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Due to dengue fever's swift global expansion and the lack of effective antiviral remedies, it is crucial to discover and develop new antiviral drugs. The study aimed to assess the antiviral potential of the extract and fractions from the leaves of Goniothalamus lanceolatus Miq. (Annonaceae). New Guinea C strain DENV-2, at a multiplicity of infection of 0.4, was used to infect Vero cells. The assessment of antiviral effectiveness was conducted through the plaque reduction assay. Deep metabolome analysis of the active fraction identified nine styryllactones based on reference standards and eighteen styryllactones were further annotated through a molecular database search. One new 2 H -tetrahydropyran derivative, 3- epi -goniothalesdiol A (19), together with seven known styryllactones (8 , 11 , 14 , 16 , 17 , 18 , and 22) were isolated from the leaves of G. lanceolatus. The active bis-styryllactone goniolanceolatin A (22) with the highest selectivity index (SI) underwent further evaluation using quantitative reverse transcription qRT-PCR to determine the viral RNA level. The qRT-PCR data showed that the IC 50 value for the active compound was 5.07 µg/mL, and its corresponding SI value was 5.30. Following comprehensive docking studies, the bis-styryllactone derivative 22 showed potential binding interactions with crucial amino acids of the Envelope (E) of DENV proteins comparable to those of ribavirin. [Display omitted] • In vitro evaluation of Goniothalamus lanceolatus leaf dichloromethane (GLLD) extract showed the strongest anti-dengue activity. • One new 2H-tetrahydropyran derivative was successfully isolated from the leaves of G. lanceolatus during a bioactivity-directed. • In vitro and in silico evaluation of bis-styryl lactone isolated from the most active fraction of leaves of G. lanceolatus showed the most potential anti-dengue activity. [ABSTRACT FROM AUTHOR]

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant‐based compound, mimosine, in MCF‐7 cells by in silico model. Cell viability and proliferation, ERα‐SRC1 coactivator activity and expression of specific ERα‐dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17β‐oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson–Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 μM with significant cell proliferation (120.5%) compared to 17β‐oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 μM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1‐fold at 0.1 μM) and PGR (13.9‐fold at 0.01 μM) genes. ERα‐mimosine binding energy was −49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα‐LBD. The results suggested that mimosine has oestrogenic activity. The oestrogenic potential of mimosine was evaluated. Mimosine stimulated oestrogen‐dependent proliferation of ER‐positive oestrogen‐responsive MCF‐7 cells. It also bound with the ERα receptor subtype through the recruitment of SRC1 coactivator. The ERα‐dependent oestrogen‐responsive marker genes TFF1 and PGR were also stimulated by mimosine. Molecular simulation showed the interaction of mimosine at the ERα ligand binding domain. [ABSTRACT FROM AUTHOR]

Malaria is a detrimental disease with a history of about 4000 years, is still endemic particularly in developing countries. Disease caused by the Plasmodium parasite that transferred in human through the infected female Anopheles mosquito was responsible for an estimated 445000 deaths worldwide in 2016. Few drugs have been well-developed and dispensed for the treatment of malaria such as chloroquine and artemisinin but ever-growing drug resistance against these classes of drugs has rendered them ineffective. Although chloroquine and its derivatives have suffered from the resistance problem, the potential of hybridisation strategy has helped to revive this important class of plasmodial agents by changing the structure of the molecule. In designing new antimalarial hybrid compounds, 8-aminoquinoline and pyranopyrazole compounds are designed together forming a hybrid and evaluated using the in-silico study. This study is utilized to recognize the binding interactions of designed 8-aminoquinoline hybrid compounds with the residues in the active site of plasmodium parasite. Five derivatives of 8-aminoquinoline hybrids were used in this study. The protein crystal structure of the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme with cofactor was retrieved from the Protein data bank (PDB ID:1CET, resolution: 2.05 Å). Discovery Studio 2016 (Accelrys Inc. San Diego, CA, USA) was used for the above protein and ligand preparation. The PDB files were prepared for docking in Molegro Virtual Docker (MVD) software. The in-silico study revealed that all five newly designed 8-aminoquinoline hybrid compounds exhibited comparable binding affinity as compared to reference established drug chloroquine(-70.4656kcal/mol) with binding affinity between -71.789kcal/mol to - 98.8203kcal/mol. All five 8-aminoquinoline hybrid compounds were suitable (RMSD:0.72Å) and successfully docked inside the chloroquine binding site using MVD software. 8-aminoquinoline hybrid compounds exhibited promising binding affinity by forming hydrogen bond with the amino acid residue besides exhibited similar interactions with the amino acid residues as per chloroquine bind to PfLDH enzyme. Those amino acid involve includes VAL26, ALA98, ILE54, GLU122 and ILE119. [ABSTRACT FROM AUTHOR]

Introduction: Basal-like phenotype triple-negative breast cancer (B-TNBC) accounting for 50 -75% of all TNBC subtypes was associated with aggressive behaviour and poor prognosis. Previous studies showed that the symmetrical curcumin derivatives were able to suppress non-basal-like TNBC cells growth in vitro, but the effects of asymmetrical derivatives on B-TNBC are still unclear. Methods: Five asymmetrical compounds (a1-5) bearing different heterocyclic linkers were synthesised using the ultrasonic-aldol condensation method. Compounds were tested on B-TNBC derived HCC-1806 cells, and their selectivity was compared with non-B-TNBC derived MDA-MB-231 and non-cancerous cells (Beas-2B, BV-2, HEK-293 and pHME). The lead compound was further tested on cell cycle arrest, apoptosis and proteasome inhibition effect in vitro. Docking simulation was applied to explain the binding interactions of the lead compound with 20S proteasome β5 subunit active binding site. Results: Compound a5 [3-(methylbenzylidene)- 5(4-hydroxy-3-methoxybenzylidene) dihydro-2H-pyran-4(3H)-one] exerted excellent growth inhibition on basal-like HCC-1806 (IC50 = 0.59±0.16 μM). When compared to non-basal-like MDA-MB-231 cells, a5 exhibited 7.34-fold more selective to HCC-1806. Furthermore, it displayed 1.29-, 1.69-, 6.49- and 6.61-fold selective to HCC-1806 cells over non-cancerous HEK-293, pHMEC, BEAS-2B and BV-2 cells, respectively. It arrested the G2/M phase cell-cycle progression, promoted apoptosis and inhibited the proteasome activity dose-dependently in vitro. Docking analysis revealed that compound a5 could form hydrophobic interactions with the hydrophobic residues in the binding pocket. It could also form hydrogen bonds via hydroxyl group with the Thr1 residue in the β5 subunit binding pocket. Conclusion: The present study suggests that asymmetrical curcumin derivative embedded with a heterocyclic linker could serve as a potential anti-cancer agent targeting B-TNBC. [ABSTRACT FROM AUTHOR]

Introduction: Cancer is a life-threatening disease, posing therapeutic challenges in the quest for total cure. Researchers have been looking for potential therapeutic agents from natural sources. Synclisia scarbida, a Nigerian plant which has recently been reported to have anticancer efficacy by local traditional practitioners, was chosen for further research in our study. Methods: Methanol extract (ME) of S. scabrida root was chosen for its high yield and potency. Preliminary phytochemical studies on ME were carried out using standard methods. The methanol extract (9.0 g) was fractionated into nine fractions using column chromatography (MeOH:DCM = 1.4:8.6). The fraction4–8 (1.6 g) was combined and partitioned to obtain 24 subfractions. Based on TLC, subfractions 1–7 (2.3 g) and 8–21 (712.1 mg) were further purified by PTLC (IPA:DCM = 6:4) to yield five sub-subfractions for each case. The 3rd and 4th fractions from subfractions 1–7 were combined again. The third band (204.1 mg) of PTLC subfractions 8–21 was fractionated further to yield three sub-subfractions. MTT assay was employed to evaluate anticancer potentials of the fractions/subfractions of S. scabrida against HCT-116 (colon), MCF-7 (breast) and PANC-1 (pancreas) cancer cells. Results: The presence of alkaloids, tannins, and steroids was confirmed in an initial phytochemical screening of ME. The combined fractions 4–8 had an IC50 value of 23±14 μg/mL against PANC-1. Subfractions 1–7 had IC50 values of 78±20, 47±8 and 33±6 μg/mL in PANC-1, HCT-116, and MCF-7, respectively. However, the combined sub-subfraction 3- 4 yielded from subfractions 1–7 was only active against HCT-116 (58±3 μg/mL) and MCF-7 (43±6 μg/mL). Conclusion: PANC-1 was initially reported to be susceptible to fractions 4-8; however, the efficacy of the subfractions decreased for the PANC-1 cells, which could be due to the loss (degradation) of potent phytoconstituents during the purification process. From the preliminary study, it was confirmed that MCF-7 is the most sensitive to S. scabrida sub-fractions. Thus, more research is needed for the careful isolation of pure phytochemicals and to confirm the anticancer potential of S. scabrida. [ABSTRACT FROM AUTHOR]

