Dihydromaniwamycin E, a Heat-Shock Metabolite from Thermotolerant sp. JA74, Exhibiting Antiviral Activity against Influenza and SARS-CoV-2 Viruses.

Dihydromaniwamycin E (), a new maniwamycin derivative featuring an azoxy moiety, has been isolated from the culture extract of thermotolerant sp. JA74 along with the known analogue maniwamycin E (). Compound is produced only by cultivation of strain JA74 at 45 °C, and this type of compound has been previously designated a "heat shock metabolite (HSM)" by our research group. Compound is detected as a production-enhanced metabolite at high temperature. Structures of and are elucidated by NMR and MS spectroscopic analyses. The absolute structure of is determined after the total synthesis of four stereoisomers. Though the absolute structure of has been proposed to be the same as the structure of maniwamycin D, the NMR and the optical rotation value of are in agreement with those of maniwamycin E. Therefore, this study proposes a structural revision of maniwamycins D and E. Compounds and show inhibitory activity against the influenza (H1N1) virus infection of MDCK cells, demonstrating IC values of 25.7 and 63.2 μM, respectively. Notably, and display antiviral activity against SARS-CoV-2, the causative agent of COVID-19, when used to infect 293TA and VeroE6T cells, with and showing IC values (for infection of 293TA cells) of 19.7 and 9.7 μM, respectively. The two compounds do not exhibit cytotoxicity in these cell lines at those IC concentrations.