Diversity oriented syntheses of fused pyrimidines designed as potential antifolates

Abstract

Diversity oriented syntheses of some furo[2,3-d]pyrimidines and pyrrolo[2,3-d]pyrimidines related to folate, guanine, and diaminopyrimidine-containing drugs have been developed for the preparation of potential anti-infective and anticancer compounds. Amide couplings and Suzuki couplings on the basic heterocyclic templates were used, in the latter case yields being especially high using aromatic trifluoroborates as the coupling partner. A new ring synthesis of 6-aryl-substituted deazaguanines bearing 2-alkylthio groups has been developed using Michael addition of substituted nitrostyrenes. Diversity at C-2 has been introduced by oxidation and substitution with a range of amino nucleophiles. The chemical reactivity of these pyrrolopyrimidines with respect to both electrophilic substitution in ring synthesis and nucleophilic substitution for diversity is discussed. Several compounds were found to inhibit pteridine reductases from the protozoan parasites Trypanosoma brucei and Leishmania major at the micromolar level and to inhibit the growth of Trypanosma brucei brucei in cell culture at higher concentrations. From these results, significant structural features required for inhibition of this important drug target enzyme have been identified.

DNA Minor Groove Binders-Inspired by Nature

“…27,28 Assays for activity against T. brucei were carried out using established methods at the laboratories in Strathclyde and Glasgow Universities. 29 Compound 20 is typical of an antibacterial and antifungal minor groove binder with an MIC vs. S. Aureus 4.3 μM, vs. A. niger 4.3 μM. However, this compound was found to be inactive against T. brucei.…”

“…This was demonstrated in a number of publications. 26,29,30 These were thiazole-containing compounds, activity was found against Trypanosoma brucei (see Tables 2 and 3).…”

Chemical Biology: What is Its Role in Drug Discovery?

“…Many compounds demonstrated very promising activity in vitro. Diversity-oriented synthesis was used in the synthesis of fused pyrimidine analogues (Gibson et al, 2009). The compounds were tested against pteridine reductases from protozoan parasites and several were found to be active.…”

Diversity oriented synthesis: substitution at C5 in unreactive pyrimidines by Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4 in pteridines and pyrido[2,3-d]pyrimidines

“…With emphasis on diversity oriented synthesis in our own studies, we have identified active compounds with respect to GTP cyclohydrolase 1, 2 dihydropterin diphosphokinase, 3 dihydrofolate reductase, 4 pteridine reductase 1 5 and nitric oxide synthase. 6 Several of these targets are significant clinically and the optimisation of activity requires the availability of more diverse libraries within the same basic structural skeleton.…”

“…A significant exception is that when certain Michael acceptors are used, C5 substitution occurs in reduced yield 8 and this chemistry has been developed to provide compounds with significant activity against Trypanosoma brucei. 5 A further example of a successful C5 substitution of a 2-alkylthiopyrimidine is found in nucleoside analogue synthesis and involves Vilsmeier formylation. 9 In contrast, halogen electrophiles substitute 2-alkylthiopyrimidines in high yield and provide suitable precursors for C5 carbon substitution.…”