ProTides of N-(3-(5-(2′-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents

Abstract

The flavin-dependent thymidylate synthase X (ThyX), rare in eukaryotes and completely absent in humans, is crucial in the metabolism of thymidine (a DNA precursor) in many microorganisms including several human pathogens. Conserved in mycobacteria, including Mycobacterium leprae, and Mycobacterium tuberculosis, it represents a prospective anti-mycobacterial therapeutic target. In a M. tuberculosis ThyX-enzyme inhibition assay, N-(3-(5-(2'-deoxyuridine-5'-phosphate))prop-2-ynyl)octanamide was reported to be the most potent and selective 5-substituted 2'-deoxyuridine monophosphate analogue. In this study, we masked the two charges at the phosphate moiety of this compound using our ProTide technology in order to increase its lipophilicity and then allow permeation through the complex mycobacterial cell wall. A series of N-(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide phosphoroamidates were chemically synthesized and their biological activity as potential anti-tuberculars was evaluated. In addition to mycobacteria, several DNA viruses depend on ThyX for their DNA biosynthesis, thus these prodrugs were also screened for their antiviral properties.

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

“…In 2014 McGuigan et al applied the ProTide prodrug approach to this promising derivative, in order to enhance the drug-like characteristics of this compound [100]. This strategy consists in masking the negative charges on the monophosphate group by two lipophilic moieties: an amino acid ester and an aryloxy group [101].…”

“…A series of prodrugs of 29 was prepared. Compounds 30-32 showed moderate antimycobacterial activity ranging from MIC 99 = 62.5 to 125 mg/l against a drug-sensitive strain of M.tb (H37Rv) ( Figure 8B) [100].…”

Flavin-Dependent Thymidylate Synthase as a New Antibiotic Target

“…Attractive classes of antibiotic drugs against FDTS dependent organisms need to exhibit high specificity toward FDTS and low specificity toward human TSase in order to reduce toxicity. High throughput screening studies and synthesis of inhibitors based on substrate scaffolds have been attempted, and some of these inhibitors achieve an IC 50 in the 100 nM range against FDTS ( Table 2 ) [ 28 , 29 , 30 , 31 ].…”

Symmetrical Diamidate Prodrugs of Nucleotide Analogues for Drug Delivery

“…Using various approaches the ionizable phosphate group can be masked by derivatization, thus generating pronucleotides with increased lipophilicity (Wagner et al., ; Schultz et al., 2003; Ariza et al., ; He et al., ; Li et al., ; Peterson and McKenna ; Pertusati et al., ) The rationale behind the design of such agents is to achieve temporary blockage of the free phosphoric or phosphonic functional group until their systemic absorption and delivery, allowing the release of free drug only once at the target. Among all the different classes of prodrugs, the ProTide approach developed by McGuigan group (Mcguigan et al., ) including both aryloxy mono‐amidate (Serpi et al., ) and bis‐amidate derivatives has been proved to boost the activity of parent nucleosides by increasing the formation rate of nucleoside triphosphates, by improving intracellular transport and/or bypassing the rate limiting monophosphorylation step (Derudas et al., ; Mehellou et al., ; Mcguigan et al., ; McGuigan et al., ; Serpi et al., ; McGuigan et al., ; Slusarczyk et al., ; Toti et al., ). Several leading pharmaceutical companies have already applied the pioneering aryloxy mono‐amidate technology for anti‐viral and anticancer treatments.…”