Structure-Based Design and Synthesis of Antiparasitic Pyrrolopyrimidines Targeting Pteridine Reductase 1

Abstract

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp., has been identified as a candidate target, and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from Trypanosoma brucei (J. Med. Chem.2010, 53, 221–229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. Eight compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus, although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.

New class of 8-aryl-7-deazaguanine cell permeable fluorescent probes

“…There is interest in efficient syntheses of 8aryl 7DG as intermediates of pharmacologically active lead compounds. 17 A similar synthesis of 8aryl 7DGs was recently reported in literature without any experimental or spectroscopic details. 18 Our protocol was developed independently prior to this publication.…”

Folates in Trypanosoma brucei: Achievements and Opportunities

“…On the other hand, pyrrolopyrimidines (scaffold C) showed a preference for Tb PTR1 and promising activity, with K i values in the micromolar or sub‐micromolar range . A series of analogues characterized by the C core were synthesized in an extensive study that led to a complete structure–activity relationships study (Table ) . Substitution of the 4‐O atom with an amino group was found to be favorable in some cases, but the most important remark is the need for a bulky hydrophobic substituent on the pyrrole ring, with the most interesting compounds bearing two phenyl rings at the 5 and 6 positions.…”

“…The other compounds were tolerated up to four days when administered once daily, and reduction of parasitemia from 10 8 to below detection limits was demonstrated. Mice survived after treatment with compounds 34 and 35 , but unfortunately showed a relapse of parasitemia on day 10 …”

“…[23] As eries of analogues characterized by the Cc ore weres ynthesized in an extensive study that led to ac ompletes tructure-activity relationships study (Table 5). [24] Substitutiono ft he 4-O atom with an amino group was found to be favorable in some cases, but the most important remarkisthe need for abulky hydrophobic substituent on the pyrrole ring, with the most interesting compounds bearing two phenyl rings at the 5a nd 6p ositions. Improvementsi na ctivity were obtained with the introduction of ah alogen atom at the para or meta positions of the aryl groups appendedi np ositions 5o r6 ,w hile other modifications, such as alkylation of the heteroatom at the 4p osition, the introduction of branched alkyl groups, or as ulfone group on the aromatic rings, caused al oss of activity or worsen the solubility properties of the compounds, especially for the 4-oxo series.C rystal structures of the complexes inhibitor-NADPH-TbPTR1 were generated, showing that most of the compounds bind the enzymew ith as ubstrate-like pose.…”

A Strategy for the Triarylation of Pyrrolo­pyrimidines by Using Microwave‐Promoted Cross‐Coupling Reactions

“…The pyrrolo[2,3‐ d ]pyrimidines also known as deazapurines, because of their structural similarity to natural purines, are interesting templates for drug discovery programs in medicinal chemistry1 and have proved to be valuable scaffolds in organic chemistry 2. Compounds that contain a pyrrolopyrimidine nucleus have a variety of biological effects including antibacterial,3 anti‐inflammatory,4 antiparasitic,5 and antitumor properties 6. In addition to these pharmaceutical applications, substituted arylpyrimidine, arylpurine, and deazapurine cores with π‐conjugated systems exhibit interesting photophysical properties 7…”