Indole Schiff Base Complex: Synthesis and Optical Binding Investigation with Biogenic Amines.

Biogenic amines, produced by bacterial enzymatic reactions in food storage or processing, serve as indicators in food processing industries to assess food quality and freshness. Biogenic amines also often associated with various health problems, including abnormal immune responses and gastrointestinal disease. Previously, salphen base complexes have been reported but still exhibited low fluorescence enhancement upon biogenic amines. This research focused on synthesizing and characterizing new Zn(II) Schiff base complex with indole sidechain to enhance the fluorescence property and exploring their binding behaviour with the biogenic amines, which were phenylethylamine and cadaverine. The Zn(II) indole Schiff base complex's structure was verified by diverse spectroscopic techniques. Then, the binding behaviours between the Zn(II) indole Schiff base complex with the biogenic amines were analyzed using UV-Vis, fluorescence spectroscopy, and Job's plot analysis. UV-Vis binding study results indicated that the synthesized complexes could bind stronger with phenylethylamine than cadaverine, with binding constant, Kb= (8.21 ± 0.58) × 104 M- 1 and (2.506 ± 0.004) × 104 M- 1 respectively. Moreover, Zn(II) indole Schiff base complex-phenylethylamine binding also generated higher fluorescence enhancement than cadaverine, which were 54% and 51% respectively. Based on Job's plot analysis, the complex and biogenic amines were bound in the ratio of 1:1. To conclude, the synthesized complex has promising potential as a sensing material for biogenic amines detection in food. The complex is recommended to be deployed in the development of solid-state fluorescence sensor for biogenic amines detection for monitoring the food spoilage in the food industry in the future.

Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-ß/Smad2/3 pathway.

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-ß production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-ß inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1ß and p53, which accounts for the suppression of TGF-ß production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-ß/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.

Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes.

BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood. METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR. RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/ß-catenin and KRAS signalling pathways were upregulated while the TGF-ß signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV. CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC, a Novel Diarylpentanoid Analogue, in Mice Model.

The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC's antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC's antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway, without any potential sedative or muscle relaxant concerns.

Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer.

In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity of diarylpentanoids. Among the evaluated analogs, 8 has been identified as the lead compound due to its highest chemotherapeutic index of 9.9 and nano molar scale cytotoxicity against SW620 and RKO. Colonies formation and cell cycle analyses on 8-treated RKO cells showed that 8 exhibits strong anti-proliferative activity by inducing G2/M-phase cell arrest. Subsequent flow cytometry based annexin-V and DCFHDA studies suggested that 8 could induce apoptosis through intracellular ROS-dependent pathway. Further Western blot studies confirmed that 8 has induced intrinsic apoptosis in RKO cells through the up-regulations of Bad and Bax pro-apoptotic proteins and down-regulations of Bcl-2 and Bcl-xL pro-survival proteins. In all, the present results suggest that 8 could be a potent lead which deserves further modification and investigation in the development of small molecule-based anti-colorectal cancer agents.

Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis.

A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.

In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells.

In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.

Anti-Edematogenic and Anti-Granuloma Activity of a Synthetic Curcuminoid Analog, 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one, in Mouse Models of Inflammation.

Curcumin, derived from the rhizome Curcuma longa, has been scientifically proven to possess anti-inflammatory activity but is of limited clinical and veterinary use owing to its low bioavailability and poor solubility. Hence, analogs of curcuminoids with improved biological properties have been synthesized to overcome these limitations. This study aims to provide the pharmacological basis for the use of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a synthetic curcuminoid analog, as an anti-edematogenic and anti-granuloma agent. The carrageenan-induced paw edema and the cotton pellet-induced granuloma assays were used to assess the anti-inflammatory activity of DHHPD in mice. The effects of DHHPD on the histaminergic, serotonergic, and bradykininergic systems were determined by the histamine-, serotonin-, and bradykinin-induced paw edema tests, respectively. DHHPD (0.1, 0.3, 1, and 3 mg/kg, intraperitoneal) evoked significant reductions (p < 0.05) in carrageenan-induced paw edema at different time intervals and granuloma formation (p < 0.0001) by 22.08, 32.57, 37.20, and 49.25%, respectively. Furthermore, DHHPD significantly reduced paw edema (p < 0.05) induced by histamine, serotonin, and bradykinin. The present study suggests that DHHPD exerts anti-edematogenic activity, possibly by inhibiting the synthesis or release of autacoid mediators of inflammation through the histaminergic, serotonergic, and bradykininergic systems. The anti-granuloma effect may be attributed to the suppression of transudative, exudative, and proliferative activities associated with inflammation.

In vitro and in silico evaluations of diarylpentanoid series as α-glucosidase inhibitor.

A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor.

Analgesic Effect of 5-(3,4-Dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one in Experimental Animal Models of Nociception.

Curcuminoids derived from turmeric rhizome have been reported to exhibit antinociceptive, antioxidant and anti-inflammatory activities. We evaluated the peripheral and central antinociceptive activities of 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), a novel synthetic curcuminoid analogue at 0.1, 0.3, 1 and 3 mg/kg (intraperitoneal), through chemical and thermal models of nociception. The effects of DHHPD on the vanilloid and glutamatergic systems were evaluated through the capsaicin- and glutamate-induced paw licking tests. Results showed that DHHPD significantly (p < 0.05) attenuated the writhing response produced by the 0.8% acetic acid injection. In addition, 1 and 3 mg/kg of DHHPD significantly (p < 0.05) reduced the licking time spent by each mouse in both phases of the 2.5% formalin test and increased the response latency of mice on the hot-plate. However, the effect produced in the latter was not reversed by naloxone, a non-selective opioid receptor antagonist. Despite this, DHHPD decreased the licking latency of mice in the capsaicin- and glutamate-induced paw licking tests in a dose response manner. In conclusion, DHHPD showed excellent peripheral and central antinociceptive activities possibly by attenuation of the synthesis and/or release of pro-inflammatory mediators in addition to modulation of the vanilloid and glutamatergic systems without an apparent effect on the opioidergic system.

Zebrafish phenotypic screen identifies novel Notch antagonists.

Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27KIP1. Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines.

The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01µM and 8c, IC50=4.86µM) and U937 (8b, IC50=3.44µM and 8c, IC50=1.65µM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78µM and 15b, IC50=1.9µM while U937: 15a, IC50=0.95µM and 15b, IC50=0.92µM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-ß, ERK, JNK2, p38α and p38ß were performed using the conformation of 15a determined by single-crystal XRD.

2-Benzoyl-6-benzylidenecyclohexanone analogs as potent dual inhibitors of acetylcholinesterase and butyrylcholinesterase.

In the present study, a series of 2-benzoyl-6-benzylidenecyclohexanone analogs have been synthesized and evaluated for their anti-cholinesterase activity. Among the forty-one analogs, four compounds (38, 39, 40 and 41) have been identified as lead compounds due to their highest inhibition on both AChE and BChE activities. Compounds 39 and 40 in particular exhibited highest inhibition on both AChE and BChE with IC50 values of 1.6µM and 0.6µM, respectively. Further structure-activity relationship study suggested that presence of a long-chain heterocyclic in one of the rings played a critical role in the dual enzymes' inhibition. The Lineweaver-Burk plots and docking results suggest that both compounds could simultaneously bind to the PAS and CAS regions of the enzyme. ADMET analysis further confirmed the therapeutic potential of both compounds based upon their high BBB-penetrating. Thus, 2-benzoyl-6-benzylidenecyclohexanone containing long-chain heterocyclic amine analogs represent a new class of cholinesterase inhibitor, which deserve further investigation for their development into therapeutic agents for cognitive diseases such as Alzheimer.

Nitric oxide inhibitory activity and antioxidant evaluations of 2-benzoyl-6-benzylidenecyclohexanone analogs, a novel series of curcuminoid and diarylpentanoid derivatives.

A series of twenty-four 2-benzoyl-6-benzylidenecyclohexanone analogs were synthesized and evaluated for their nitric oxide inhibition and antioxidant activity. Six compounds (3, 8, 10, 17, 18 and 19) were found to exhibit significant NO inhibitory activity in LPS/IFN-induced RAW 264.7 macrophages, of which compound 10 demonstrated the highest activity with the IC50 value of 4.2 ± 0.2 µM. Furthermore, two compounds (10 and 17) displayed antioxidant activity upon both the DPPH scavenging and FRAP analyses. However, none of the 2-benzoyl-6-benzylidenecyclohexanone analogs significantly scavenged NO radical. Structure-activity comparison suggested that 3,4-dihydroxylphenyl ring is crucial for bioactivities of the 2-benzoyl-6-benzylidenecyclohexanone analogs. The results from this study and the reports from previous studies indicated that compound 10 could be a candidate for further investigation on its potential as a new anti-inflammatory agent.

Synthesis and sar study of diarylpentanoid analogues as new anti-inflammatory agents.

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.

