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

Diversity oriented synthesis of fused pyrimidines leads to scaffolds with many biological activities. In the case of the preparation of pyrido[2,3-d]pyrimidines from 2-alkylthiopyrimidines, the formation of a new carbon-carbon bond at C5 is required, a reaction that is very limited in scope. However Claisen type rearrangement of simple 4-allylic ethers affords C5 substituted pyrimidines readily; in cases with an ester substituent, rearrangement occurs at room temperature. Subsequent cyclisation to afford 6-methylpyrido[2,3-d]pyrimidin-7(8H)-ones was achieved in high yield. Using allylic ethers derived from 3-chloromethyl-4-arylbut-3-en-2-ones as substrates, a new titanium[IV]chloride catalysed reaction affording 6-arylmethyl-7-methylpyrido[2,3-d]pyrimidines was discovered. In contrast, 2-alkylthiopteridines are readily available. In both cases, substitution at C2 and C4 to generate diversity has been carried out and the reactivity compared; yields of substitution products were generally higher with pteridine substrates. In biological assays unexpected hits were found for activity against the Gram positive bacterium, Nocardia farcinia, and against the parasite Trypanosoma brucei brucei, illustrating the value of diversity oriented synthesis in the discovery of biologically active compound

The antibacterial drug MGB-BP3 : from discovery to clinical trial

It goes without saying now that there is a severe risk to health world wide because of the continued emergence of resistance of bacteria to many of the currently available antibacterial drugs. About 12 years ago at Strathclyde we began a project to see whether it would be possible to transform the oligoamide natural products, distamycin (1) and netropsin (2), into useful antibiotics by modifying their structures so that toxicity and unwanted biological activity was removed and selective, high antibiotic activity obtained. These natural products were well known to bind to the minor groove of DNA and details of the configuration of binding were known from X-ray crystallography [1,2]. A firm basis therefore existed for the design of new minor groove binding ligands. The research plan was to introduce additional hydrophobic components into the ligands so that binding to the non-polar regions of the minor groove could be obtained and so that the physicochemical properties of the new compounds be made more drug-like than those of distamycin and netropsin

Methyl 2-amino-5-iso­propyl-1,3-thia­zole-4-carboxyl­ate

The title compound, C8H12N2O2S, forms a supramolecular network based on N-HN hydrogen-bonded centrosymmetric dimers that are linked in turn by N-HO contacts

Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties

Reduced NO levels due to the deficiency of tetrahydrobiopterin (BH4) contribute to impaired vasodilation in pulmonary hypertension Due to the chemically unstable nature of BH4 it was hypothesised that oxidatively stable analogues of BR, would be able to support NO synthesis to improve Endothelial dysfunction in pulmonary hypertension Two analogues of BH4 namely 6-hydroxymethyl pterin (HMP) and 6-acetyl 7 7-dimethyl 7 8-dihydropterin (ADDP) were evaluated for vasodilator activity on precontracted rat pulmonary artery rings ADDP was administered to pulmonary hypertensive rats followed by measurement of pulmonary vascular resistance in perfused lungs and eNOS expression by immunohistochemistry ADDP and HMP caused significant relaxation in vitro in rat pulmonary arteries depleted of BH4 with a maximum relaxation at 0 3 mu M (both P<005) Vasodilator activity of ADDP and HMP was completely abolished following preincubation with the NO synthase inhibitor L-NAME ADDP and HMP did not alter relaxation induced by carbachol or spermine NONOate BH4 Itself did not produce relaxation In rats receiving ADDP 141 mg/kg/day pulmonary vasodilation induced by calcium ionophore A23187 was augmented and eNOS immunoreactivity was increased In conclusion ADDP and HMP are two analogues of BH4 which can act as oxidatively stable alternatives to BH4 in causing NO-mediated vasorelaxation Chronic treatment with ADDP resulted in Improvement of NO-mediated pulmonary artery dilation and enhanced expression of eNOS in the pulmonary vascular endothelium Chemically stable analogue, of BH4 may be able to limit endothelial dysfunction in the pulmonary vasculatur

2,2,2-Trifluoro-N-(isoquinolin-5-ylmeth­yl)acetamide

The mol­ecular structure of the title compound at 123 K, C12H9F3N2O, presents a rotationally disordered CF3 group. Hydrogen bonds between the amide NH group and the N atom of the isoquinoline form a chain in the b-axis direction. The packed structure forms alternate layers of isoquinoline and amide groups parallel to the ab plane

Design, synthesis and antibacterial activity of minor groove binders: the role of non-cationic tail groups

he design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups

Selectivity in anti-infective minor groove binders

Minor groove binders for DNA synthesised at the University of Strathclyde (S-MGBs) have been successfully shown to be active against a wide range of infectious organisms including bacteria, fungi, and parasites in particular through collaborations with a worldwide network of partners. S-MGBs can be obtained from a wide range of structures and physicochemical properties that influence the S-MGB’s effect on a given class of target organism. A dominant feature that determines selectivity is access of the S-MGB to the DNA of the target organism which requires passing through the external cell membrane or cell wall and any further intracellular barriers. For infectious organisms that reside inside the host mammalian cell, passage through the mammalian cell membrane must also occur. Experiments have shown that S-MGBs containing alkene links in place of an amide are in general most effective against all the infective agents studied but significant activity against some fungi has also been observed in S-MGBs with amidine links. More subtle effects in anti-fungal activity have also been observed relating to the structure of the fungal cell wall: dicationic S-MGBs were active against C. neoformans, which lacks phosphate esters in its outer cell wall, but inactive against C. albicans, whose cell wall contains phosphate esters to which the dicationic S-MGB can bind thereby preventing cell penetration. Comparison of toxicity with mammalian cells shows significant but not optimal selectivity indices for the best compounds. In the case of M. tuberculososis, improved selectivity indices were obtained using non-ionic surfactant vesicles in the formulation. Together these results are helpful to identify clusters of S-MGBs that can be optimised to be selective against a given infectious agent

Crystal structure of N,N-dimethyl-2-[(4-methylbenzyl)sulfonyl]ethanamine

In the crystal, the title compound, C12H19NO2S, has a disordered structure with two equally populated conformations of the amine fragment. A pair of weak C—HO intermolecular interactions between the CH2 and SO2 groups gives a one-dimensional supramolecular structure that propagates through translation along the a-axis direction

Selective anti-malarial minor groove binders

A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30–500 nM and therapeutic ratios in the range 10–>500. Many active compounds contained a C-alkylthiazole building block. Active compounds with log D7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia