Synthesis, spectroscopic characterization, DFT calculations, in silico-ADMET and molecular docking analysis of novel quinoline-substituted 5H-chromeno [2,3-b] pyridine derivatives as antibacterial agents.

A convenient, straightforward, and effective one-step reaction for the synthesis of a three-component compound of biologically relevant novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno[2,3-b] pyridine-3-carbonitrile derivatives was designed and synthesized. The synthesis was developed by the reaction between salicylaldehyde 1, 8-hydroxyquinoline 2, 2-aminopropene-1,1,3-tricarbonitrile 3, and the catalytic amount of triethylamine in ethanol at 78 °C. This methodology has many beneficial features, including the use of inexpensive and non-hazardous starting materials, single-flask reactions, optimized reaction conditions, the termination of intermediate isolation, easy workup, reducing organic waste products, being chromatography-free, and decreasing the reaction time along with quantitative yields with high functional group tolerance. A proposed mechanism with supporting experimental data is presented, including 1H NMR, 13C NMR, 2D NMR (HMBC, COSY, HSQC), mass, and IR spectroscopy, which are used to characterize the complete derivatives. All synthesized compounds were evaluated in vitro for their antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains via the agar-well diffusion method compared with the reference drug gentamicin. The data indicated that compounds 4A, 4F, 4G, 4 J, and 4K consistently demonstrated strong antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, a molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds via the crystal structure of the S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT). Density functional theory (DFT) calculations were performed to determine the various molecular properties of the synthesized novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno [2,3-b] pyridine-3-carbonitrile derivatives (4A-4 M). On the basis of the reactive sites explored by the molecular electrostatic potential maps, the antibacterial activities of the compounds were screened.

Identification of novel scaffold using ligand and structure based approach targeting shikimate kinase.

Tuberculosis (TB) remains a major global health problem. It causes ill-health among millions of people each year and rank as the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Shikimate kinase is one of the major enzymes targeted for TB. Most approaches to overcome TB were based on synthesis and screening of a known compounds to obtain a few representatives with desired potency. In this study, we have applied a virtual screening approach which combines ligand- and structure-based approaches to screen a large library of compounds as a starting point for the identification of new scaffolds for the development of shikimate kinase inhibitors. The combined approach has identified 2 new scaffolds as potential inhibitors of shikimate kinase. To prove the approach, few of the molecules and their derivatives, a total of 17 compounds, were synthesized. The compounds were tested for biological activity and shows moderate activity against shikimate kinase. The shikimate kinase enzyme inhibition study reveals that the compounds showed inhibition (IC50) at concentrations of 50 µg/mL (Compounds 21, 22, 24, 25, 26, 27, 30, 32, 34) and 25 µg/mL (14, 19, 23, 31, 33).

Syn vs Anti Carboxylic Acids in Hybrid Peptides: Experimental and Theoretical Charge Density and Chemical Bonding Analysis.

A comparative study of syn vs anti carboxylic acids in hybrid peptides based on experimental electron density studies and theoretical calculations shows that, in the anti form, all three bond angles surrounding Ccarboxyl of the -COOH group are close to ∼120°, as expected for a C-sp2 atom, whereas in the syn form, the ∠Cα-C(O)-Ohydroxyl angle is significantly smaller by 5-10°. The oxygen atom in the carboxyl group is more electronegative in the anti form, so the polarity of the acidic O-H bond is higher in the anti form compared to the syn form, as observed within the limitations of H atom treatment in X-ray diffraction. Consequently, the investigated anti carboxylic acid forms the strongest O-H···O hydrogen bond among all model compounds. Furthermore, according to natural bond orbital analysis, the oxygen lone pairs are clearly nonequivalent, as opposed to the general notion of hybridization of equivalent sp2 and sp3 lone pairs on carbonyl or hydroxyl oxygen atoms. The hybridization of the lone pairs is directly related to the directionality and strength of hydrogen bonds.

Directing peptide conformation with centrally positioned pre-organized dipeptide segments: studies of a 12-residue helix and ß-hairpin.

Secondary structure formation in oligopeptides can be induced by short nucleating segments with a high propensity to form hydrogen bonded turn conformations. Type I/III turns facilitate helical folding while type II'/I' turns favour hairpin formation. This principle is experimentally verified by studies of two designed dodecapeptides, Boc-Val-Phe-Leu-Phe-Val-Aib-Aib-Val-Phe-Leu-Phe-Val-OMe 1 and Boc-Val-Phe-Leu-Phe-Val-(D)Pro-(L)Pro-Val-Phe-Leu-Phe-Val-OMe 2. The N- and C-terminal flanking pentapeptide sequences in both cases are identical. Peptide 1 adopts a largely α-helical conformation in crystals, with a small 310 helical segment at the N-terminus. The overall helical fold is maintained in methanol solution as evidenced by NMR studies. Peptide 2 adopts an antiparallel ß-hairpin conformation stabilized by 6 interstrand hydrogen bonds. Key nuclear Overhauser effects (NOEs) provide evidence for the antiparallel ß-hairpin structure. Aromatic proton chemical shifts provide a clear distinction between the conformation of peptides 1 (helical) and 2 (ß-hairpin). The proximity of facing aromatic residues positioned at non-hydrogen bonding positions in the hairpin results in extensively ring current shifted proton resonances in peptide 2.