Background: The phytoconstituents phytic acid and 4-hydroxyisoleucine have been reported to posses various biological properties., Objective: This prompted us to carry out the docking study on these two ligands (phytic acid & 4-hydroxyisoleucine) against eleven targeted enzymes., Materials and Methods: Phytic acid & 4-hydroxyisoleucine were evaluated on the docking behaviour of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), tyrosinase, human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), xanthine oxidase (XO), squalene synthase (SQS), nitric oxide synthase (NOS), human aldose reductase (HAR) and lipoxygenase (LOX) using Discovery Studio Version 3.1 (except for LOX, where Autodock 4.2 tool was used)., Results: Docking and binding free energy analysis revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase and HNE. Interestingly, we found that 4-hydroxyisoleucine has the potential to dock and bind with all of the eleven targeted enzymes., Conclusion: This present study has paved a new insight in understanding 4-hydroxyisoleucine as potential inhibitor against COX-2, mPGES-2, tyrosinase, HNE, MMP 2, MMP 9, XO, SQS, NOS, HAR and LOX., Summary: 4-hydroxyisoleucine has the potential to dock and bind with all 11targeted enzymes such as (cyclooxygenase-2 [COX-2], microsomal prostaglandin E synthase-2 [mPGES-2], tyrosinase, human neutrophil elastase [HNE], matrix metalloproteinase [MMP-2 and -9], xanthine oxidase, squalene synthase, nitric oxide synthase, human aldose reductase, and lipoxygenase)Moreover, docking studies and binding free energy calculations revealed that phytic acid exhibited the maximum binding energy for four target enzymes such as COX-2, mPGES-2, tyrosinase, and HNE; however, for other six target enzymes, it fails to dock. Abbreviations used: COX-2: Cyclooxygenase-2, mPGES-2: Microsomal prostaglandin E synthase-2, HNE: Human neutrophil elastase, MMP-2 and -9: Matrix metalloproteinase-2 and -9, XO: Xanthine oxidase, SQS: Squalene synthase, NOS: Nitric oxide synthase, HAR: Human aldose reductase, LOX: Lipoxygenase, ADME: Absorption, distribution, metabolism, and excretion, TOPKAT: Toxicity Prediction by Computer-assisted Technology., Competing Interests: There are no conflicts of interest.

