Aryl Sulfonamides made easy

Sulfonamide moieties are ubiquitous across commercial drugs and have been used in a wide range of therapeutic areas such as antimicrobial, diuretics, antiretrovirals and antiinflammatories. Among the drugs featuring sulfonamides are COX-2 inhibitor Celebrex (1), HIV protease inhibitor Amprenavir (2) and WHO’s list of essential medicine Sulfadiazine (3) (Figure 1).

Michael Fig 1 30-11-2015

Figure 1. Sulfonamide-containing drugs

Synthetically, sulfonamides can be readily accessed from (hetero)aryl or alkyl sulfonyl chlorides and amines. These sulfonyl chlorides have often the tendency to be instable due to their reactivity and their preparation itself can be challenging.

Of the many reported methods for the preparation of aryl sulfonyl chlorides, the main access still remains via aromatic electrophilic substitution. However, this methodology is dependent upon the aromatic characteristic of the arenes employed toward the electrophilic substitutions. Of the other methods available, worth mentioning is the conversion of thiol derivatives under oxidative conditions, often limiting the compatibility with other functional groups.

Mike Willis previously reported the preparation of aryl ammonium sulfinates under palladium-catalysed sulfination of aryl iodides. Based on the understanding that DABSO (Scheme 1) could be used as a convenient surrogate of SO2 gas in a number of transformations, Willis has shown that ammonium sulfinates could be readily obtained from aryl halides (Scheme 1).

Michael Scheme 1 30-11-2015

Scheme 1. Palladium catalysed cross coupling of aryl iodide with DABSO

To evaluate the scope of the reaction, the sulfinates were converted to the corresponding sulfones in situ by reaction with bromo tert-butyl acetate as the electrophile (Figure 2).

Michael Fig 2 30-11-2015

Figure 2. Sulfones from ammonium sulfonates

Shortly after, Willis also reported a simple and efficient one-pot synthesis of (hetero)aryl sulfonamides obtained from magnesium sulfonates prepared in situ with DABSO and a Grignard reagent and a N-chloro-amine as the electrophilic partner, also generated in situ from bleach and the relevant amine (Figure 3).

Michael Fig 3 30-11-2015

Figure 3. Organometallic reagent scope for the one-pot preparation of sulfonamides

In his latest publication, Willis reports a combination of the previous two DABSO-based methodologies where the ammonium sulfonate intermediate obtained from palladium catalysed sulfination of an (hetero)aryl iodide is further reacted with an amine in the presence of sodium hypochlorite (Scheme 2). Both electron withdrawing and donating groups are tolerated on the aryl moiety. More interesting however is the compatibility of the reaction conditions with the presence of other functional groups (esters, nitriles, ketones, phenols) but also thiols, allowing for the presence of sulfur atoms at different oxidative levels in the same molecule.

Michael Scheme 2 30-11-2015

Scheme 2.

The scope of the amines also tolerated was examined and the telescoped two steps, one pot procedure is highly tolerant of vulnerable functional groups. Example 4b in the table below clearly highlights how tolerant the reaction is to sensitive functionalities with both methyl thiol and acetal moieties untouched (Figure 4).

Michael Fig 4 30-11-2015

Figure 4. Reaction scope

Willis clearly exemplifies over a few publications how having access to an easy to handle surrogate of SO2 allows for the rapid development of novel reactions to prepare key functional groups such as sulphonamides.

Blog written by Michael Paradowski


Palladium-Catalyzed Synthesis of Ammonium Sulfinates from Aryl Halides and a Sulfur Dioxide Surrogate: A Gas- and Reductant-Free Process; Edward J. Emmett, Barry R. Hayter, and Michael C. Willis*; Angew. Chem. Int . Ed. 2014, 53, 10204 –10208

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis; Alex S. Deeming, Claire J. Russell, and Michael C. Willis*; Angew. Chem. Int. Ed. 2015, 54, 1168 –1171

One-Pot Sulfonamide Synthesis Exploiting the Palladium-Catalyzed Sulfination of Aryl Iodides; Emmanuel Ferrer Flegeau, Jack M. Harrison, Michael C. Willis*; Synlett, 2015, DOI: 10.1055/s-0035-1560578.

Halt Inflammation! Friend or Foe?

At the recent UK Cystic Fibrosis (CF) conference in Manchester, Professor Stuart Elborn gave a talk highlighting the change in understanding of the pulmonary microbiome, in health and disease and the implications for CF therapy. Originally the lung was thought of as a sterile environment, however, in the last decade with new DNA-based sequencing detection techniques, it has shown an unappreciated complexity in the bacterial microbiome of the respiratory tract (Figure 1) akin to the well-established Gut microflora paradigm. The healthy lung has a plethora of bacteria which help maintain a healthy airway, this homeostasis in chronic lung diseases however, is upset and shifts to an overgrowth of anaerobic Proteobacteira and Actinobacteria, (dysbiosis) which can lead to a cycle of infection, airway obstruction and uncontrolled inflammation as seen in CF. These findings have further extended an already growing list of “emerging CF pathogens,” but this raises interesting questions not only about exactly which microbes contribute to CF lung disease, but also about how the complex CF spectrum of microbial communities respond to antibiotics currently in use and under evaluation (Chmiel et al, 2014).

Roy 25-11-2015 Figure 1

Figure 1 Bacterial dysbiosis during chronic lung disorders. a | In healthy individuals, the composition of the airway microbiota is diverse and well balanced. Chronic lung disorders such as asthma, chronic obstructive pulmonary disease (COPD) and its exacerbations, and cystic fibrosis are accompanied by bacterial dysbiosis, which is due to the outgrowth of certain bacteria. Patients with asthma and COPD have many similarities in the bacteria causing dysbiosis. b | Bacterial dysbiosis during asthma is caused by an outgrowth of the Proteobacteria phylum and a shift in the proportion of Streptococci in the Firmicutes phylum. c | In patients with COPD, bacterial communities show an increase in Staphylococci and Streptococci, in addition to an outgrowth of the whole Proteobacteria phylum. d | Shifts in bacterial communities in the lungs of patients with cystic fibrosis are of a slightly different nature. As in asthma and COPD, Proteobacteria outgrow in the lungs of patients with cystic fibrosis. However, no changes in the Firmicutes phylum have been detected, whereas Actinobacteria are clearly overrepresented (Marsland and Gollwitzer, 2014)

In CF, gene mutations in CFTR leads to loss of function in CFTR on the epithelial apical membrane, meaning chloride and bicarbonate ions can no longer be secreted in to the airways. As a consequence of this, increased amounts of Na+ are absorbed into the cell, with Cl following through the paracellular pathway. Subsequently water is drawn from the airway surface layer (ASL) into the cells. This depletion of water from the ASL results in (i) increased mucus concentration, (ii) flattening of the cilia, and (iii) adhesion of the mucus layer to the airway surface (Buchanan et al 2009). The environment produced as a consequence is rich in thick sticky mucus and provides the perfect milieu for colonization and propagation of bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus. Infection with the gram-positive organisms P. aeruginosa, S. aureus in the CF lung are associated with poorer clinical outcomes, such as rapid lung function decline, increased risk of pulmonary exacerbation, and greater rates of mortality or need for lung transplantation. Infections by both Gram-positive and Gram-negative bacteria aggravate the underlying mutations in the CF lung by exaggerating the host’s pro-inflammatory response e.g. increased levels of inflammatory cytokines, catecholamines, temperature, glucose and free ATP; along with bronchoconstriction altering regional oxygen concentrations and pH. With acute mucus production and vascular permeability this increases local nutrient supply and airway mucus also introduces further gradients of local anoxia and hyperthermia, all of which selectively favour the growth of the CF specific lung pathogens of S. aureus and P.aeruginosa (Dickson et al., 2014). This causes the recruitment of additional neutrophils to the airways resulting in further release of pro-inflammatory mediators, which leads to the self-perpetuating cycles of airway obstruction, infection, and inflammation (Figure 2).

Roy 25-11-2015 Figure 2

Figure 2. A model for cystic fibrosis (CF) lung disease pathophysiology. According to this model, defective ion and fluid transport due to a CFTR mutation results in inadequate clearance of mucus and the material it traps in CF airways. The retained material results in a cycle of airways obstruction, inflammation, and infection (Hoffman & Ramsey 2012).

With the promise of the new CF therapies in the next decade, i.e. CFTR potentiators and CFTR correctors for all CF patients, along with the existing therapies such as Pulmozyme, mannitol and hypertonic saline, it is likely that most patients will soon be able to maintain improved lung function and nutritional status well into adulthood.

As our understanding of the dynamics of airway bacterial ecology continues to expand, so too will the opportunities to develop novel strategies to better manage airway dysbiosis in CF. The CF airway should now be considered an integrated microbial community, rather than the domain of a few key pathogens, with the future focus on improving and maintaining a healthy bacterial community balance; through the specific killing of the ‘bad bugs’, but also research and develop improved therapies of ASL hydration and therefore improve muco-ciliary clearance which will return the lung to homeostasis.

Blog written by Roy Fox

Invertebrate models for CNS drug discovery

The blood brain barrier (BBB) provides an added challenge to successful neuroscience drug discovery programs. The presence of metabolising enzymes, tight junctions and efflux transporters in the BBB are effective at preventing the passage of xenobiotics into the central nervous system (CNS).

In response to this extra barrier, a variety of in silico, in vivo and in vitro models have been generated to try to understand and assess BBB permeability at earlier stages in the drug discovery process reviewed in depth by Abbott.[1] In general the majority in vitro models lack the structural and functional complexity of the BBB and require multiple assays for an adequate prediction of permeability. In vivo models on the other hand are reflective of the real situation of the BBB, but unfortunately are both low through put and resource intensive, making them inadequate for screening larger sets of compounds needed at the early stages of a drug discovery project.

This year I attended a conference (ISNTD-d3 2015), where I saw a presentation by Dr Peter Nielsen from the company N2MO, on an ex vivo insect brain model for assessing BBB permeability. (Presentation found here: The model itself provides medium throughput (~6 compounds a day) method of assessing BBB permeability of a compound. The advantage this model provides is that the insect BBB is similar in structure to the mammalian BBB. Tight junctions, high content of lipids and similar ABC and SLC transporters are all present in the insect brain,[2] suggesting reasons for why the model correlates well to rat perfusion models, where in vitro models fail. The model also provides the opportunity to measure the kinetics of permeability, as well as generating a figure of total uptake, paracellular diffusion and transcellular transport can also be discriminated.[3] Overall the extent of data generated from this model provides an adequate platform for the early assessment of BBB permeability, a bonus considering that these assays can be run with the first research batch of compound as requirement of material is low.[4] A model well worth considering for neuroscience drug discovery projects.

N2MO company website –

Blog written by Ryan West

[1]         N. J. Abbott, Drug Discov. Today Technol. 2004, 407–416.

[2]         S. Al-qadi, M. Schiøtt, S. Honoré, P. Aadal, L. Badolo, BBA – Gen. Subj. 2015, 1850, 2439–2451.

[3]         K. Hellman, P. A. Nielsen, L. R. Olsen, R. Verdonck, N. J. Abbott, J. Vanden Broeck, G. Andersson, Pharmacol. Res. Perspect. 2014, 2, 1–12.

[4]         P. A. Nielsen, O. Andersson, S. Honore, G. Andersson, Drug Discov. Today 2011, 16, 12–15.

XB or not XB? Pondering the question

Although halogen substituents are omnipresent in fragment screening libraries and drugs, their contribution to the inhibitor’s affinity is poorly understood to date. In rational drug design, only the impact of halogens’ steric and lipophilic influence has often been considered. In recent years, however, the topic of halogen interactions has received a lot of attention. This article explores the range of such interactions, which halogens form with biological macromolecules, mainly halogen bonding and multipolar interactions, with the obvious omission of the halides’ reactivity.

The observation of halogen bonding is not new, but it is not yet widely utilised in structure-based drug design. Compounds containing chlorine, bromine, or iodine can form contacts of the type R−X···Y−R′, where the halogen X acts as a Lewis acid and Y can be any electron donor moiety. This interaction, referred to as “halogen bonding”, is analogous to hydrogen bonding and is driven by a positively charged region, called the σ-hole, on the hind side of X along the R−X bond axis that is caused by anisotropy of electron density on the halogen.

Organic fluorines usually do not have the ability to act as halogen bond donors due to fluorine’s strong electronegativity. However, interactions between carbofluorines and the backbone oxygens of proteins are known. One group applied their analysis of the Protein Data Bank (PDB) and the evidence of short C−F···O contacts (3.0−3.7 Å) in protein−ligand complexes to their own work on the thienopyrimidine class of menin−MLL inhibitors. They found that their inhibitor formed multipolar C−F···O interactions between two CF3 groups and the carbonyls of the two structurally different backbone conformations. This finding could be useful in the design of small molecule inhibitors targeting protein−protein interactions (PPIs). Moreover, these interactions had unique orthogonal geometry relative to the protein backbone. This observation could be utilised in drug design cases where the formation of hydrogen bonds might not be feasible.

A group of scientists has produced a number of publications on the role of halogens and their interactions in drug discovery. In their most recent paper in order to access the importance of the halogen-containing compounds in drug discovery, Zhijian Xu et al. analysed three databases, Thomson Reuters Pharma, ZINC (ZINC Is Not Commercial), and PDB (Protein Data Bank, April 2013 release), and came to some interesting results. The first observation was that the percentage of halogenated drugs is higher in clinical trials (average 34%) than in launched drugs (25%), indicating that organohalogens are more favoured nowadays. Secondly, the percentage of heavy organohalogens has increased from clinical trials to the launched phase, highlighting the attrition of organofluorides during the drug discovery process (Figure 1).

Figure 1. Composition of the organohalogens in different stages during drug discovery and development.

Figure 1. Composition of the organohalogens in different stages during drug discovery and development.

From the analysis of 2,462 PDB structures that have heavy halogenated ligands, a quarter of structures were found to possess 778 halogen bonds. Of those, 82.4% halogen bonds are formed between heavy organohalogens and biomacromolecules and 16.6% are formed between heavy organohalogens and water molecules. The percentage of the latter should be even higher, since not all water molecules could be resolved in a structure with poor resolution. Among the 778 halogen bonds, C−X···Y (O, N, S) halogen bonds were found to be more prevalent (567) in biological systems, the others being C−X···π interactions. C−X···O halogen bonds account for 84.1% of C−X···Y halogen bonds with C−Cl···O halogen bonds contributing 43.6%, two thirds of which are formed to the protein backbone. C−X···Y can also be formed between a halogenated ligand and side chain groups, such as hydroxyls in serine, threonine, and tyrosine, carboxylate groups in aspartate and glutamate, sulfurs in cysteine and methionine, nitrogens in histidine. This plethora of different possibilities in ligand−protein interactions makes halogen bonding a very useful tool to enhance ligand affinities.

In heavy organohalogens, the size of the σ-hole increases with halogen size from chlorine to iodine, resulting in a stronger halogen bonding going from chlorine to iodine. Despite the increasing strength of halogen interactions, an assessment of the possible drawbacks of using bromine and iodine in drug discovery is important. Bromine and iodine atoms considerably increase the overall molecular weight. Yet, other parameters such as size, volume, or molecular surface area, do not change dramatically. The increase in lipophilicity with these atoms is also typically moderate. It is therefore unreasonable to assume that molecular weight-based models can be applied to bromine and iodine in order to characterize them correctly. Bromo and iodo groups are also perceived as problematic in drug design, particularly with respect to oxidative dehalogenation by cytochrome P450 enzymes. This fact, perhaps, explains the prevalence of fluoro- and chloro-containing drugs on the market. However, the choice of the core scaffold, that the halogen is attached to, also plays a role on the strength of halogen bonding, as Rainer Wilcken et al. discussed in their paper. The introduction of electron-withdrawing substituents on the halogen-bearing scaffold typically increases the strength of the halogen bonding and may also have an effect on the metabolic stability of the molecule, thus allowing the possibility to tune both properties.

Currently, there are very few computational molecular design packages that recognize halogen bonding as a favourable interaction, and they have not yet become part of the regular drug discovery workflow, a fact that impedes more widespread use and recognition of the phenomenon. Clearly, more attention should be given to heavy organohalogens than organofluorine during the drug discovery stage.

R. Wilken et al. further investigated both computationally and experimentally whether an ethynyl moiety is a suitable bioisostere to replace labile iodine in ligands that form halogen bonds with the protein backbone. They found that the molecular electrostatic potentials for halobenzenes (Cl, Br, I) and phenylacetylene are remarkably similar in distribution of positive and negative charges of the C-X/H bond (where X=Cl, Br, I or ethynyl) (Figure 2a). Such bioisosteric replacement was successfully utilised in the EGFR inhibitors erlotinib (Figure 2b,c), as well as in a series of 1,4-benzodiazepine-2,5-dione inhibitors of the HDM2-p53 interaction.

Figure 2. Potential for bioisosterism between ethynyl and halogen substituents. (a) Electrostatic potentials plotted onto the isodensity surfaces at 0.003 au for chlorobenzene, bromobenzene, iodobenzene and phenylacetylene. Color ranges of energies in atomic units are also shown. Calculations were done at the MP2/TZVPP level of theory. (b) Structural formulae for gefitinib (left) and erlotinib (right), with the chlorine-to-ethynyl substitution highlighted. (c) Co-crystal structure of gefitinib bound to EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry of the Cl···O halogen bond is highlighted in yellow.

Figure 2. Potential for bioisosterism between ethynyl and halogen substituents. (a) Electrostatic potentials plotted onto the isodensity surfaces at 0.003 au for chlorobenzene, bromobenzene, iodobenzene and phenylacetylene. Color ranges of energies in atomic units are also shown. Calculations were done at the MP2/TZVPP level of theory. (b) Structural formulae for gefitinib (left) and erlotinib (right), with the chlorine-to-ethynyl substitution highlighted. (c) Co-crystal structure of gefitinib bound to EGFR (PDB: 2ITY) in an overlay with the binding mode of erlotinib from PDB 4HJO. The geometry of the Cl···O halogen bond is highlighted in yellow.

However, in their own work the authors found that similar transformation led to an approximately 13-fold loss in affinity for the p53 cancer mutant Y220C inhibitor. The computational calculations suggested that this loss in affinity could be explained by the larger extent and the reduced directionality of the ethynyl group, and therefore is specific to the particular binding site. Nevertheless, halogen to acetylene bioisosteric transformation should be explored where applicable, thanks to other successful examples of drug development, e.g. Tarceva.

Blog written by Irina Chuckowree

Tianeptine-like compounds may be useful for treatment of reverse post-operative respiratory depression associated with opiates

Opiates are analgesic agents and commonly prescribed for the relief of postoperative pain. However the unwanted effects of opiates include respiratory depression which is a concern to physicians. The ability of opiates to reduce respiratory rate, tidal volume and respiratory sensitivity to CO2 has long been known and can be life threatening (3). Central respiratory drive is generated by respiratory neurons in the ventral region of medulla oblongata (specifically RVLM neurons) and has been shown to be responsible for the decrease in the respiratory output following systemic administration of opiates (4). In an emergency, administration of µ-opiate receptor antagonists such as naloxone is highly effective for reversing the respiratory depression. However administration of naloxone also takes the patient out of analgesia. Therefore development of novel compounds that prevent respiratory depression associated with opiate analgesia without interfering with their analgesic effects is important for postoperative depression.

What are AMPAkines?

AMPAkines are positive allosteric modulators (PAMs) for the treatment for respiratory depression.

  • Glutamate is the major excitatory neurotransmitter in the CNS and fast excitatory transmission is mediated by AMPA-type glutamate receptors
  • AMPAkines are positive allosteric modulators of the AMPA-type glutamate receptor. AMPAkines prolong and strengthen synaptic transmission
  • Neurons in this brainstem region (RVLM) control in respiratory breathing rhythm and use AMPA receptors for signaling (4).
  • Opiates mediate their inhibitory effects on breathing at this brain region (RVLM) and AMPA-PAMs normalize breathing by enhancing firing of RVLM respiratory rhythm neurons.

What is Tianeptine?

Tianeptine, is a new class of antidepressant agent which increases the serotonin uptake in the brain and reduces stress-induced atrophy of neuronal dendrites without the side effects associated with SSRI (2). As well acting on serotonergic system tianeptine also shown to act on other neuronal pathways. A study by Kole at al shown that tianeptine enhanced, or prolong, synaptic plasticity and suggested that this actions are modulating the glutamate receptors in the CA3 region of the hippocampus (it modulate glutamate receptors by stabilising NMDA receptor to AMPA/kainate receptor-mediated currents (6). Study by Zhang et al shown that tianeptine enhanced the amplitude of excitatory post synaptic potentials (EPSPs) in murine hippocampal slices, an effect which is blocked by kinase inhibitors (5). However the exact mechanism of action is still unclear.

The ability of tianeptine to facilitate AMPA-mediated glutamatergic transmission is shown in a recent publication by Cavalla et al. The authors have tested the effects of tianeptine compounds on opiate-induced respiratory depression in a conscious rat animal model. The study has demonstrated that in conscious rats, when tianeptine is administered systemically, it increases the respiratory output and prevents morphine-induced respiratory depression without effecting opiate induced analgesia. They also tested CX-546 (an AMPAkine) on morphine-induced respiratory depression on the same model, showing that upregulation in the respiratory rate, tidal volume and minute ventilation are induced by successive injection of CX546 and morphine in conscious rats. There are concerns that up-regulated AMPA-mediated signaling can potentially induce patients to epileptic seizures, but seizures were not observed in this study (1).

This study provides encouraging evidence that Tianeptine can counter and reduce respiratory depression without interfering with analgesia. Development of therapeutic agents in this area will bring great clinical benefit.

Blog written by Hedaythul Choudhury


  1. Cavalla D, Chianelli F, Korsak A, Hosford PS, Gourine AV, Marina N. (2015) Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats. EJP 761 (2015) 268-272
  2. Wagstaff AJ, Ormrod D, Spencer CM. (2001) Tianeptine: a review of its use in depressive disorders. CNS Drugs. 2001; 15 (3):231-59.
  3. Shook JE1, Watkins WD, Camporesi EM. (1990) Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis. 1990 Oct; 142(4):895-909.
  4. Richter DW, Spyer KM. (2001) Studying rhythmogenesis of breathing: comparison of in vivo and in vitro models. Trends Neurosci. 2001 Aug; 24(8):464-72.
  5. Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, Chaouloff F, Spedding M, Lambert JJ, Choquet D, Groc L. (2013) Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol Psychiatry. 2013 Apr; 18(4):471-84. doi: 10.1038/mp.2012.80. Epub 2012 Jun 26.
  6. Kole MH, Swan L, Fuchs E. (2002) The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur J Neurosci. 2002 Sep; 16 (5):807-16.

The impact of N-methylation on aqueous solubility and lipophilicity

N-Methylation is a common transformation used by medicinal chemists in drug discovery programs. This small transformation, which only adds 14 units of molar mass, can be carried out to improve the pharmacological effect of a compound by filling an additional pocket in an enzyme binding site or to mask a hydrogen bond donor responsible for a poor DMPK property. For instance, hydrogen bond donors can drive transporters recognition and their removal can significantly improve compound absorption. However, this small chemical modification often induces a change in other physicochemical properties of the drug such as clearance, aqueous solubility and lipophilicity.

