Design and Synthesis of Potential Read-Through Compounds

Nonsense mutations substitute a regular amino acid codon by a premature termination codon (PTC). mRNAs bearing PTCs typically form defective truncated proteins, resulting in severe forms of disease1. Small molecules can induce read-through of PTCs, which allows translation of functional full-length protein2. In an effort to develop novel read-through drugs, we synthesized a library of 5-thio-1,2,4-triazoles (5-10) and 2-thio-benzimidazoles (13)3. Condensation followed by cyclization of hydrazides 1 and isothiocyanates 2 gave 1,2,4-triazole-3-thiols 3 in moderate to excellent yields. Next, 3 was alkylated with the corresponding halide 4 to obtain the final products 5a-u, 6a-m, 7a-i, 8, 9 and 10. Additionally, we performed alkylation of benzimidazole-2-thiols 11 and 12 to give 13a-c in excellent yields. The activity of these compounds was assessed through in vitro toxicity screens using HEK-293T cells, and % of cell viability was used to determine activity. SAR results are described below.