The Synthesis and Antimicrobial Activity of Heterocyclic Derivatives of Totarol

Abstract

The synthesis and antimicrobial activity heterocyclic analogs of the diterpenoid totarol are described. An advanced synthetic intermediate with a ketone on the A-ring is used to attach fused heterocycles and a carbon-to-nitrogen atom replacement is made on the B-ring by de novo synthesis. A-ring analogs with an indole attached exhibit, for the first time, enhanced antimicrobial activity relative to the parent natural product. Preliminary experiments demonstrate that the indole analogs do not target the bacterial cell division protein FtsZ as had been hypothesized for totarol.

FtsZ as an Antibacterial Target: Status and Guidelines for Progressing This Avenue

“…Aggregation was overcome by the addition of the detergent Triton X100, which then resulted in the complete loss of FtsZ GTPase activity. 72 The addition of Triton X100 is a standard procedure for commercial high throughput screening, suggesting that it should be incorporated into the 90°angle light scattering and polymerization sedimentation assays. 73 One caveat should be noted: Triton X100 and other mild detergents have been found to bind to tubulin (the eukaryotic homologue of FtsZ), modifying its structure and assembly.…”

“…This causes the protein to partially denature, leading to nonspecific inhibition, which consequently yields the observable inhibition of FtsZ function in those assays. , This was well documented for the natural product totarol, initially reported as an FtsZ inhibitor due to inhibition of FtsZ polymerization; it was later established that the compound was aggregating, yielding false-positive results. Aggregation was overcome by the addition of the detergent Triton X100, which then resulted in the complete loss of FtsZ GTPase activity . The addition of Triton X100 is a standard procedure for commercial high throughput screening, suggesting that it should be incorporated into the 90° angle light scattering and polymerization sedimentation assays .…”

The Current Status of the Pharmaceutical Potential of Juniperus L. Metabolites

“…It is the most abundant compound in the hexane extract of J. brevifolia bark (11 mg of compound by 100 mg of extract) [ 54 ], being also found in species from other genus [ 63 ]. This compound seems to be a good bet towards new interesting active drugs development since it displays a range of interesting bioactivities such as antibacterial [ 64 , 65 , 66 ], antimycobacterial [ 38 ], antileishmanial [ 36 ], antimalarial [ 67 , 68 ], antistaphylococcal activity caused by efflux inhibitory properties [ 69 ], as well as nematicidal activity and antifouling attributes [ 36 ]. Furthermore, totarol could also be used as activity enhancer of some conventional drugs [ 70 ].…”

Protease activated receptor-2 (PAR2): possible target of phytochemicals

“…It is established to act as antispasmodial, antifungal, and antimicrobial. There is not much information on the mechanism of its action; however, some evidence indicates that it inhibits membrane transport, disrupts phospholipid membranes, and also targets bacterial protein FtsZ (Kim et al, 2012). Piperine (trans-trans isomer of 1-piperoyl piperidine), which has shown promising free energy of ligand binding but relatively less Glide score (−9.592357), is the active principle and the main ingredient of black pepper.…”