Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents

Abstract

The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination, and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 μg ml−1) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired E. coli strain. These results provide validated leads for further optimization and development.

Synthesis and antibacterial evaluation of macrocyclic diarylheptanoid derivatives

“…The o - and m -fluorosubstituted derivatives 16 and 17 exhibited generally comparable antibacterial activity relative to the p -fluoro analog 15 . Notably, consistent with our previous finding, 19 the macrocyclic derivatives 19 and 22 with two basic nitrogen functionalities were largely inactive when tested at 100 μg/mL likely due to the decreased cellular membrane penetration. 25 Compound 32 bearing the methylpiperazine moiety showed weak antibacterial activity with MICs ranging from 50 to 100 μg/mL.…”

“…19 Antibacterial evaluation revealed that the N -substituted secondary amine derivatives ( 1 in Fig. 1) exhibited moderate antitubercular and antibacterial activities with minimum inhibitory concentrations (MIC) of 12.5-50 μg/mL.…”

“…1) exhibited moderate antitubercular and antibacterial activities with minimum inhibitory concentrations (MIC) of 12.5-50 μg/mL. 19 In this current study, we explore the further synthesis and optimization of N -substituted macrocyclic diarylheptanoids in an effort to obtain compounds with improved antibacterial properties. Specifically, an extended chemical library of macrocyclic amine derivatives 9-35 was synthesized to expand the scope of amine substrates.…”

“…Moreover, the free phenol macrocycles 34 and 35 showed weaker antibacterial activity compared to their corresponding methyl ether derivatives. 19 …”

The Synthesis of Macrocycles for Drug Discovery

“…This microwave process was employed as the key step in the construction of a small library of engelhardione analogues from which antibacterial activity was garnered. 94 More recently, conditions for this transformation have been studied in detail Figure 11.4 Representative macrocyclic structures from S N Ar chemistry.…”