Small molecules can bind DNA and disrupt pathogenic protein-DNA interactions in vivo and modulate the transcription of genes in vitro. The inhibition of these processes can be important for minimizing disease symptoms, such as those experienced in myotonic dystrophy type I. FDA-approved drug pentamidine, a bisaryl-amidine, binds to the minor groove of DNA and has previously been used as a small molecule therapeutic to treat microbial infections. Pentamidine’s mechanism of action has prompted further investigations into its sequence specific small molecule interactions with nucleic acids. Towards this, a series of N-substituted pentamidine derivatives will be synthesized to increase noncovalent interactions between the aryl-amidine and DNA or RNA. Reported herein is the synthesis of a pentamidine derivative with the substituent group 3-(5-methylfuryl)propan-1-amine. Relative to pentamidine and select N-substituted derivatives, the N-substituted furyl pentamidine derivative showed an increase in binding energy when docked to a double-stranded DNA oligomer at an AATT sequence in silico. In the future, the ability of this derivative and others to bind DNA at sequence specific sites will be assayed.

Design and synthesis of a nucleotide-binding, sequence-specific furyl-substituted bisaryl-amidine

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