The rational design, development and synthesis of structurally diverse small molecule that target RNA is immensely important in antibacterial therapy. Utilizing rational design approach to drug discovery, two lead 4,5-disubstituted 2-oxazolidinone compounds that bind to the highly conserved region of bacterial RNA with high affinity and specificity had been previously identified. This biological target called the T box antiterminator system regulates the expression of many genes including aminoacyl synthethase genes and is found predominantly in Gram-positive pathogens.
But, owing to the moderate solubilities of these leads, the focus was directed to improving the solubility challenges without compromising biological activity. To address the solubility challenges with the intent of enhancing or maintaining biological activity, a library of one hundred eight 1,4-disubstituted 1,2,3-triazole compounds that encompasses the diversity elements of the oxazolidinones were developed. This library, which entailed the bioisosteric replacement of the oxazolidinone scaffold was afforded in high yield and purity by employing the regioselective copper(I)-catalyzed azide/alkyne cycloaddition reaction. Three lead compounds, GHB-7, GHB-9 and GHB-16 with enhanced biological activity were identified that rendered them important candidates for structural activity relationship studies (SAR). Besides the SAR studies, few 1,5-regioisomers were prepared to investigate the effect of regioselectivity on biological activity.
By embarking on empirical observations, thirty-two structurally relevant analogs were prepared for the SAR and other structural elaboration studies. While biological evaluation is currently ongoing, the preliminary data of the analogs, GHB-144, GHB-151, GHB-153, GHB-156 and GHB-157 coupled with the enhanced biological activity of GHB-7 relative to the lead oxazolidinone compounds re-inforce the plausibility of finding new 1,4-substituted 1,2,3-triazole compounds with improved antibacterial activity.