Synthesis and cytotoxic activity of 5-(1-hydroxy-2-haloethyl)-, 5-oxiranyl- and (E)-5-(2-iodovinyl)-2,4-dichloro (or dimethoxy) pyrimidines

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

“…In earlier studies, 16 we observed that in addition to 5-alkyl side chains, 5-alkylalkynyl (5-decynyl and 5-dodecynyl) moieties at the C-5 position of the specific N-1 substituted pyrimidines also contribute to significant antimycobacterial activities. Therefore, to further establish the structural requirements at the 5-position of pyrimidines for antimycobacterial activity, we explored various 5-alkyl (or aryl)alkynyl pyrimidines (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Within these, 5-alkylalkynyl substituted pyrimidines (17-22, Table 1) were found to be inactive as antimycobacterial agents despite their varying chain lengths at the C-5 position.…”

“…Synthesis of 5-alkyl uracils (9-16) (Scheme 1) was carried out using reported procedures described by us earlier. 18 5-Alkynyl pyrimidines (17-22, 24, 25) were prepared by the Pdcatalyzed coupling reaction of 5-iodoracil (5) with appropriate alkylacetylenes, arylacetylenes, and para substituted arylacetylenes to yield the target 5-alkynyl pyrimidines 17-22, 24, 25 as described in Scheme 2. The 5-(2-phenylethynyl)-uracil (23) was synthesized using a previously reported method.…”

“…Cyclization 21 of selective 5-alkynyl uracils (17)(18)(19)(20) in the presence of copper iodide and triethylamine in dry methanol at reflux temperature yielded the corresponding bicyclic furanopyrimidines (28-31) in 38-64% yields (Scheme 2).…”

“…12,14,15 In these studies, we also noted that 5-(1azido (or halo)-2-haloethyl) substituents and 5-alkylalkynyl moieties at the C-5 position of the substituted pyrimidines contributed to significant antimycobacterial activities. 13,16 As part of our ongoing program to identify agents that display potent anti-TB activity and to further explore the SARs, we have now designed, synthesized, and evaluated a new series of 5-alkyl (7, 9-16) and 5-alkyl (or aryl)alkynyl pyrimidines (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(28)(29)(30)(31) for their antimycobacterial properties. In these studies, we discovered that pyrimidines with 5-arylalkynyl pharmacophores (23)(24)(25)(26) exhibit potent inhibition of M. bovis and M. tuberculosis in comparison to their 5-alkyl (7, 9-16) and 5-alkylalkynyl (17)(18)(19)(20)(21)(22) counterparts.…”

“…13,16 As part of our ongoing program to identify agents that display potent anti-TB activity and to further explore the SARs, we have now designed, synthesized, and evaluated a new series of 5-alkyl (7, 9-16) and 5-alkyl (or aryl)alkynyl pyrimidines (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(28)(29)(30)(31) for their antimycobacterial properties. In these studies, we discovered that pyrimidines with 5-arylalkynyl pharmacophores (23)(24)(25)(26) exhibit potent inhibition of M. bovis and M. tuberculosis in comparison to their 5-alkyl (7, 9-16) and 5-alkylalkynyl (17)(18)(19)(20)(21)(22) counterparts. Among the 5-arylalkynyl pyrimidine compounds, 5-(2-pyridylethynyl)uracil (26) demonstrated most potent activity against M. tuberculosis (H37Ra) and was tested for its efficacy in a murine model of H37Ra infection.…”