Inhibition of Mycobacterial Replication by Pyrimidines Possessing Various C-5 Functionalities and Related 2′-Deoxynucleoside Analogues Using in Vitro and in Vivo Models

Srivastav, Naveen C.; Rai, Dinesh; Tse, Christopher; Agrawal, Babita; Kunimoto, Dennis; Kumar, Rakesh

doi:10.1021/jm100568q

Cited by 33 publications

(25 citation statements)

References 27 publications

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“…At a dose of 50 mg/kg for 5 weeks, statistically significant reduction in mycobacterial load was observed in lungs, livers and spleens of the treated mice. This is the first evidence of antimycobacterial potential of 5-substituted pyrimidine nucleosides in an animal model as a potential new class of antituberculosis agents [58]. …”

Section: Drug Discovery Programmentioning

confidence: 99%

Chemotherapeutic Interventions Against Tuberculosis

et al. 2012

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Tuberculosis is the second leading cause of infectious deaths globally. Many effective conventional antimycobacterial drugs have been available, however, emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has overshadowed the effectiveness of the current first and second line drugs. Further, currently available agents are complicated by serious side effects, drug interactions and long-term administration. This has prompted urgent research efforts in the discovery and development of new anti-tuberculosis agent(s). Several families of compounds are currently being explored for the treatment of tuberculosis. This review article presents an account of the existing chemotherapeutics and highlights the therapeutic potential of emerging molecules that are at different stages of development for the management of tuberculosis disease.

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Section: Drug Discovery Programmentioning

confidence: 99%

Chemotherapeutic Interventions Against Tuberculosis

et al. 2012

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“…In 2010 the first antimycobacterial in vivo data in a mouse model infected with H37Ra M.tb strain were published [126]. After synthesis and antimycobacterial in vitro evaluation of a novel series of 5-alkyl and 5-alkyl(or aryl)alkynyl pyrimidines, 5-(2-pyridylethynyl)-uracil (74) was selected as a potent candidate for further investigations ( Figure 14A) [126].…”

Section: Nucleoside Analogs With Unclear Targetmentioning

confidence: 99%

“…After synthesis and antimycobacterial in vitro evaluation of a novel series of 5-alkyl and 5-alkyl(or aryl)alkynyl pyrimidines, 5-(2-pyridylethynyl)-uracil (74) was selected as a potent candidate for further investigations ( Figure 14A) [126]. The promising in vitro activity of this compound (MIC 50 = 1-5 μg/ml on M. bovis, MIC 50 = 5 μg/ml on M.tb] prompted to in vivo evaluation of its efficacy in female BALB/c mice infected with H37Ra at a dose of 50 mg/kg, formulated in 10% DMSO-saline, by the intraperitoneal route.…”

Section: Nucleoside Analogs With Unclear Targetmentioning

confidence: 99%

“…In the same study, both the 2′-deoxyuridine (75) and the 2′-deoxycytidine (76) analogs of 74 were synthesized and their in vitro antimycobacterial activity against M.tb showed an improvement (68-70% inhibition at 10 μg/ml) as compared with 74 (70% inhibition at 50 μg/ml) ( Figure 14A) [126]. Compound 76 demonstrated no cytotoxicity in Huh-7 cells up to a concentration of greater than 200 μg/ml, whereas compound 75 showed 25% inhibition in cell viability at 200 μg/ml; therefore, 76 was selected to test its potency in a mouse model infected with H37Ra mycobacterial strain.…”

Section: Nucleoside Analogs With Unclear Targetmentioning

confidence: 99%

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Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

Ferrari

Serpi

2015

Future Med. Chem.

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Purine and pyrimidine nucleoside and nucleotide analogs have been extensively studied as anticancer and antiviral agents. In addition to this, they have recently shown great potential against Mycobacterium Tuberculosis, the causative agent of TB. TB ranks as the tenth most common cause of death in the world. The current treatment for TB infection is limited by side effects and cost of the drugs and most importantly by the development of resistance to the therapy. Therefore the development of novel drugs, capable of overcoming the drawbacks of the existing treatments, has become the focus of many research programs. In parallel to that, a tremendous effort has been made to elucidate the unique metabolism of this pathogen with the aim to identify new possible targets. This review presents the state of the art in nucleoside and nucleotide analogs in the treatment of TB. In particular, we report on the inhibitory activity of this class of compounds, both in enzymatic and whole-cell assays, providing a brief insight to which reported target these novel compounds are hitting.

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“…Nucleoside analogues are also extensively studied as therapeutic agents against the proliferation of cancer cells, against virus replication, and, recently, also against bacterial infections (24). Among them, the 2=-deoxy-4=-thiopyrimidine nucleosides have been reported to be inhibitors of some herpesviruses, and they are listed in Table 1 (25,26).…”

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confidence: 99%

KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo

Duraffour

Drillien

Haraguchi

et al. 2014

Antimicrob Agents Chemother

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The availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1=-methyl-substituted 4=-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses. In vitro, KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK; J2R) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7-to 6.0-fold and cross-resistance to 5-bromo-2=-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1=-carbon-substituted 4=-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.

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Inhibition of Mycobacterial Replication by Pyrimidines Possessing Various C-5 Functionalities and Related 2′-Deoxynucleoside Analogues Using in Vitro and in Vivo Models

Cited by 33 publications

References 27 publications

Chemotherapeutic Interventions Against Tuberculosis

Chemotherapeutic Interventions Against Tuberculosis

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

KAY-2-41, a Novel Nucleoside Analogue Inhibitor of OrthopoxvirusesIn VitroandIn Vivo

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