An efficient Cu catalyzed regioselective Ortho-nitration approach for the synthesis of 2-nitroarylcyanamides: Molecular docking and ADME studies

• An efficient Cu(II) promoted regio-selective protocol for the selective ortho -nitration of diverse arylcycnamides has been described. • A simple, non- toxic, inexpensive and readily available CuCl 2 .2H 2 O and iron(III) nitrate are used as Cu catalyst and nitro source. • All the reactions are general, clean and efficient with excellent substrate tolerance, gave the products in good to excellent yields. • The 2-nitroarylcyanamides prepared were investigated as Cathepsin K and AChBP inhibitors by in silico molecular docking and the ADME predictions suggest a generally favorable pharmacokinetic profile for all the top compounds. Copper catalyzed regio-selective organic functional group insertions have been developed as a prevailing tool in organic synthesis. In this work, we report a regio-selective ortho -nitration of C−H bond of aryl cyanamides with Cu(II)-catalyst beneath mild reaction conditions exploiting inexpensive iron(III) nitrate as a nitration source. A series of arylcycnamides with electron-releasing and electron withdrawing substituents were readily nitrated with admirable regio-selectivity and generated the products in modest to superior yields. Mechanistic studies validated the absence of a free radical mechanism in this protocol. The developed technique is practically verified for gram scale prodcution. Further, we investigated the interactions of the obtained 2-nitroarylcyanamides with Cathepsin K and AChBP proteins by molecular docking. The cyanamides 2h, 2i, and 2j showed good interaction with the active site pocket of Cathepsin K, where as the cyanamides 2a, 2b, 2c, and 2i exhibited good interactions with in the active site pocket of AChBP . In the present in silico study, the docking simulation of the prepared cynamide compounds revealed that overall compounds exhibited consistently better binding affinity and interaction profiles with AchBP compared to Cathepsin K. The cyanamide 2i displayed better binding affinity with both the Cathepsin K and AchBP targets. Moreover, the metabolism, physico-chemical, and drug likeliness properties of the prepared compounds( 2a-n ) have been evaluated using ADME studies. Graphical abstract synopsis: Cu(II) catalyzed regioselective ortho -nitration of arylcycnamides has been demonstrated using inexpensive iron(III)nitrate as nitro source under mild reaction conditions. Different ortho -nitro arylcycnamides are obtained in good to excellent yields. In silico molecualr docking stuides were done to elucidate the structure based mechanistic insights with Cathepsin K and AChBP proteins. The in silico ADME studies were performed for the evaluation of physico-chemical, metabolism and drug likeliness properties of prepared compounds.