Background: Clinacanthus nutans (Burm. f.) Lindau has gained popularity among Malaysians as a traditional plant for anti-inflammatory activity., Objective: This prompted us to carry out the present study on a selected 11 constituents of C. nutans which are clinacoside A-C, cycloclinacoside A1, shaftoside, vitexin, orientin, isovitexin, isoorientin, lupeol and β-sitosterol., Materials and Methods: Selected 11 constituents of C. nutans were evaluated on the docking behavior of xanthine oxidase (XO), nitric oxide synthase (NOS), human neutrophil elastase (HNE), matrix metalloproteinase (MMP 2 and 9), and squalene synthase (SQS) using Discovery Studio Version 3.1. Also, molecular physicochemical, bioactivity, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and toxicity prediction by computer assisted technology analyzes were also carried out., Results: The molecular physicochemical analysis revealed that four ligands, namely clinacoside A-C and cycloclinacoside A1 showed nil violations and complied with Lipinski's rule of five. As for the analysis of bioactivity, all the 11 selected constituents of C. nutans exhibited active score (>0) toward enzyme inhibitors descriptor. ADMET analysis showed that the ligands except orientin and isoorientin were predicted to have Cytochrome P4502D6 inhibition effect. Docking studies and binding free energy calculations revealed that clinacoside B exhibited the least binding energy for the target enzymes except for XO and SQS. Isovitexin and isoorientin showed the potentials in the docking and binding with all of the six targeted enzymes, whereas vitexin and orientin docked and bound with only NOS and HNE., Conclusion: This present study has paved a new insight in understanding these 11 C. nutans ligands as potential inhibitors against XO, NOS, HNE, MMP 2, MMP 9, and SQS., Summary: Isovitexin and isoorientin (Clinacanthus nutans constituent) showed potentials in the docking and binding with all of the six targeted enzymes (xanthine oxidase [XO], nitric oxide synthase [NOS], human neutrophil elastase [HNE], matrix metalloproteinase [MMP 2 and 9], and squalene synthase [SQS])Moreover, clinacoside B (C. nutans constituent) exhibited the least binding energy for the target enzymes except for XO and SQSInterestingly, all of the selected ligands from C. nutans showed the potential to dock and bind with HNE. Abbreviations used: C. nutans: Clinacanthus nutans, XO: Xanthine oxidase, NOS: Nitric oxide synthase, HNE: Human neutrophil elastase, MMP: Matrix metalloproteinase, SQS: Squalene synthase, ADMET: Absorption, Distribution, Metabolism, Excretion, and Toxicity, TOPKAT: Toxicity prediction by the computer assisted technology.

Purpose: In recent year's anti-angiogenesis agents have been recognized as effective drugs for the treatment of solid tumors, this prompted us to conduct the present study., Methods: The anti-angiogenic activity of dimeric form of embelin (vilangin) was evaluated using endothelial cell (in vitro) and chorioallantoic membrane (CAM) egg yolk angiogenesis model (in vivo) and in addition the docking behaviour of human nitric oxide synthases (NOS) with four different ligands was evaluated along with their putative binding sites using Discovery Studio Version 3.1 (in silico) compared with the parent compound (embelin)., Results: Vilangin exhibits 50% cytotoxic at 92 ± 1 µg/ml concentration level with reference to ECV 304 endothelial cells. Both vilangin and embelin, showed inhibitory effects on wound healing, single cell migration, nitric oxide production, and endothelial ring formation at 0.1 and 1.0 µg/ml concentration level. Similarly, CAM assay also showed inhibitory effect of vilangin and embelin with respect their reduction in length, size and junctions of blood capillaries compared to untreated egg yolk. Docking studies and binding free energy calculations revealed that vilangin has maximum interaction energy (-74.6 kcal/mol) as compared to the other investigated ligands., Conclusion: The results suggest that both vilangin and embelin attenuates angiogenesis in similar manner.

A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-γ)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 ± 0.2 µM), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 ± 0.3 µM and 9.6 ± 0.5 µM, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta- and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.

A series of novel isoxazole and pyrazoline derivatives has been synthesized and evaluated for their effects on the chemiluminescence and chemotactic activity of human phagocytes. Their effects on the chemotactic migration of isolated polymorphonuclear leukocytes (PMNs) and on the release of reactive oxygen species (ROS) during respiratory burst of human whole blood and PMNs were carried out using the Boyden chamber technique and luminol-based chemiluminescence assay, respectively. Of the compounds tested, compounds 8, 9, 11 and 12 exhibited higher inhibitory activity on the release of ROS (with IC50 values ranging from 5.6 to 8.4 μM) than acetylsalicylic acid (IC50 = 9.5 μ M). These compounds also showed strong inhibitory activity on the migration of PMNs with compound 8 exhibiting an IC50 value lower than that of ibuprofen. The results suggest that some of these isoxazole and pyrazoline derivatives have ability to modulate the innate immune response of phagocytes at different steps, indicating their potential as a source of new immunomodulatory agents.