3′-Bromo Analogues of Pyrimidine Nucleosides as a New Class of Potent Inhibitors ofMycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a major health problem worldwide. We herein report a new class of pyrimidine nucleosides as potent inhibitors of Mycobacterium tuberculosis (M. tuberculosis). Various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases were synthesized and evaluated for antimycobacterial activities. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (33) was the most effective antituberculosis agent in the in vitro assays against wild-type M. tuberculosis strain (H37Ra) (MIC(50) = 1 microg/mL) as well as drug-resistant (H37Rv) (rifampicin-resistant and isoniazid-resistant) strains of M. tuberculosis (MIC(50) = 1-2 microg/mL). Compound 33 also inhibited intracellular M. tuberculosis in a human monocytic cell line infected with H37Ra, demonstrating higher activity against intramacrophagic mycobacteria (80% reduction at 10 microg/mL concentration) than extracellular mycobacteria (75% reduction at 10 microg/mL concentration). In contrast, pyrimidine nucleosides possessing 5-fluorouracil base were weak inhibitors of M. tuberculosis. No cytotoxicity was found up to the highest concentration of compounds tested (CC(50) > 100-200 microg/mL) against a human cell line. Overall, these encouraging results substantiate the potential of this new class of compounds as promising antituberculosis agents.

Chemotherapeutic Interventions Against Tuberculosis

“…In recent studies, we synthesized and investigated various 2'- or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and a thymine base [56]. In this class, compound 11 was found to be the most effective antituberculosis agent in the in vitro assays against wild-type Mtb strain (H37Ra, MIC 50 = 1 μg/mL), and drug-resistant (H37Rv) strains of Mtb (RMP-resistant and INH-resistant, MIC 50 = 1–2 μg/mL).…”

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

“…Most intriguingly, compound 77 also inhibited intracellular M.tb in a human monocytic cell line (THP-1) infected with H37Ra, with a greater than 90% of reduction of the number of surviving bacteria at a concentration of 25 μg/ml, demonstrating higher activity against intramacrophagic mycobacteria than extramacrophagic mycobacteria [127]. Moreover, no cytotoxicity was found up to the highest concentration of compound tested (CC 50 > 100-200 μg/ml) [127].…”

“…In another study, various 2′-or 3′-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil and thymine bases were synthesized and evaluated as antimycobacterial agents [127]. 3′-Bromo-3′-deoxy-arabinofuranosylthymine (77) was the most effective agent (MIC 50 = 1 μg/ml) in vitro against wild-type M.tb strain (H37Ra) as well as rifampicin and isoniazid-resistant strain of M.tb (H37Rv) (MIC 50 = 1-2 μg/ml) ( Figure 14B) [127].…”

“…3′-Bromo-3′-deoxy-arabinofuranosylthymine (77) was the most effective agent (MIC 50 = 1 μg/ml) in vitro against wild-type M.tb strain (H37Ra) as well as rifampicin and isoniazid-resistant strain of M.tb (H37Rv) (MIC 50 = 1-2 μg/ml) ( Figure 14B) [127]. Most intriguingly, compound 77 also inhibited intracellular M.tb in a human monocytic cell line (THP-1) infected with H37Ra, with a greater than 90% of reduction of the number of surviving bacteria at a concentration of 25 μg/ml, demonstrating higher activity against intramacrophagic mycobacteria than extramacrophagic mycobacteria [127]. Moreover, no cytotoxicity was found up to the highest concentration of compound tested (CC 50 > 100-200 μg/ml) [127].…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…The compounds 13 and 14, were also subjected to determine their antimycobacterial activity against a RMP-resistant H37Rv strain (ATCC 35838, resistant to RMP at 2 g/mL) of Mtb using the radiometric-BACTEC assay. The drug- In a subsequent article in the same year by our group , in vitro antimycobacterial activities of several 5-substituted acyclic pyrimidine nucleosides containing 1-(2-hydroxyethoxy)methyl and 1- [(2-hydroxy-1-(hydroxymethyl) In continued efforts in drug design and discovery for anti-tuberculosis agents, our group (Shakya et al, 2010) investigated various 2'-or 3'-halogeno derivatives of pyrimidine nucleosides containing uracil, 5-fluorouracil, and thymine bases. Among the compounds tested, 3'-bromo-3'-deoxy-arabinofuranosylthymine (17) was the most effective antituberculosis agent in the in vitro assays against wild-type Mtb strain (H37Ra) which displayed MIC 50 = 1 μg/mL by the MABA assay.…”