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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 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.

SUBMITTER: Perez-Villanueva J

PROVIDER: S-EPMC6150295 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Pérez-Villanueva Jaime J Yépez-Mulia Lilián L González-Sánchez Ignacio I Palacios-Espinosa Juan Francisco JF Soria-Arteche Olivia O Sainz-Espuñes Teresita Del Rosario TDR Cerbón Marco A MA Rodríguez-Villar Karen K Rodríguez-Vicente Ana Karina AK Cortés-Gines Miguel M Custodio-Galván Zeltzin Z Estrada-Castro Dante B DB

Molecules (Basel, Switzerland) 20171031 11

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 an ...[more]

PMID: 29088121

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Project description:Novel quinoxaline derivatives (2a-d, 3, 4a, 4b and 5-15) have been synthesized via the reaction of 4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (1) with different aldehydes, ketones, diketones, ketoesters, as well as hydrazine, phenyl isothiocyanate, carbon disulphide. The synthesized products have been screened for their in vitro anticancer and COX inhibitory activities. Most of the synthesized compounds exhibited good anticancer and COX-2 inhibitory activities. MTT assay revealed that compounds 11 and 13 were the most potent and exhibited very strong anticancer activity against the three cancer cell lines with IC50 values ranging from 0.81 μM to 2.91 μM. Compounds 4a and 5 come next and displayed strong anticancer activity against the three cancer cell lines with IC50 values ranging from 3.21 μM to 4.54 μM. Mechanistically, compounds 4a and 13 were the most active and potently inhibited EGFR with IC50 = 0.3 and 0.4 μM, respectively. Compounds 11 and 5 come next with IC50 = 0.6 and 0.9 μM, respectively. Moreover, compounds 11 and 13 were the most potent as COX-2 inhibitors and displayed higher potency against COX-2 (IC50 = 0.62 and 0.46 μM, respectively) more than COX-1 (IC50 = 37.96 and 30.41 μM, respectively) with selectivity indexes (SI) of 61.23 and 66.11, respectively. Compounds 4a and 5 comes next with IC50 = 1.17 and 0.83 μM and SI of 24.61 and 48.58, respectively. Molecular docking studies into the catalytic binding pocket of both protein receptors, EGFR and COX-2, showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and Veber's standard were calculated and revealed that compounds 4a, 5, 11 and 13 had a reasonable drug-likeness with acceptable physicochemical properties. Therefore, based on the obtained biological results accompanied with the docking study and physicochemical parameters, it could be concluded that compounds 4a, 5, 11 and 13 could be used as promising orally absorbed dual anti-inflammatory agents via inhibition of COX-2 enzyme and anticancer candidates via inhibition of EGFR enzyme and could be used as a future template for further investigations.

Dataset Information

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

Publications

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

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