/thymol interacts with DNA via minor grooves confirmed by docking method. Altogether, our reports underlined the potential of OEO to be considered as a new candidate for cancer therapy.

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“…ADV ina shows the docking scores as binding free energy (Δ G ). And ultimately all figures were visualized using PYMOL software 98 – 101 .…”

Section: Methodsmentioning

confidence: 99%

In-vitro evaluation of apoptotic effect of OEO and thymol in 2D and 3D cell cultures and the study of their interaction mode with DNA

Jamali

Kavoosi

Safavi

et al. 2018

Sci Rep

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“…All chemicals used in this study were purchased from Aldrich, Fluka AG and E. Merck. 6-substitute-3(2H)-pyridazinones, ethyl 6-substitute-3(2H)-pyridazinon-2-yl acetates and 6-substitute-3(2H)-pyridazinon-2-yl acetohydrazides were synthesized according to literature methods [11][12][13]. Analytical thin-layer chromatography (TLC) was performed on plates precoated with silica gel (Merck Kieselgel F254 plates.…”

Section: Methodsmentioning

confidence: 99%

“…They reported that all compounds showed bactericidal and fungicidal activity compared with ciprofloxacin and fluconazole. In this study, molecular modelling studies of synthesized compounds against glucosamine-6-phosphate synthase and A. niger phytase enzymes have also been made and it has been reported that compounds show high binding affinity to receptors [11] (Figure 3). Based on the above literatures, the synthesis of new 3(2H)-pyridazinone derivative compounds was carried out and the antibacterial-antifungal activities of these compounds were investigated.…”

Section: Introductionmentioning

confidence: 99%

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Studies on a novel series of 3(2H)-pyridazinones: Synthesis, molecular modelling, antimicrobial activity

Özdemi̇r¹,

Alagöz²,

Akdemir³

et al. 2019

jrp

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Efforts to develop new potent and effective antimicrobial compounds with lower side effects are important not only for controlling serious infections but also for cancer, surgical operations, and preventing possible infections which are related to other threats. Therefore, it is getting more important to develop new antibacterial and antifungal compounds with wide spectrum, systemic effect and lower side effects. In this study eight new 3(2H)pyridazinone derivatives were synthesized and their antimicrobial activities were evaluated by using broth microdilution method agains two Gr (+) (Staphylococcus aureus, Enterococcus faecalis), two Gr (-) bacteria (Pseudomonas aeruginosa, Escherichia coli) and three yeasts like fungi (Candida albicans, Candida krusei). Compound D2a had the best antibacterial activity among the synthesized compounds. All compounds were more effective against the fungus than the bacteria. In this study, we performed molecular modelling studies to provide in depth understanding of their CYP51 inhibition. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed D2aas highly active compound. The molecular docking studies showed similarities in binding interactions in active site gorges of the enzymes with known inhibitors, such as VT1, fluconazole.

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“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and PLATON (Spek, 2009); software used to prepare material for publication: publCIF (Westrip, 2010). During recent years, pyridazinones have been a subject of numerous recent studies (Boukharsa et al, 2014) owing to their wide spectrum of pharmacological activities such as antimicrobial (Nagle et al, 2014), anti-fungal (El-Hashash et al, 2014), analgesic & anti-inflammatory (Tiryaki et al, 2013), anticancer (Csókás et al, 2013, anti-tubercular (Asif et al, 2014) and anti-hypertensive activities (Garkani-Nejad & Poshteh-Shirani, 2013). It has also been reported that pyridazinone derivative have remarkable insecticidal (Cao et al, 2003) and herbicidal activities (Jamet & Piedallu, 1975).…”

Section: Related Literaturementioning

confidence: 99%

Crystal structure of ethyl 2-{4-[(5-chloro-1-benzofuran-2-yl)methyl]-3-methyl-6-oxo-1,6-dihydropyridazin-1-yl}acetate

Boukharsa

Ammari²,

Taoufik

et al. 2015

Acta Cryst E

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In the title compound, C18H17ClN2O4, the dihedral angle between the benzofuran ring system [maximum deviation 0.014 (2) Å] and the oxopyradizine ring is 73.33 (8)°. The structure is characterized by disorder of the ethyl group, which is split into two parts, with a major component of 0.57 (3), and the acetate carbonyl O atom, which is statistically disordered. In the crystal, the molecules are linked by C—H⋯O interactions, forming a three-dimensional network.

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Docking simulation, synthesis and biological evaluation of novel pyridazinone containing thymol as potential antimicrobial agents

Cited by 30 publications

References 11 publications

In-vitro evaluation of apoptotic effect of OEO and thymol in 2D and 3D cell cultures and the study of their interaction mode with DNA

In-vitro evaluation of apoptotic effect of OEO and thymol in 2D and 3D cell cultures and the study of their interaction mode with DNA

Studies on a novel series of 3(2H)-pyridazinones: Synthesis, molecular modelling, antimicrobial activity

Crystal structure of ethyl 2-{4-[(5-chloro-1-benzofuran-2-yl)methyl]-3-methyl-6-oxo-1,6-dihydropyridazin-1-yl}acetate

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