Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2 H-Indazole Derivatives

Abstract

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan's cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.

Keywords: Entamoeba histolytica; Giardia intestinalis; Trichomonas vaginalis; indazole; structure-activity relationships.

Scheme 1

Synthesis of the 2-phenylindazole derivatives. Reagents and conditions: (a) 1. R¹C₆H₄NH₂, ultrasound, 40 °C, neat, 2. P(OEt)₃, reflux; (b) BBr₃, CH₂Cl₂, 0 °C; (c) 1. NaOH, H₂O, reflux, 2. HCl; (d) HCl, MeOH, MW.

Figure 1

Principally SAR features derived from the 2-phenyl-2H-indazole derivatives tested.

Figure 2

Property space and activity range for 2-phenyl-2H-indazole derivatives (1–22) synthesized in this work (yellow), a collection of antiprotozoal 1H-benzimidazole derivatives (blue) and ChEMBL collection of antiprotozoals (gray). The two principal components taken together account for 75.34, 72.44 and 75.71% of the variance for E. histolytica, G. intestinalis, and T. vaginalis, respectively.

Figure 3

Structure-Activity Similarity Maps using Molecular ACCess System keys (MACCS) and Extended Connectivity Fingerprint (ECFP) divided by thresholds in structure similarity and activity differences in regions I–IV. Each data point indicates a pairwise comparison of the 22 synthesized 2-phenyl-2H-indazole derivatives (231 datapoints in yellow, A–F) and 111 benzimidazoles tested against E. histolytica (6105 datapoints in blue, A,B), 159 benzimidazoles tested against G. intestinalis (12,561 datapoints in blue, C,D), and 134 benzimidazoles tested against T. vaginalis (8911 datapoints in blue, E,F).

Figure 4

General form of the structure–activity similarity (SAS) maps showing four major regions.