Minor groove binders: some recent research in drug development

The role of the naturally occurring polyamides distamycin and netropsin as antibacterial agents is described. Also, the importance of the modifications to the lipophilic and hydrophobic moieties is discussed. It has also been shown that these DNA minor groove binding compds. can be used to treat other diseases such as sleeping sickness when the right modifications have been employed. Examples of the synthetic strategy of these polypyrroles are also highlighted in this review

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

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

DNA minor groove binders-inspired by nature

The synthesis and biological activity of a variety of analogues to the naturally occurring anti-bacterial and anti-fungal Distamycin A were explored by a number of authors. These compounds were subject to a large array of assays. Some of these compounds showed high activity against a range of Gram-positive, Gram-negative bacteria as well as fungi. To explore the anti-parasitic activity of this class of compounds, specific modifications had to be made. A number of these compounds proved to be active against Trypanosoma brucei. The binding of a number of these compounds to short sequences of DNA were also examined using footprinting assays as well as NMR spectroscopy. Computer modelling was employed on selected compounds to understand the way these compounds bind to specific DNA sequences. A large number of variations were made to the standard structure of Distamycin. These changes involved the replacement of the pyrrole moieties as well as the head and tail groups with a number of heterocyclic compounds. Some of these MGBs were also investigated for their capability for the treatment of cancer and in particular lung cancer

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

Facile synthesis of Schiff and Mannich bases of isatin derivatives

We report herein on the synthesis of some isatin Schiff’s bases (1–11), which were prepared from the reaction of isatin and some aromatic amines. These in turn were converted to the corresponding Mannich bases (12-23) by reaction with a number of secondary amines and formaldehyde, taking advantage of the active –NH group in the isatin. The structures of these compounds were elucidated using standard spectroscopic and analytical methods

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

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

A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation

In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2 : 1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol-1) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol-1). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development

Novel minor groove binders cure animal African trypanosomiasis in an in vivo mouse model

Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT, Trypanosoma congolense and T. vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative using 2 applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalised via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for animal African trypanosomiasis