Indazole is considered a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g., antimicrobial and anti-inflammatory agents. Considering that infectious diseases are associated to an inflammatory response, we designed a set of 2H-indazole derivatives by hybridization of cyclic systems commonly found in antimicrobial and anti-inflammatory compounds. The derivatives were synthesized and tested against selected intestinal and vaginal pathogens, including the protozoa Giardia intestinalis, Entamoeba histolytica, and Trichomonas vaginalis; the bacteria Escherichia coli and Salmonella enterica serovar Typhi; and the yeasts Candida albicans and Candida glabrata. Biological evaluations revealed that synthesized compounds have antiprotozoal activity and, in most cases, are more potent than the reference drug metronidazole, e.g., compound 18 is 12.8 times more active than metronidazole against G. intestinalis. Furthermore, two 2,3-diphenyl-2H-indazole derivatives (18 and 23) showed in vitro growth inhibition against Candida albicans and Candida glabrata. In addition to their antimicrobial activity, the anti-inflammatory potential for selected compounds was evaluated in silico and in vitro against human cyclooxygenase-2 (COX-2). The results showed that compounds 18, 21, 23, and 26 display in vitro inhibitory activity against COX-2, whereas docking calculations suggest a similar binding mode as compared to rofecoxib, the crystallographic reference.
In this work we report the synthesis and physical properties (thermal stability, diffraction patterns, and conductivity measurements) of a methacrylate-type polymer with zwitterionic pendant groups. The parent polymer, poly(sulfobutylbetaine of 12-ethyl-3,6,9-trioxa-12-azatetradec-1-yl 2-methylacrylate) (herein labeled PMBS-4) is used to prepare polymer/lithium salt complexes (PMBS-4/LiCl, PMBS-4/Li-triflate, and PMBS-4/LiClO 4 ). The resulting electrolyte polymers show mechanical properties akin to elastic solids. The glass transition temperature is close to 20 °C for all specimens, and PMBS-4/LiCl is thermally stable up to 187 °C. The conductivity of these materials varies with temperature, following an Arrhenius-like relationship. The conductivity of the solid polymer electrolytes, SPE, follows the order PMBS-4/LiClO 4 > PMBS-4/LiCl > PMBS-4/Li-triflate. The ionic conductivity of these materials is clearly affected by the anion of Li salt.
Activity cliffs have large impact in drug discovery; therefore, their detection and quantification are of major importance. This work introduces the metric activity cliff enrichment factor and expands the previously reported activity cliff generator concept by adding chemotype information to representations of the activity landscape. To exemplify these concepts, three molecular databases with multiple biological activities were characterized. Compounds in each database were grouped into chemotype classes. Then, pairwise comparisons of structure similarities and activity differences were calculated for each compound and used to construct chemotype-based structure-activity similarity (SAS) maps. Different landscape distributions among four major regions of the SAS maps were observed for different subsets of molecules grouped in chemotypes. Based on this observation, the activity cliff enrichment factor was calculated to numerically detect chemotypes enriched in activity cliffs. Several chemotype classes were detected having major proportion of activity cliffs than the entire database. In addition, some chemotype classes comprising compounds with smooth structure activity relationships (SAR) were detected. Finally, the activity cliff generator concept was applied to compounds grouped in chemotypes to extract valuable SAR information.
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