Revisiting aryl amidine synthesis using metal amide and/or ammonia gas: Novel molecules and their biological evaluation

ABSTRACT

Amidines, due to their unique biocompatibility and desirable physical characteristics, have been the functionality of choice as a scaffold for large number of drug synthesis. But still synthesis of amidines in the presence of other active functional groups or pharmacophore, remained a challenge. In this work, a simple and reliable protocol for conversion of nitrile-amide to unsubstituted amidine–amide is developed using metal amide and/or ammonia gas. The scope and efficiency of this synthetic strategy are demonstrated on several substrates which differ in functional groups will be discussed. In this process, 10 novel aryl amidines in good yields (upto 85%) were synthesized. Biological evaluation revealed that compound 4-(aminoiminomethyl)-N-(2-furanyl methyl) benzamide (IC₅₀ = 9 µM) and 4-(aminoiminomethyl)-N-(3-pyridinylmethyl) benzamide (73.36% growth inhibition) showed moderate efficacy for cancer cells.

GRAPHICAL ABSTRACT

KEYWORDS:

• Amide
• amidine
• antiproliferative activity
• NCI
• single crystal

Acknowledgment

PSG thank Department of Science and Technology, New Delhi (SR/S1/IC-43/2009) for financial support. IIS thanks JRF and SRF to DST-project and UGC-BSR fellowship. We would like to thank Dr. Hemant Mande for single crystal X-ray study. The authors also thank the DST-PURSE Single Crystal X-ray Diffraction facility at the Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara. The authors thank the NCI for evaluating compounds 7b–d and 7g in the NCI’s Developmental Therapeutics Program (DTP) in vitro cell line screening.

Supplementary data

Supplementary data (experimental procedures and full spectroscopic data for all new compounds) associated with this article can be found, in the online version. CCDC 1432792 (7j) contains the supplementary crystallographic data for this paper. These data can be obtained from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.

Conflict of interest

The authors declare no conflict of interest.