The Discovery and Structure‐Activity Evaluation of (+)‐Floyocidin B and Synthetic Analogs

Abstract

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis.The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.

Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients

“…Antipseudomonal potency of darobactins B and B9 was assessed by broth microdilution assays with only minor modifications to previous reports ( 42 – 44 ). All compounds were dissolved in water and tested in triplicate.…”

Natural epoxyquinoids: isolation, biological activity and synthesis. An update

“…(+)-Floyocidins A, B and C were isolated from strain ST003901 from the Fraunhofer–Sanofi strain collection. 66 The structure of (+)-floyocidin B was unambiguously determined by total synthesis and single crystal X-ray diffraction analysis. (+)-Floyocidins A and B showed weak activity against the surrogate strain M. smegmatis with MIC values 32–64 μg mL −1 .…”

“…65 (+)-Floyocidins A, B and C were isolated from strain ST003901 from the Fraunhofer-Sanofi strain collection. 66 Fig. 12 Isolated natural products with premacrophorin core.…”

“…This journal is © The Royal Society of Chemistry 2023 4.2.5 Synthesis of (+)-floyocidin B. Floyocidin B isomers (Scheme 11) were synthesized by analogy with that mentioned above for (−)-avicennone C (see Section 4.2.4). 66 Diastereomers 50 and 51 were separated and converted into (+)-floyocidin B and compound 52, respectively. Total synthesis of (+)-floyocidin B was combined with single crystal X-ray diffraction analysis, which unambiguously determined its structure.…”

Total Synthesis of Floyocidin B: 4,5-Regioselective Functionalization of 2-Chloropyridines

“…Antimicrobially active (+)ambuic acid (1) [2] represents a prominent example, which inspired synthetic chemists to develop several total syntheses for this epoxyquinone (Figure 1) [3][4][5]. During a recent activityguided screening campaign for new antitubercular NPs, further natural epoxyquinone congeners such as (+)-floyocidin A (3) and B (4) were discovered (Figure 1) [6]. Similarly to the structurally related NP (−)-avicennone C (2), for which the relative stereochemistry was misassigned based on nuclear magnetic resonance (NMR) data [7,8], structure elucidation of (+)-floyocidin B (4) was only possible by total synthesis [6].…”