Novel 4‐((Benzimidazol‐2‐yl)methyl)‐resorcinol Derivatives as Potential Hsp90 Inhibitors: Synthesis and Initial Inhibition Evaluation

Human Hsp90 is a well-established target for cancer treatment, also showing promise for managing certain neurological disorders and infections. This study presents an efficient synthesis of Hsp90 inhibitors featuring resorcinol and benzimidazole moieties connected by a methylene bridge. The reaction time was significantly reduced by using microwave irradiation instead of conventional heating, addressing the instability of 4-[(benzimidazol-2-yl)methyl]-6-benzylresorcinols at higher temperatures. For the comparison, directly connected resorcinol-benzimidazole compounds were synthesized, resulting in 25 desirable compounds. The synthesized compounds were assessed for their binding affinity to human Hsp90. The results indicated a preference for the alpha isoform over the beta isoform. Only the compounds that included a linker between the benzimidazole and resorcinol moieties showed positive results. Among these, compounds without substituents on the benzimidazole and those containing fluorine exhibited the strongest binding affinity. Overall, the findings suggest that the molecular structure plays a crucial role in binding affinity, and expanding the variety of substituents on the molecular framework may enhance the specificity and affinity of Hsp90 inhibitors.