Synthesis and Biological Evaluation of 2H-Indazole Derivatives: Towards Antimicrobial and Anti-Inflammatory Dual Agents

Abstract

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 2<i>H</i>-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 <i>Giardia intestinalis</i>, <i>Entamoeba histolytica</i>, and <i>Trichomonas vaginalis</i>; the bacteria <i>Escherichia coli</i> and <i>Salmonella enterica</i> serovar Typhi; and the yeasts <i>Candida albicans</i> and <i>Candida glabrata</i>. Biological evaluations revealed that synthesized compounds have antiprotozoal activity and, in most cases, are more potent than the reference drug metronidazole, e.g., compound <b>18</b> is 12.8 times more active than metronidazole against <i>G. intestinalis</i>. Furthermore, two 2,3-diphenyl-2<i>H</i>-indazole derivatives (<b>18</b> and <b>23</b>) showed in vitro growth inhibition against <i>Candida albicans</i> and <i>Candida glabrata</i>. 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 <b>18</b>, <b>21</b>, <b>23</b>, and <b>26</b> display in vitro inhibitory activity against COX-2, whereas docking calculations suggest a similar binding mode as compared to rofecoxib, the crystallographic reference.