In silico studies, sonochemical synthesis and biological evaluation of 4-substituted pyrimido[1,2- b ]indazoles

Based on the known link of inflammation with the diseases (especially cancer) for which pyrimido[1,2- b ]indazoles have been explored previously, the anti-inflammatory potential of this class of compounds were assessed in the current study. Initially, the feasibility of this idea was examined with the help of in silico docking studies using TNF-α as the target protein. Indeed, some of the pyrimido[1,2- b ]indazoles tested emerged as possible inhibitors of TNF-α in this study. The sonochemical synthesis of targeted 4-substituted pyrimido[1,2- b ]indazoles was carried out via the 3-component reaction of 3-amino-1 H -indazole with a terminal alkyne and formaldehyde in the presence of TfOH in AcOH under open air. The method afforded a variety of desired products and appeared to be selective for the 4-substituted derivatives. The method seemed to be an atom efficient process as except water no other by-products were formed during the transformation. The scalable potential of the methodology was also demonstrated. When tested in vitro some of the synthesized compounds e.g. 3b, 3c, 3i etc. showed encouraging inhibition of TNF-α. Indeed, these molecules showed good interactions (including H-bonding with TYR151 etc.) with the protein in silico with the docking score in the range -97 to -91 kcal/mol. The current study also helped in obtaining an overview of the SAR within the series and in silico ADME/toxicity prediction for best active compounds. Being identified as an initial hit, the compound 3i is of further pharmacological interest.