0000000000207866
AUTHOR
Alexander D. Crawford
Fishing anti-inflammatories from known drugs: In silico repurposing, design, synthesis and biological evaluation of bisacodyl analogues
Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several bi…
Discovery of novel anti-inflammatory drug-like compounds by aligning in silico and in vivo screening: The nitroindazolinone chemotype
In this report, we propose the combination of computational methods and in vivo primary screening in zebrafish larvae and confirmatory in mice models as a novel strategy to accelerate anti-inflammatory drug discovery. Initially, a database of 1213 organic chemicals with great structural variability - 587 of them anti-inflammatory agents plus 626 compounds with other clinical uses - was divided into training and test groups. Atom-based quadratic indices - a TOMOCOMD-CARDD molecular descriptors family - and linear discriminant analysis (LDA) were used to develop a total of 13 models to describe the anti-inflammatory activity. The best model (Eq. (13)) shows an accuracy of 87.70% in the traini…
Anti-Inflammatory Activity and Cheminformatics Analysis of New Poten t 2-Substituted 1-Methyl-5-Nitroindazolinones.
After the identification of the anti-inflammatory properties of VA5-13l (2-benzyl-1- methyl-5-nitroindazolinone) in previous investigations, some of its analogous compounds were designed, synthesized and evaluated in two anti-inflammatory methods: LPS-enhanced leukocyte migration assay in zebrafish; and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. The products evaluated (3, 6, 8, 9 and 10) showed the lower values of relative leukocyte migration at 30#181;M (0.14, 0.07, 0.10, 0.13 and 0.07, respectively), while in ear edema and myeloperoxidase activity methods, all the compounds reduced inflammation, only 4 and 16 yielded unsatisfactory results. The relationship linkin…
<strong>In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues</strong>
In a recent article was described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative.