Miroslav Bajic

Inhibition of the HIV-1 rev-RRE complex formation by unfused aromatic cations.

RNA viruses cause a wide range of human diseases. Development of new agents to target such viruses is an active area of research. Towards this goal, a series of diphenylfuran cations as potential inhibitors of the Rev-RRE complex have been designed and synthesized. Analysis of the interaction of the diphenylfurans with RRE and TAR RNA model systems by gel shift assays indicates that they exhibit both sequence and structure-dependent binding modes. Our results show a strong interaction between the diphenylfuran ring system and RRE bases, while the TAR interactions are much weaker with the compounds that are the best inhibitors of Rev-RRE.

Anti-Pneumocystis carinii pneumonia activity of dicationic diaryl methylprimidines

Summary Synthesis of 2,4-bis-(4-amidinophenyl)-6-methylpyrimidine 5 , 2,4-bis-[(4-imidazolin-2-yl)phenyl]-6-methylpyrimidine 6 , 2,4-bis[(4- N-i -propylamidino)phenyl]-6-methylpyrimidine 7, and 2,4-bis[(4- N -isopentylamidino)phenyl]-6-methylpyrimidine 8 starting from 4-bromobenzamidine and 4′-bromoacetophenone is reported. The synthesis of 2,4-bis-(4-amidinophenyl)-5-methylpyrimidine 12 and 2,4-bis-[(4-imidazolin-2-yl)phenyl]-5-methylpyrimidine 13 , also beginning with 4-bromobenzamidine and 4′-bromopropiophenone is described. A synthesis of 4,6-bis-(4-amidinophenyl)-2-methylpyrimidine 17 , 4,6-bis-[(4-imidazolin-2-yl)phenyl]-2-methylpyrimidine 18 , 4,6-bis[(4- N-i -propylamidino)phenyl]-2-methylpyrimidine 19 and 4,6-bis[(4- N-n -propylamidino)phenyl]-2-methylpyrimidine 20 starting from acetamidine and 1,3-bis(4-bromophenyl)propenone is reported. Compounds 5–7 and 17–20 all bind strongly to the minor groove of poly-dA-dT whereas 8, 12 and 13 bind less tightly as judged by their Δ T in values. A similar trend was noted for binding of these compounds to the 12-mer-d(CGCGAATTCGCG) 2 . Compounds 5, 7, and 17 are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model.

Synthesis of Some Furyl- and Thienylacrylates or Diacrylates and Aacrylic Acids by the Palladium Catalysed Vinylation of Substituted Bromofurans and Bromothiophenes

Furyl- and thienylacrylates (8-14) and acrylic acids (8a,10a-14a) are prepared in moderate yields by palladium catalysed coupling of substituted bromofurans and bromothiophenes with ethyl acrylate

Electron impact mass spectra of some bis-(2-benzothiazolyl)furans and bis-(2-benzothiazolyl)thiophenes.

The electron impact mass spectra of some bis-(2-benzothiazolyl)furans and bis-(2-benzothiazolyl)thiophenes have been recorded and the identity of various ions in the mass spectra established. Compounds 1 and 2 present model substances and it is found that their fragmentation pathway is similar to the mono-(2-benzothiazoles). Compounds where the benzothiazolyl groups are directly substituted on the furan nuclei, but in different positions, exhibit two main pathways of fragmentation: fragmentation of the furan nucleus and fragmentation of the benzothiazole nucleus. Other compounds studied show specific fragmentation characteristic for divinyl furan compounds and for compounds with a phenyl substituent between two heterocyclic nuclei.

SYNTHESIS OF 2,4-BIS [4-(5-AMIDINO AND 5-SUBSTITUTEDAMIDINO-2-BENZIMIDAZOYL) PYRIMIDINES

The syntheses of 2,4-bis[4-(5-imidazohn-2yl-2-benzimidazolyl)phenyI]pyrimidine, 2,4-bis[4-(5amidino-2-benzimidazolyl)phenyl]pyrimidine, and 2,4-bis[4-(5-N-isopropylamidino-2benzimidazolyl)phenyl]pyrimidine from 2,4-bis-(4-cyanophenyl)pyrimidine are reported. Introduction We recently reported that dicationic 2,4-diarylpyrimidines bind strongly in the minor-groove of AT rich DNA (1). We demonstrated that by careful manulipation of structure highly DNA selective molecules could be developed. It has been further shown that dicationic 2,4-diarylpyrimidines have useful activity against the important AIDS associated pathogen Pneumocystis carinii pneumonia. Certain of the dicationic 2,4diarylpyrimidines are quite active in the immunosuppressed rat model (2). Modeling studies suggest that the parent dicationic 2,4-diarylpyrimidine system occupies approximately 3 to 4 base pairs when binding in the DNA minorgroove. Potentially, base-pair selectivity can be increased by employing larger molecules which on binding to DNA would interact with more base pairs. In a study of the influence of structural changes on the minor-groove binding affinity of the benzimidazole Hoechst 33258 and related compounds we found that DNA binding affinity was increased much more significantly by the addition of a second benzimidazole ring than by addition of a second cationic center (3). Based upon our work with the Hoechst analogs we expect that the binding affinity of the 2,4-diarylpyrimidine system should be enhanced by addition of benzimidazole rings to the parent structure. In order to make such compounds available for biophysical and antimicrobial evaluation, we undertook the synthesis of 2,4-bis[4-(5-substituted-2benzimidazolyl)phenyl]pyrimidines, which are expected to show strong DNA binding affinity and occupy 6 or more base pairs on binding to DNA. Results and Discussion The synthesis of the extended 2,4-diarylpyrimidines is based upon our previously reported approach to 2,4-bis[diaryl]pyrimidines and uses 2,4-bis[4-cyanophenyl]pyrimidine(l) as the key starting molecule (1). We chose to incorporate benzimidazoles units in the 2,4-diarylpyrimidine parent system by using orthophenylenediamine methodology. These are two general approaches for formation of benzimidazole rings starting from orr/io-phenylenediamines; one involves direct condensation with a carboxylic acid group (or other functional group of the same carbon oxidation level) (4) and the second employs condensation with an aldehyde and subsequent oxidation of the condensation product to form the benzimidazole ring (5). For the synthesis of dicationic aryl molecules it is typically desirable to make an appropriate bis-nitrile so that it can serve as precursor.

Synthesis of 2,4,6-Tris(4-N-isopropylamidinophenyl)pyrimidine trihydrochloride

The synthesis of 2,4,6-tris(4-N-isopropylamidinophenyl)pyrimidine from 1,3-di(4-bromophenyl)propen-3-one and 4-bromobenzamidine is reported.