(E)-2,3-Bis(4-methoxy­phen­yl)acrylic acid

In the title mol­ecule, C17H16O4, the angle between the aromatic ring planes is 69.1 (6)°. The crystal structure is stabilized by inter­molecular O—H⋯O hydrogen bonds; mol­ecules related by a centre of symmetry are linked to form inversion dimers

Design, synthesis, <i>in vitro</i> and <i>in vivo</i> biological evaluation of pterostilbene derivatives for anti-inflammation therapy

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 μM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.</p

Structure-activity relationship studies of tolfenpyrad reveal sub-nanomolar inhibitors of Haemonchus contortus development

Recently, we discovered that the registered pesticide, tolfenpyrad (TFP), unexpectedly and potently inhibits the development of L4 larval stages of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 µM while displaying good selectivity, with an IC50 of 37.9 µM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships (SAR) for this chemical. Modifications of the left hand side (LHS), right hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29 and 33 were shown to be the most potent compounds of the series, with IC50 values at a sub-nanomolar levels of potency against the chemotherapeutically-relevant fourth larval (L4) stages of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes such as hookworms and whipworms

Novel 1-methyl-1 H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity

A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1 H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms

Optimization of novel 1-methyl-1 h-pyrazole-5-carboxamides leads to high potency larval development inhibitors of the barber's pole worm

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC; 50; of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC; 50; of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM