Application of sulfoximines in medicinal chemistry from 2013 to 2020.

In recent years, interest in sulfoximine chemistry has been greatly increased. For example, at least three sulfoximine containing drugs BAY 1143572, BAY 1251152 and AZD6738 have entered the clinic. Despite the increasing interest in sulfoximines and their chemistry, the routine application of this structure in drug discovery is still hampered due to limited experience in physicochemical and in vitro parameters of sulfoximines. Therefore, we reviewed all relevant articles from 2013 to the present in terms of potency and pharmacokinetic properties in order to support the addition of the sulfoximine component to the toolbox of medicinal chemists.

Profiling and Identification of Biocatalyzed Transformation of Sulfoxaflor In Vivo.

In the present study, we investigated the biotransformation of the neonicotinoid pesticide sulfoxaflor and the metabolic responses in Sprague-Dawley rats. Sulfoxaflor transformation was catalyzed by cytochrome P450 while five phase I and four phase II metabolites were identified for the first time in vivo. The experimental results demonstrated that sulfoxaflor brought about the metabolic profiling disturbances in liver and bile. Exposure to sulfoxaflor caused dysregulation of bile acid synthesis and reabsorption by the expression of farnesoid X receptor (FXR). Our data provided insights into biotransformation of chemicals while enabling the implementation of a new toolbox for the design of sulfoximine compounds.

Major sulfonate transporter Soa1 in Saccharomyces cerevisiae and considerable substrate diversity in its fungal family.

Sulfate is a well-established sulfur source for fungi; however, in soils sulfonates and sulfate esters, especially choline sulfate, are often much more prominent. Here we show that Saccharomyces cerevisiae YIL166C(SOA1) encodes an inorganic sulfur (sulfate, sulfite and thiosulfate) transporter that also catalyses sulfonate and choline sulfate uptake. Phylogenetic analysis of fungal SOA1 orthologues and expression of 20 members in the sul1Δ sul2Δ soa1Δ strain, which is deficient in inorganic and organic sulfur compound uptake, reveals that these transporters have diverse substrate preferences for sulfur compounds. We further show that SOA2, a S. cerevisiae SOA1 paralogue found in S. uvarum, S. eubayanus and S. arboricola is likely to be an evolutionary remnant of the uncharacterized open reading frames YOL163W and YOL162W. Our work highlights the importance of sulfonates and choline sulfate as sulfur sources in the natural environment of S. cerevisiae and other fungi by identifying fungal transporters for these compounds.

Preclinical characterization of acyl sulfonimidamides: potential carboxylic acid bioisosteres with tunable properties.

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pKa , lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities.

The tert-butyl group is a common motif in medicinal chemistry. Its incorporation into bioactive compounds is often accompanied by unwanted property modulation, such as increased lipophilicity and decreased metabolic stability. Several alternative substituents are available for the drug discovery process. Herein, physicochemical data of two series of drug analogues of bosentan and vercirnon are documented as part of a comparative study of tert-butyl, pentafluorosulfanyl, trifluoromethyl, bicyclo[1.1.1]pentanyl, and cyclopropyl-trifluoromethyl substituents.

Isotope dilution mass spectrometry for the quantification of sulfane sulfurs.

Sulfane sulfurs are one type of important reactive sulfur species. These molecules have unique reactivity that allows them to attach reversibly to other sulfur atoms and exhibit regulatory effects in diverse biological systems. Recent studies have suggested that sulfane sulfurs are involved in signal transduction processes regulated by hydrogen sulfide (H2S). Accurate and reliable measurements of sulfane sulfurs in biological samples are thus needed to reveal their production and mechanisms of actions. Herein we report a convenient and accurate method for the determination of sulfane sulfur concentrations. The method employs a triphenylphosphine derivative (P2) to capture sulfane sulfurs as a stable phosphine sulfide product, PS2. The concentration of PS2 was then determined by isotope dilution mass spectrometry, using a (13)C3-labeled phosphine sulfide, PS1, as the internal standard. The specificity and efficiency of the method were proven by model reactions. It was also applied to the measurement of sulfane sulfurs in mouse tissues including brain, kidney, lung, liver, heart, spleen, and blood.

Application of a novel integrated toxicity testing strategy incorporating "3R" principles of animal research to evaluate the safety of a new agrochemical sulfoxaflor.

Plant protection products (PPPs) and the active substance(s) contained within them are rigorously and comprehensively tested prior to registration to ensure that human health is not impacted by their use. In recent years, there has been a widespread drive to have more relevant testing strategies (e.g., ILSI/HESI-ACSA and new EU Directives), which also take account of animal welfare, including the 3R (replacement, refinement, and reduction) principles. The toxicity potential of one such new active substance, sulfoxaflor, a sulfoximine insecticide (CAS #946578-00-3), was evaluated utilizing innovative testing strategies comprising: (1) an integrated testing scheme to optimize information obtained from as few animals as possible (i.e., 3R principles) through modifications of standard protocols, such as enhanced palatability study design, to include molecular endpoints, additional neurotoxicity and immunotoxicity parameters in a subchronic toxicity study, and combining multiple test guidelines into one study protocol; (2) generation of toxicokinetic data across dose levels, sexes, study durations, species, strains and life stages, without using satellite animals, which was a first for PPP development, and (3) addition of prospective mode of action (MoA) endpoints within repeat dose toxicity studies as well as proactive inclusion of specific MoA studies as an integral part of the development program. These novel approaches to generate key data early in the safety evaluation program facilitated informed decision-making on the need for additional studies and contributed to a more relevant human health risk assessment. This supplement also contains papers which describe in more detail the approach taken to establish the MoA and human relevance framework related to toxicities elicited by sulfoxaflor in the mammalian toxicology studies: developmental toxicity in rats mediated via the fetal muscle nicotinic acetylcholine receptor (nAChR) ( Ellis-Hutchings et al. 2014 ); liver tumors in rodents mediated via CAR/PXR ( LeBaron et al. 2014 ); and Leydig cell tumors in Fischer 344 rats ( Rasoulpour et al. 2014 ).

Digestive recovery of sulfur-methyl-L-methionine and its bioaccessibility in Kimchi cabbages using a simulated in vitro digestion model system.

BACKGROUND: Sulfur-methyl-L-methionine (SMM) has been known to provide various biological functions such as radical scavenging effect, inhibition of adipocyte differentiation, and prevention of gastric mucosal damage. Kimchi cabbages are known to be a major food source providing SMM but its bioaccessibility has not been studied. The objective of current study was to determine both the digestive stability of SMM and the amount released from Kimchi cabbages under a simulated in vitro digestion model system. RESULTS: The in vitro digestion model system simulating a human gastrointestinal tract was carried out for measuring digestive recovery and bioaccessibility of SMM. SMM was quantified by using high-performance liquid chromatography with a fluorescence detector. Recovery of an SMM standard after digestion was 0.68 and 0.65% for fasted and fed conditions, respectively, indicating that the digestive stability of the SMM standard was not affected by dietary energy or co-ingested food matrix. The SMM standard was also significantly stable in acidic pH (P < 0.05). The bioaccessibility of SMM from Kimchi cabbages was measured under a fasted condition, resulted in 8.83, 14.71 and 10.88%, for salivary, gastric and small intestinal phases, respectively. CONCLUSION: Results from our study suggest that SMM from Kimchi cabbages, a component of food sources, is more bioavailable than SMM by itself.

Potential therapeutic effects of functionally active compounds isolated from garlic.

The medicinal properties of functionally active organosulfur compounds such as allin, diallyl disulfide, S-allylmercaptocysteine, and S-trityl-L-cysteine isolated from garlic have received great attention from a large number of investigators who have studied their pharmacological effects for the treatment of various diseases. These organosulfur compounds are able to prevent for development of cancer, cardiovascular, neurological, and liver diseases as well as allergy and arthritis. There have been also many reports on toxicities and pharmacokinetics of these compounds. The aim of this study is to review a variety of experimental and clinical reports, and describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of pharmaceutical actions of functionally active compounds isolated from garlic.

Expedition of in vitro dissolution and in vivo pharmacokinetic profiling of sulfur nanoparticles based antimicrobials.

A comprehensive pharmacokinetic profiling of novel drugs and therapeutics is a definite prerequisite of drug discovery and development. The present study expedites the in vivo and in vitro pharmacokinetic properties of colloidal sulfur nanoparticles (SNPs). In vitro dissolution properties of SNPs have been demonstrated and compared with the in vivo pharmacokinetic parameters of rabbit (Oryctolagus cuniculus) serum sample. The present study was also aimed at developing levels of correlation between in vitro and in vivo pharmacokinetic parameters. Cumulative results of the proposed study also suggest good in vitro-in vivo correlation of these novel nanocolloids and suggest their immediate profiling as an antimicrobial drug.

A review of developmental and reproductive toxicity of CS2 and H2 S generated by the pesticide sodium tetrathiocarbonate.

BACKGROUND: Sodium tetrathiocarbonate (STTC) is an example of a pesticide that when prepared for use in aqueous solution releases two toxic products carbon disulfide (CS2 ) (active ingredient) and hydrogen sulfide (H2 S) in ambient air in equimolar concentrations resulting in potential exposure to workers and bystanders. CS2 and H2 S are pollutants that are generated from several pesticides as well as in industrial settings. METHODS: Registrant submitted reports and open literature studies for STTC, CS2 and H2 S were reviewed. Previous reports suggest that CS2 was a concern as a developmental and reproductive toxicant. H2 S was also examined since it is a neurotoxicant and potentially harmful to developing fetuses. RESULTS: STTC did not induce developmental or reproductive effects in animal studies. CS2 was a developmental neurobehavioral toxin in rat pups (inhalation no observed effect level [NOEL]=0.01 ppm). Reproductive effects occurred in male and female factory workers after CS2 exposure (NOEL=1 ppm). H2 S had developmental effects in rats at doses at or above those observed for nasal pathology (NOEL=10 ppm) but was not a reproductive or developmental toxin in humans. CONCLUSIONS: The database for CS2 indicates a strong potential for developmental neurotoxicity in animals at low doses but it is lacking in acceptable, well-performed studies. There is also a lack of studies performed with CS2 and H2 S as a mixture.

Determination of a highly selective mixed-affinity sigma receptor ligand, in rat plasma by ultra performance liquid chromatography mass spectrometry and its application to a pharmacokinetic study.

A selective, rapid and sensitive ultra performance liquid chromatography mass spectrometry (UPLC/MS) method was developed and validated to quantitate a highly selective mixed-affinity sigma receptor ligand, CM156 (3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d] thiazole-2(3H)-thione), in rat plasma. CM156 and the internal standard (aripiprazole) were extracted from plasma samples by a single step liquid-liquid extraction using chloroform. The analysis was carried out on an ACQUITY UPLC™ BEH HILIC column (1.7 µm, 2.1 mm×50 mm) with isocratic elution at flow rate of 0.2 mL/min using 10mM ammonium formate in 0.1% formic acid and acetonitrile (10:90) as the mobile phase. The detection of the analyte was performed on a mass spectrometer operated in selected ion recording (SIR) mode with positive electrospray ionization (ESI). The validated analytical method resulted in a run time of 4 min and the retention times observed were 2.6±0.1 and 2.1±0.1 min for CM156 and the IS, respectively. The calibration curve exhibited excellent linearity over a concentration range of 5-4000 ng/mL with the lower limit of quantification of 5 ng/mL. The intra- and inter-day precision values were below 15% and accuracy ranged from -6.5% to 5.0%. The mean recovery of CM156 from plasma was 96.8%. The validated method was applied to a pilot intravenous pharmacokinetic study in rats.

Idiosyncratic reactions and metabolism of sulfur-containing drugs.

INTRODUCTION: Idiosyncratic drug reactions (IDRs) that involve the formation of toxic metabolites followed by covalent binding to cellular proteins often go undiscovered until after post-marketing. The goal of this article is to review the current status of IDRs, potential mechanisms and the challenges associated with predicting drug toxicity. AREAS COVERED: The authors review the metabolic pathways of five select classes of sulfur-containing drugs (captopril, troglitazone, tienilic acid, zileuton, methimazole and sudoxicam) suggesting that bioactivation plays a crucial role in the occurrence of IDRs. The reader will gain further awareness that the sulfur atom can propagate as the bioactivation site for the formation of reactive and conceivably toxic metabolites. As such, it is the body's capacity to detoxify these drug products that may determine whether IDRs occur. EXPERT OPINION: Incomplete understanding of mechanisms culminating in IDR occurrence represents a monumental impediment toward their abrogation. Moreover, current technology utilized to predict their manifestation (including structure-toxicity relationships) is not infallible and thus, development of novel tools and strategies is indispensible. In an attempt to streamline clinical development and drug approval processes, consortiums have been instated under the US FDA Critical Path Initiative. Collectively, these parameters along with the availability of validated biomarkers and new/updated regulatory guidance could positively influence the outcome of drug toxicity profiles and direct future drug development.

Percutaneous penetration modifiers and formulation effects: thermal and spectral analyses.

The study investigated the formulation effects of laurocapram and iminosulfurane derived penetration modifiers on human stratum corneum using thermal and spectral analyses. Firstly, formulations of penetration modifiers were assessed as enhancers/retardants using the model permeant, diethyl-m-toluamide followed by investigation of their mechanisms of action using differential scanning calorimetry (DSC) and attenuated total reflectance Fourier-transform infra-red spectroscopy. The penetration modifiers investigated were laurocapram, 3-dodecanoyloxazolidin-2-one (N-0915), S,S-dimethyl-N-(4-bromobenzoyl) iminosulfurane (DMBIS), S,S-dimethyl-N-(2-methoxycarbonylbenzenesulfonyl) iminosulfurane (DMMCBI) and tert-butyl 1-dodecyl-2-oxoazepan-3-yl-carbamate (TBDOC) that were formulated in either water, propylene glycol (PG), ethanol or polyethylene glycol 400 (PEG 400). The results explain the mechanism for the first time why an enhancer can become a retardant or vice versa depending upon the vehicle in which it is applied to the skin. DSC indicated that penetration modifier formulations enhanced permeation of active mainly by disruption and fluidization of the stratum corneum lipid bilayers while IR data indicated characteristic blue shifts with decreases in peak intensity. On the other hand, DSC of penetration modifier formulations showing retardation depicted elevated T (m2) with a strengthening of lipid-protein complex while IR results indicated formation of multiple peaks around 1,738 cm(-1) transition in stratum corneum spectra suggesting retardation may be caused by organization of SC lipids by increased H-bonding.

Ionic liquids screening for desulfurization of natural gasoline by liquid-liquid extraction.

Seventy five ionic liquids (ILs) were tested as a sequestering agent of sulfured compounds in natural gasoline (NG). Desulphurization of NG was performed by means of liquid-liquid extraction method at room temperature and atmospheric pressure. Experimental ILs containing imidazolium, pyridinium, and ammonium cations along with organic and inorganic anions were synthesized conventionally and under microwave and sonochemical conditions. The effect of the molecular structure of ILs on the desulfurization efficiency of NG with high sulfur content was evaluated. Analysis indicated that the anion type played a more important role than the cation on the desulphurization process. ILs based on halogen-ferrates and halogen-aluminates exhibited the highest efficiency in sulfur removal, and their efficiency is further improved when there is an excess of metallic salt in a ratio of at least 1:1.3 during the synthesis of the corresponding IL. An explanation for the ability of metallic ILs to remove sulfur-containing compounds from natural gasoline based on the ratio of the ionic charge to the atomic radius is proposed. Furthermore, a method to recover and reuse water-sensitive to halogenated precursors is described.

Glutathione S-transferase catalyzed desulfonylation of a sulfonylfuropyridine.

MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.

An investigation of the interaction of iminosulfurane transdermal penetration enhancers with model skin preparations using NMR spectroscopy.

The (31)P NMR resonance from the inner and outer leaflets of DMPC in unilamellar vesicle bilayers has been split by use of the slowly penetrating paramagnetic shift reagent, Pr(3+). The perturbing effect of subsequently added iminosulfurane transdermal penetration enhancers (TPEs) is to accelerate the collapse of this splitting, especially in the case of the bromo derivative 3. The aforementioned acceleration of the splitting is enhanced by the addition of 16 mol% cholesterol. Conversely, 33 mol% cholesterol appears to seal the bilayer to the effect of the TPEs--even when present at 20 mol%. These observations are consistent with the deep penetration of the TPEs into the DMPC bilayer, i.e., the perturbation of the bilayer is transmembrane and supports a model in which a subset of the bromo TPE derivative 3 is kinetically trapped in the bilayer. This feature leads to an enhanced residence time of 3 in the bilayer, and by extension to the skin, and therefore to an explanation for the markedly enhanced activity of the bromo TPE derivative relative to that of other halogenated derivatives in the series of iminosulfuranes studied.

In vivo uptake of inhaled particles by airway phagocytes is enhanced in patients with mild asthma compared with normal volunteers.

BACKGROUND: The uptake of inhaled particulate matter by airway phagocytes is an important defence mechanism contributing to the clearance of potentially toxic substances, including aeroallergens, from the lung. Since airway monocytes and macrophages can also function as antigen presenting cells, their ability to engulf materials deposited on the airway surface is of particular interest in patients with allergic asthma. To determine whether airway mononuclear phagocytes of patients with allergic asthma might have enhanced phagocytic activity, the in vivo uptake of inhaled radiolabelled particles was compared in 10 patients with mild allergic asthma and 8 healthy (non-allergic) individuals. METHODS: Phagocyte function was assessed by quantifying the proportion of radioactivity associated with cellular and supernatant fractions of induced sputum 2 h after inhalation of radiolabelled sulfur colloid particles. All subjects were pretreated with albuterol before sputum induction. A standardised breathing pattern was used to target aerosol deposition in the bronchial airways. RESULTS: In vivo particle uptake by airway cells was significantly greater in patients with asthma than in healthy volunteers (57.2% (95% CI 46.5% to 67.9%) vs 22.3% (95% CI 4.9% to 39.6%), p<0.01), as was in vitro phagocytosis of opsonised zymosan-A bioparticles. There was also a significant correlation (r = 0.85, p<0.01) between the percentage of sputum mononuclear phagocytes and the percentage uptake of particles in the patients with asthma but not in the control subjects. CONCLUSIONS: In vivo particle uptake by airway macrophages is enhanced in persons with mild asthma. Enhanced uptake and processing of particulate antigens could contribute to the pathogenesis and progression of allergic airways disease and may contribute to the increased risk of disease exacerbation associated with particulate exposure.

Basic design and synthesis of sulfonated contrast agents for magnetic resonance imaging based on gadolinium complexes.

Magnetic resonance angiography (MRA) is an imaging method to examine blood vessels based on the magnetic resonance imaging (MRI) technique. For this purpose, blood pool contrast agents have been developed to selectively increase the signal intensity of the intravascular lumen for improvement of the contrast-to-noise ratio in MR images. Here, we describe the design and the syntheses of six novel sulfonated contrast agents (KMR-Sulfo1 - 6), their chemical properties and their in vivo applications. In this study, we investigated the lipophilicity and the hydrophilicity of a gadolinium complex using a convenient two-step synthesis route, with the goal of prolonging the plasma half-life by binding mainly to human serum albumin. We confirmed that KMR-Sulfo5 fulfilled the requirements as a blood pool contrast agent: it showed a sufficient relaxivity r(1) of 5.9 mM(-1) s(-1), a long plasma half-life of 25.7 min and complete elimination from the body within 12 h after the administration.

Evaluation of capravirine as a CYP3A probe substrate: in vitro and in vivo metabolism of capravirine in rats and dogs.

Metabolism of [(14)C]capravirine was studied via both in vitro and in vivo means in rats and dogs. Mass balance was achieved in rats and dogs, with mean total recovery of radioactivity >86% for each species. Capravirine was well absorbed in rats but only moderately so in dogs. The very low levels of recovered unchanged capravirine and the large number of metabolites observed in rats and dogs indicate that capravirine was eliminated predominantly by metabolism in both species. Capravirine underwent extensive metabolism via oxygenation reactions (predominant pathways in both species), depicolylation and carboxylation in rats, and decarbamation in dogs. The major circulating metabolites of capravirine were two depicolylated products in rats and three decarbamated products in dogs. However, none of the five metabolites was observed in humans, indicating significant species differences in terms of identities and relative abundances of circulating capravirine metabolites. Because the majority of in vivo oxygenated metabolites of capravirine were observed in liver microsomal incubations, the in vitro models provided good insight into the in vivo oxygenation pathways. In conclusion, the diversity (i.e., hydroxylation, sulfoxidation, sulfone formation, and N-oxidation), multiplicity (i.e., mono-, di-, tri-, and tetraoxygenations), and high enzymatic specificity (>90% contribution by CYP3A4 in humans, CYP3A1/2 in rats, and CYP3A12 in dogs) of the capravirine oxygenation reactions observed in humans, rats, and dogs in vivo and in vitro suggest that capravirine can be a useful CYP3A substrate for probing catalytic mechanisms and kinetics of CYP3A enzymes in humans and animal species.