Quinazoline antifolate thymidylate synthase inhibitors: heterocyclic benzoyl ring modifications

Abstract

The synthesis is described of a series of C2-methyl-N10-alkylquinazoline-based antifolates in which the p-aminobenzoate ring is replaced by the heterocycles thiophene, thiazole, thiadiazole, pyridine, and pyrimidine. These were generally elaborated by the reaction of (bromomethyl)quinazoline 18 or its N3-[(pivaloyloxy)methyl]-protected derivative 36 with suitable heterocyclic amines although each heterocyclic system required its own particular synthetic approach. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of L1210 cells in culture. The thiophene system 7 and its related thiazole 8 gave analogues that were considerably more potent than the parent benzene series 2 as inhibitors of L1210 cell growth although in general these heterocycles were somewhat poorer inhibitors of the isolated TS enzyme. The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folylpolyglutamate synthetase. The replacement of the C2-methyl group by C2-(fluoromethyl) and C2-(hydroxymethyl) substituents in the thiophene and thiazole series gave derivatives that were only slightly less potent inhibitors of the TS enzyme but which were considerably less cytotoxic.

TomudexTM (ZD1694): from concept to care, a programme in rational drug discovery

“…With the aid of these assays a group of rapidly transported and highly polyglutamated compounds were developed. Most notable of these were those which possessed a fluorinated benzoyl [51,52], or a thiophene or thiazole heterocycle isostere of the PABA ring system [58]. Contrary to the structure-activity relationships seen in the benzoyl series, Nl~ had little influence on TS inhibition in the thiophene or thiazole series.…”

Reactions of organolithium reagents with quinazoline derivatives

“…56,70 The synthesis of quinazoline derivatives has attracted the attention of chemists and has importance in medicinal chemistry because of the pharmacological applications for this heterocyclic ring system. [71][72][73][74][75][76][77][78][79][80][81] Also, quinazoline derivatives are important intermediates in the synthesis of a variety of valuable heterocyclic compounds. [82][83][84][85][86] Therefore, methods for the syntheses and/or modification of this ring system are always of interest.…”

Nitrofurans as Novel Anti-tuberculosis Agents: Identification, Development and Evaluation

“…5, eq. 3). The nitrothiofuran series was prepared from 5-nitro-thiophene-2-carboxylic acid (45), which was converted to the corresponding acid chloride 46 by treating with oxalyl chloride and direct coupling to a panel of amines to produce a series of nitrothiophenyl amides 47-51 [26].…”