Design and Studies of Novel 5-Substituted Alkynylpyrimidine Nucleosides as Potent Inhibitors of Mycobacteria

Abstract

We herein report a new category of 5-substituted pyrimidine nucleosides as potent inhibitors of mycobacteria. A series of 5-alkynyl derivatives of 2'-deoxyuridine (1-8), 2'-deoxycytidine (9-14), uridine (15-17), and 2'-O-methyluridine (18, 19) were synthesized and evaluated for their antimycobacterial activity in vitro. 5-Decynyl, 5-dodecynyl, and 5-tetradecynyl derivatives showed the highest antimycobacterial potency against M. bovis and M. avium, with the 2'-deoxyribose derivatives being more effective than the ribose analogues. Nucleosides bearing short alkynyl side chains 5-ethynyl, 5-propynyl, 5-pentynyl, and 5-heptynyl were mostly not inhibitory. Incorporation of a phenylethynyl function at the 5-position diminished the antimicrobial effect. Furthermore, related bicyclic analogues (20-24) were devoid of antimycobacterial activity, indicating that an acyclic side chain at the C-5 position of the pyrimidine ring is essential for potent activity. Compounds 1-17 were synthesized by the Pd-catalyzed coupling reactions of respective alkynes with 5-iodo derivatives of 2'-deoxyuridine, 2'-deoxycytidine, and uridine. Intramolecular cyclization of 1 and 3-6 in the presence of Cu afforded the corresponding bicyclic compounds 20-24. The investigated nucleosides are recognized here for the first time to be potent inhibitors of mycobacteria. This class of compounds could be of interest for lead optimization as antimycobacterial agents.

New 5-Modified Pyrimidine Nucleoside Inhibitors of Mycobacterial Growth

“…1, 1–10 ). 5–(1–Dodecynyl)– and 5–(1–tetradecynyl)–2ʹ–deoxyuridine ( 1 and 2 , respectively) used as a control were prepared by the method in [11]. 5–Alkyloxymethyl–pyrimidine nucleoside derivatives ( 6–10 ) were synthesized using our method in [15], and nucleoside 5ʹ–monophosphates ( 3–5 ) were synthesized by the method in [15–16].…”

“…Recently, 5–modified pyrimidine nucleosides with lengthy 1–alkinyl radicals have demonstrated an inhibitory effect on Mycobacterium tuberculosis and M. bovis in vitro [11–14]. The best antibacterial activity has been demonstrated for nucleoside 5–(1–dodecynyl) and 5–(1–tetradecynyl) derivatives.…”

“…The best antibacterial activity has been demonstrated for nucleoside 5–(1–dodecynyl) and 5–(1–tetradecynyl) derivatives. The study on the influence of the carbohydrate fragment modification on the antibacterial properties of 5–modificed nucleosides has demonstrated that virtually all 2ʹ–deoxy–, 2ʹ, 3ʹ–dideoxy–, 3ʹ–fluoro–2ʹ, 3ʹ–dideoxy–, and 2ʹ–fluoro–2ʹ, 3ʹ–dideoxynucleosides, as well as acyclic and arabinonucleosides with long 1–alkynyl radicals, have displayed anti–TB activity [11–14]. This work is devoted to an investigation of the Mycobacterium tuberculosis growth inhibitory capability of newly synthesized 2ʹ–deoxy–, 3ʹ–azido–2ʹ, 3ʹ–dideoxy–, and 3ʹ–amino–2ʹ, 3ʹ–dideoxy–pyrimidine nucleosides containing lengthy alkyloxymethyl radicals at their position 5.…”

Nucleoside Analogs and Tuberculosis: New Weapons Against an Old Enemy

“…5-Dodecynyl (57, 60), 5-tetradecynyl (58) and 5-decynyl (59) derivatives of 2′-deoxyuridine and/or 2′-deoxycytidine showed moderate activity against M. bovis growth, with MIC 90 values ranging from 10 to 50 μg/ml ( Figure 13B), while the introduction of either a ribose sugar moiety or smaller 5-alkynyl chains induced a decrease in antitubercular activity [120].…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…In our subsequent studies, we designed, synthesized and examined a variety of 2-, 4-, 5-and/or 6-substituted/unsubstituted pyrimidine nucleosides containing various deoxyribose, ribose, arabinose, dideoxyribose and acyclic moieties. During our continued search of novel anti-TB agents, we found that 5-alkynyl substituted pyrimidine nucleosides were very potent inhibitors of mycobacteria (Rai et al, 2005). We , reported that pyrimidine nucleoside analogs 1--D-2'-arabinofuranosyl-5-dodecynyluracil (10), 1-(2'-deoxy-2'-fluoro--D-ribofuranosyl)-5-dodecynyluracil (11), and 1-(2'-deoxy-2'-fluoro--D-ribofuranosyl)-5-tetradecynyluracil (12) In the same year, we (Rai et al, 2007) further reported syntheses and evaluation of a series of 5-acetylenic derivatives of 2',3-dideoxyuridine, and 3'-fluoro-2',3'-dideoxyuridine for their antimycobacterial activity against M. bovis, Mtb, and M. avium.…”