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Riboswitches recently emerged as possible targets for the development of alternative antimicrobial approaches. Guanine-sensing riboswitches in the bacterial pathogen Clostridioides difficile (formerly known as Clostridium difficile) constitute potential targets based on their involvement in the regulation of basal metabolic control of purine compounds. In this study, we deciphered the structure-activity relationship of several guanine derivatives on the guanine riboswitch and determined their antimicrobial activity. We describe the synthesis of purine analogs modified in ring B as well as positions 2 and 6. Their biological activity was determined by measuring their affinity for the C. difficile guanine riboswitch and their inhibitory effect on bacterial growth, including a counter-screen to discriminate against riboswitch-independent antibacterial effects. Altogether, our results suggest that improvements in riboswitch binding affinity in vitro do not necessarily translate into improved antibacterial activity in bacteria, despite the fact that some structure-activity relationship was observed at least with respect to binding affinity.