One-pot sonochemical synthesis and in silico/in vitro antitubercular evaluation of 1-methyl-3-propyl-1H-pyrazole containing polynuclear fused N-heteroarenes

A series of molecules containing the fragment based on 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide were explored as the potential inhibitors of chorismate mutase (or CM that plays an important role in the survival of bacteria). These molecules were evaluated in silico via their docking at the interface site of MtbCM (PDB: 2FP2). Prompted by the promising docking results the ultrasound assisted one-pot synthesis of target molecules i.e. 6-arylpyrazolo[4′,3′:4,5]pyrimido[2,1-a]isoquinolin-8(9H)-one derivatives were undertaken. The methodology involved Sonogashira coupling of 2-iodobenzaldehyde with a terminal alkyne to afford the 2-alkynylbenzaldehyde intermediate in situ that on Yb(III)-catalyzed sequential reaction with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide afforded the desired product in good to acceptable yield. To build a small library of compounds, a range of terminal alkynes as well as 2-iodobenzaldehydes were employed and the one-pot cascade reaction proceeded well in all these cases. The strategy was also used to prepare 6-aryl-8H-isoquinolino[1,2-b]quinazolin-8-ones. Three derivatives i.e. 4b, 4h and 4l that participated in good interaction with MtbCM (including a common H-bond with SER70) in silico with the docking score in the range -91 to -84 kcal/mol, exhibited encouraging (60–67%) inhibition at 10 µM in vitro. Further, a brief SAR within the series and in silico ADME prediction for best active compounds are presented. The compound 4l seemed to be of further interest form the view point of discovery and development of new anti-tubercular agents. 2009 Elsevier Ltd. All rights reserved.