RESUMO
Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates.
RESUMO
Benzothiazinones (BTZs) have widely inspired medicinal chemistry and translational research due to their remarkable antitubercular potency and clinical potential. While most structure-activity relationship campaigns have largely focused on lateral chain modifications and substituents on the BTZ core, scaffold hopping strategies have been rarely investigated previously. In this work, we report the first example of ring expansion of the BTZ core toward benzofuran- and naphthalene-fused thiazinones. In vitro testing showed micromolar activity for both compounds, and molecular docking simulations provided insights into their reduced inhibitory capacity toward the enzymatic target (DprE1). Calculated electrochemical potentials revealed a lower susceptibility to reduction as opposed to BTZ drug candidates, in line with the mechanistic requirement for covalent binding.
Assuntos
Benzofuranos , Mycobacterium tuberculosis , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Antituberculosos/farmacologia , Antituberculosos/química , Benzofuranos/farmacologia , Naftalenos/farmacologiaRESUMO
Nitrobenzothiazinones (BTZs) are a very potent class of antibiotics against Mycobacterium tuberculosis. However, relationships between their structural properties and whole cell activity remain poorly predictable. Herein, we present the synthesis and antimycobacterial evaluation of a diverse set of BTZs. High potency was predominantly achieved by piperidine and piperazine substitutions, whereupon three compounds were identified as promising candidates, showing preferable metabolic stability. Lack of correlation between potency and calculated binding energies suggested that target inhibition is not the only requirement to obtain suitable antimycobacterial agents. In contrast, prediction of whole cell activity class was successfully accomplished by extensively validated machine learning models. The performance of the superior model was further verified by >70% correct class predictions for a large set of reported BTZs. Our generated model is thus a key prerequisite to streamline lead optimization endeavors, particularly regarding the improvement of overall hit rates in whole cell antimycobacterial assays.
Assuntos
Antituberculosos , Mycobacterium tuberculosis , Antituberculosos/química , Testes de Sensibilidade MicrobianaRESUMO
Here, we applied and optimized a solid support (SP)-based Horner-Wadsworth-Emmons reagent to prepare SP-bound vinylogous amino acids. Subsequent SP-based peptide synthesis, global deprotection, and chemical modifications yielded 14 lipodipeptides carrying vinylogous amino acids, including the natural product barnesin A (1). Biological evaluation revealed that several synthesized derivatives show micromolar to nanomolar inhibitory activity against papain-like cysteine proteases, human cathepsin L, and rhodesain.
Assuntos
Antiprotozoários/síntese química , Cisteína Endopeptidases/química , Antiprotozoários/química , Técnicas de Química Sintética , Humanos , Estrutura Molecular , Técnicas de Síntese em Fase SólidaRESUMO
Despite the wealth of physiological knowledge and plentiful genomes available, only few natural products of anaerobic bacteria have been identified until today and even less have been linked to their biosynthetic gene cluster. Here, we analyzed a unique NRPS-PKS hybrid gene cluster from an anaerobic Epsilonproteobacterium ( Sulfurospirillum barnesii). Phylogenetic analysis of key biosynthetic genes, gene expression studies, and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite: a lipo-dipeptide with a vinylogous side chain, called barnesin A. The absolute structure was verified by a modular total synthesis, and barnesin and derivatives were found to have antimicrobial activity, as well as selective and nanomolar inhibitory activity, against pharmacological important cysteine proteases, such as cathepsin B.