Homoharringtonine promotes non-small-cell lung cancer cell death via modulating HIF-1α/ERß/E2F1 feedforward loop.

OBJECTIVES: Hypoxia conditions promote the adaptation and progression of non-small-cell lung cancer (NSCLC) via hypoxia-inducible factors (HIF). HIF-1α may regulate estrogen receptor ß (ERß) and promote the progression of NSCLC. The phytochemical homoharringtonine (HHT) exerts strong inhibitory potency on NSCLC, with molecular mechanism under hypoxia being elusive. METHODS: The effects of HHT on NSCLC growth were determined by cell viability assay, colony formation, flow cytometry, and H460 xenograft models. Western blotting, molecular docking program, site-directed mutagenesis assay, immunohistochemical assay, and immunofluorescence assay were performed to explore the underlying mechanisms of HHT-induced growth inhibition in NSCLC. KEY FINDINGS: HIF-1α/ERß signaling-related E2F1 is highly expressed and contributes to unfavorable survival and tumor growth. The findings in hypoxic cells, HIF-1α overexpressing cells, as well as ERß- or E2F1-overexpressed and knockdown cells suggest that the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC cell growth. HHT suppresses HIF-1α/ERß/E2F1 signaling via the ubiquitin-proteasome pathway, which is dependent on the inhibition of the protein expression of HIF-1α and ERß. Molecular docking and site-directed mutagenesis revealed that HHT binds to the GLU305 site of ERß. HHT inhibits cell proliferation and colony formation and promotes apoptosis in both NSCLC cells and xenograft models. CONCLUSION: The formation of the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.

Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages.

Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.

A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer.

Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 µM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 µM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.

[Box: see text].

Preliminary insight on diarylpentanoids as potential antimalarials: In silico, in vitro pLDH and in vivo zebrafish toxicity assessment.

Malaria remains a major public health problem worldwide, including in Southeast Asia. Chemotherapeutic agents such as chloroquine (CQ) are effective, but problems with drug resistance and toxicity have necessitated a continuous search for new effective antimalarial agents. Here we report on a virtual screening of ∼300 diarylpentanoids and derivatives, in search of potential Plasmodium falciparum lactate dehydrogenase (PfLDH) inhibitors with acceptable drug-like properties. Several molecules with binding affinities comparable to CQ were chosen for in vitro validation of antimalarial efficacy. Among them, MS33A, MS33C and MS34C are the most promising against CQ-sensitive (3D7) with EC50 values of 1.6, 2.5 and 3.1 µM, respectively. Meanwhile, MS87 (EC50 of 1.85 µM) shown the most active against the CQ-resistant Gombak A strain, and MS33A and MS33C the most effective P. knowlesi inhibitors (EC50 of 3.6 and 5.1 µM, respectively). The in vitro cytotoxicity of selected diarylpentanoids (MS33A, MS33C, MS34C and MS87) was tested on Vero mammalian cells to evaluate parasite selectivity (SI), showing moderate to low cytotoxicity (CC50 > 82 µM). In addition, MS87 exhibited a high SI and the lowest resistance index (RI), suggesting that MS87 may exert effective parasite inhibition with low resistance potential in the CQ-resistant P. falciparum strain. Furthermore, the in vivo toxicity of the molecules on early embryonic development, the cardiovascular system, heart rate, motor activity and apoptosis were assessed in a zebrafish animal model. The overall results indicate the preliminary potential of diarylpentanoids, which need further investigation for their development as new antimalarial agents.

Discovery of a novel dual functional phenylpyrazole-styryl hybrid that induces apoptotic and autophagic cell death in bladder cancer cells.

Unpleasant side effects and resistance development remained the Achilles heel of chemotherapy. Since low tumor-selectivity and monotonous effect of chemotherapy are closely related to such bottleneck, targeting tumor-selective multi-functional anticancer agents may be an ideal strategy in the search of new safer drugs. Herein, we report the discovery of compound 21, a nitro-substituted 1,5-diphenyl-3-styryl-1H-pyrazole that possesses dual functional characteristics. The 2D- and 3D-culture-based studies revealed that 21 not only could induce ROS-independent apoptotic and EGFR/AKT/mTOR-mediated autophagic cell deaths in EJ28 cells simultaneously but also has the ability in inducing cell death at both proliferating and quiescent zones of EJ28 spheroids. The molecular modelling analysis showed that 21 possesses EGFR targeting capability as it forms stable interactions in the EGFR active site. Together with its good safety profile in the zebrafish-based model, the present study showed that 21 is promising and may lead to the discovery of tumor-selective multi-functional anti-cancer agents.