Abstract
The introductions of the bicyclic 4-nitroimidazole and the oxazolidinone classes of antimicrobial agents represented the most significant advancements in the infectious disease area during the past two decades. Pretomanid, a bicyclic 4-nitroimidazole, and linezolid, an oxazolidinone, are also part of a combination regimen approved recently by the US Food and Drug Administration for the treatment of pulmonary, extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) Mycobacterium tuberculosis (TB). To identify new antimicrobial agents with reduced propensity for the development of resistance, a series of dual-acting nitroimidazole-oxazolidinone conjugates were designed, synthesized and evaluated for their antimicrobial activity. Compounds in this conjugate series have shown synergistic activity against a panel of anaerobic bacteria, including those responsible for serious bacterial infections.
Highlights
Oxazolidinones, as represented by linezolid (1) and tedizolid (2), and bicyclic 4-nitroimidazoles, as represented by pretomanid (3) and delamanid (4), are two relatively new classes of antimicrobial agents (Figure 1)
Oxazolidinone ring and the acetamide group on the right side of the molecule are essential for the high resolution analysis of the of crystal structure of linezolid bound to the ribosomal subunit target interactions
The morpholino indicated that oxazolidinone ring to and the significant acetamide group on thewith rightthe side of the molecule are ring on the leftthe side does not appear have interactions binding site, which is essential for the target interactions
Summary
Oxazolidinones, as represented by linezolid (1) and tedizolid (2), and bicyclic 4-nitroimidazoles, as represented by pretomanid (3) and delamanid (4), are two relatively new classes of antimicrobial agents (Figure 1). The first oxazolidinone approved for clinical use, was introduced in 2000 for the treatment of Gram-positive bacterial infections, including those that are resistant to other classes of antibiotics [1]. This drug class inhibits bacterial protein synthesis by binding to rRNA on both the 30S and 50S ribosomal subunits and preventing the formation of a translation initiation complex. The first bicyclic 4-nitroimidazole, delamanid, was introduced in 2014 for the treatment of drug-resistant tuberculosis (TB) This drug class utilizes a deazaflavin-dependent nitroreductase (Ddn) to catalyze the bioreduction of the 4-nitroimidazole core, leading to the intracellular generation of reactive chemical. This drug class utilizes a deazaflavin-dependent nitroreductase (Ddn) catalyze the tobioreduction
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