Using matched molecular pair analysis, a team of scientist at GSK highlighted the effect of methylating heteroatoms on measured CLND aqueous solubility and lipophilicity (Med. Chem. Commun., 2015, 6, 1787-1797). All experimental CLND solubility and chromatographic log D data were collected from GSK in-house dataset. As a medicinal chemist working on a lead optimisation project and trying to balance pharmacological potency with physicochemical properties, I found this information of considerable value and thought that it would be useful to share it with my fellow medicinal chemists.

The analysis conducted by the authors reveals that overall N-methylation of secondary amides leads to an increase in log solubility despite a concomitant increase in log D. However, three distinct classes of secondary amides can be distinguished. Upon N-methylation, amides derived from aliphatic acids show a small increase in solubility and higher log D, whereas amides from aromatic acids exhibit a more pronounced solubility increase and less impact on log D. In the case of amides derived from aromatic acids and anilines, the solubility increase is accompanied by a significant log D reduction. This is explained by a change in the conformation of the compound upon N-methylation. The variation in the C-C-N-C torsion angle indicates a switch from Z- to E-amide geometry. Despite the loss of the polar NH and addition of a hydrophobic methyl group, the loss of planarity increases water-accessible polar surface area, leading to higher solubility and lower lipophilicity. N-methylation of primary aliphatic and aromatic amides has little effect on solubility but increases lipophilicity. N-methylation of cyclic secondary amide does not increase solubility but induces a pronounced increase in log D, indicating that in this case there is no conformational modification but simply the replacement of a polar hydrogen by a hydrophobic methyl.

Amide NH can be part of intramolecular hydrogen bonds with a suitable acceptor at proximity. The majority of molecules with such motifs adopt planar conformations which have impact on physical properties, such as membrane permeability, protein binding, aqueous solubility and lipophilicity. N-methylating amides with intramolecular H-bonds generally induce an increase in solubility and a log D decrease, although the magnitude of these effects depends on the type of intramolecular H-bond.

In contrast to amides, the N-methylation of sulfonamides results in a more expected behavior, with an increase in log D and decrease in solubility. The rationale behind this behavior is that N-methylation of sulfonamides has little impact on conformation. Addition of the hydrophobic methyl decreases polar surface area and hence increases lipophilicity and decrease solubility. The sulfonamide NH can also have an acidic pKa, being partially deprotonated at physiological pH and masking this solubilizing moiety increases lipophilicity and lowers solubility.

Ureas are known to hamper the solubility of drug molecules. This analysis of the GSK dataset revealed that methylation of ureas derived from anilines appears to increase solubility considerably, to a larger extent than what was observed for amides. Upon N-methylation, aromatic ureas gain conformational freedom, leading to increase solubility despite an increase in lipophilicity.

N-methylation of secondary amines has little impact on solubility but log D increases, independently on their structure. A small reduction in basicity is also observed with a reduction of pKa of 1 unit for the amine nitrogen upon methylation.

The effect of O-methylation is also described and gives very predictive results with a significant increase in lipophilicity and a concomitant decrease in solubility. This effect is more pronounced when the transformation is carried out on carboxylic acids. However, this transformation is not of interest for medicinal chemists since introduction of esters in drug molecules is undesired.

Figure 1: Scatter plot summarising the impact of N-methylation on aqueous solubility and lipophilicity for a variety of substrate

Figure 1: Scatter plot summarising the impact of N-methylation on aqueous solubility and lipophilicity for a variety of substrate

The conclusion form this study is that a small change in structure such as a methylation can lead to profound changes in conformation and physical properties. Depending on the substrate, N-methylation can have opposite effect on solubility and lipophilicity (Figure 1). The results emphasize the importance of the local chemical environment around the methylation heteroatom.

Blog written by Tristan Reullion