Höfundar:
Goraksha Khose, Elvar Viktorsson
Introduction:
Tuberculosis (TB), caused by Mycobacterium tuberculosis is a global health problem and the WHO estimated 1.6 million deaths and 10.6 million new cases in 2021. Of main concern are multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. MDR-TB strains are resistant to the most effective first-line medications, such as isoniazid and rifampicin. MDR strains are among the top ten causes of death observed worldwide. Myxin is a natural product from the phenazine class of compounds and preliminary studies have revealed high potency in the nanomolar range against the target pathogen (H37Rv).
Methodology:
The primary aims were to synthesize four phenazine scaffolds derived from the phenazine natural product myxin. These scaffolds will then be developed further by aid of conventional structure-activity relationship studies (SAR) to impact factors like tuberculosis potency, mammalian cell line toxicity and aqueous solubility. This workflow ensures that the right derivatives will be chosen for further studies on resistant clinical isolates and expanded toxicity and teratogenicity studies in zebrafish models. Our synthesis is focused on providing biodegradable prodrug analogs of each scaffold with improved aqueous solubility.
Results:
At this point, 3 phenazine scaffolds have been successfully synthesized and characterized. Moreover, multiple derivatives of these scaffolds have been produced to obtain biological data from antimicrobial studies and cell-line toxicity studies that are currently ongoing.
Conclusions:
Three phenazine lead scaffolds have been successfully synthesized and multiple analogs of these scaffolds have been produced. Biological data on these new compounds are currently being produced.