Trichoxanes A and B: Molecular Networking-Guided Discovery of Cage-Like Sorbicillinoids as Mycobacterium tuberculosis GlmU Inhibitors

Abstract

Trichoxanes A (1) and B (2), two novel sorbicillinoids featuring a unique cage-like 2,7-dioxa-pentacyclo[7.4.0.03,8.05,13.06,10]tridecane scaffold, were isolated from Trichoderma reesei via a molecular networking strategy. Their structures were elucidated by spectroscopic analyses, CASE, DP4+ NMR calculations, and ECD analyses. Biosynthetically, a Diels–Alder reaction between botryenol and oxosorbicillinol, followed by cascade rearrangements, is proposed. Both compounds potently inhibited GlmU acetyltransferase, with IC50 values of 0.722 ± 0.043 μM (1) and 1.285 ± 0.074 μM (2). Compound 1 exhibited noncompetitive inhibition with respect to acetyl-CoA (Ki = 0.27 μM) and uncompetitive inhibition with respect to GlcN-1-P (Ki = 0.34 μM).