Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine

Abstract

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.

Tailored therapeutic release from polycaprolactone-silica hybrids for the treatment of osteomyelitis: antibiotic rifampicin and osteogenic silicates

“…This result is in agreement with data from the literature. 72,73 In addition, they are consistent with our findings in terms of antibiotic release: PSRH is expected to release in αMEM a quantity of rifampicin (Fig. 10) with a detrimental effect on osteoblasts (Fig.…”

Clofazimine for the treatment of tuberculosis

“…Much effort has been dedicated to developing clofazimine derivatives with improved pharmacokinetic and toxicity profiles by targeting less lipophilic compounds, anticipated to cause less tissue accumulation and discolouration as well as improved oral bioavailability ( Jagannath et al, 1995 ; Reddy et al, 1996 ; van Rensburg et al, 2000 ; Kamal et al, 2005 ; Lu et al, 2011 ; Zhang et al, 2012b ; Li et al, 2012 ; Liu et al, 2012 ; Zhang et al, 2014 ; Xu et al, 2019 ; Bvumbi et al, 2021 ; Saravanan et al, 2021 ). An attempt has also been made to alter the intrinsic colour, but this required modifications to the phenazine core, which eliminated antituberculosis activity ( Liu et al, 2012 ).…”

Macrocycle-Antibiotic Hybrids: A Path to Clinical Candidates

“…Conjugation with polymyxins can not only extend activity against Gram-negative bacteria but also retain activity against resistance mechanism involving overexpression of efflux pumps as well (Negash et al, 2019). Various other hybrid chemical entities have also been reported, including polymyxin B3-tobramycin hybrids with Pseudomonas eruginosa-selective antibacterial activity and strong potentiation of rifampicin, minocycline, and vancomycin (Domalaon et al, 2017), azithromycin-benzoxaborole hybrid derivatives (Tevyashova et al, 2019), as well as antitubercular rifampicin and clofazimine hybrid (Saravanan et al, 2021). Very recently, design and synthesis of vitamin B12-antibiotic conjugates led to advanced candidates with >500-fold improved activity against Gram-negative bacteria including E. coli, relative to ampicillin, demonstrating that the vitamin B12 conjugate strategy is effective for enabling cellular uptake and antibiotic delivery, thus improving antibacterial efficacy (Zhao et al, 2020).…”