Temperature-induced reversible first-order single crystal to single crystal phase transition in Boc-γ(4)(R)Val-Val-OH: interplay of enthalpy and entropy.

Crystals of Boc-γ(4)(R)Val-Val-OH undergo a reversible first-order single crystal to single crystal phase transition at Tc ≈ 205 K from the orthorhombic space group P22121 (Z' = 1) to the monoclinic space group P21 (Z' = 2) with a hysteresis of ∼2.1 K. The low-temperature monoclinic form is best described as a nonmerohedral twin with ∼50% contributions from its two components. The thermal behavior of the dipeptide crystals was characterized by differential scanning calorimetry experiments. Visual changes in birefringence of the sample during heating and cooling cycles on a hot-stage microscope with polarized light supported the phase transition. Variable-temperature unit cell check measurements from 300 to 100 K showed discontinuity in the volume and cell parameters near the transition temperature, supporting the first-order behavior. A detailed comparison of the room-temperature orthorhombic form with the low-temperature (100 K) monoclinic form revealed that the strong hydrogen-bonding motif is retained in both crystal systems, whereas the non-covalent interactions involving side chains of the dipeptide differ significantly, leading to a small change in molecular conformation in the monoclinic form as well as a small reorientation of the molecules along the ac plane. A rigid-body thermal motion analysis (translation, libration, screw; correlation of translation and libration) was performed to study the crystal entropy. The reversible nature of the phase transition is probably the result of an interplay between enthalpy and entropy: the low-temperature monoclinic form is enthalpically favored, whereas the room-temperature orthorhombic form is entropically favored.

Transition metals-doped g-C3N4 nanostructures as advanced photocatalysts for energy and environmental applications.

Graphitic carbon nitride (g-C3N4)-based heterostructured photocatalysts have received significant attention for its potential applications in the treatment of wastewater and hydrogen evolution. The utilization of semiconductor materials in heterogeneous photocatalysis has recently received great attention due to their potential and eco-friendly properties. Doping with metal ions plays a crucial role in altering the photochemical characteristics of g-C3N4, effectively enhancing photoabsorption into the visible range and thus improving the photocatalytic performance of doped photocatalysts. As an emerging nanomaterial, nanostructured g-C3N4 represents a visible light-active semiconducting photocatalyst that has attracted significant interest in the photocatalysis field, particularly for its practical water treatment applications. To the best of our knowledge, investigations of functionalized photocatalytic (PC) materials on 3d transition metal-doped g-C3N4 remain unexplored in the existing literature. g-C3N4 based heterohybrid photocatalysts have demonstrated excellent reusability, making them highly promising for wastewater treatment applications. This paper describes the overview of numerous studies conducted on the heterostructured g-C3N4 photocatalysts with various 3d metals. Research studies have revealed that the introduction of element doping with various 3d transition metals (e.g., Ti, Mn, Fe, Co, Ni, Cu, Zn, etc.) into g-C3N4 is an efficient approach to enhance degradation efficacy and boost photocatalytic activity (PCA) of doped g-C3N4 catalysts. Moreover, the significance of g-C3N4 heterostructured nanohybrids is highlighted, particularly in the context of wastewater treatment applications. The study concludes by providing insights into future perspectives in this developing area of research, with a specific focus on the degradation of various organic contaminants.

An overview of mechanism and chemical inhibitors of shikimate kinase.

Tuberculosis is a highly infectious disease other than HIV/AIDS and it is one of the top ten causes of death worldwide. Resistance development in the bacteria occurs because of genetic alterations, and the molecular insights suggest that the accumulation of mutation in the individual drug target genes is the primary mechanism of multi-drug resistant tuberculosis. Chorismate is an essential structural fragment for the synthesis of aromatic amino acids and synthesized biochemically by a number of bacteria, including Mycobacterium tuberculosis, utilizing the shikimate pathway. This shikimate kinase is the newer possible target for the generation of novel antitubercular drug because this pathway is expressed only in mycobacterium and not in Mammals. The discovery and development of shikimate kinase inhibitors provide an opportunity for the development of novel selective medications. Multiple shikimate kinase inhibitors have been identified via insilico virtual screening and related protein-ligand interactions along with their in-vitro studies. These inhibitors bind to the active site in a similar fashion to shikimate. In the current review, we present an overview of the biology and chemistry of the shikimate kinase protein and its inhibitors, with special emphasis on the various active scaffold against the enzyme. A variety of chemically diversified synthetic scaffolds including Benzothiazoles, Oxadiazoles, Thiobarbiturates, Naphthoquinones, Thiazoleacetonitriles, Hybridized Pyrazolone derivatives, Orthologous biological macromolecule derivatives, Manzamine Alkaloids derivatives, Dipeptide inhibitor, and Chalcones are discussed in detail. These derivatives bind to the specific target appropriately proving their potential ability through different binding interactions and effectively explored as an effective and selective Sk inhibitor.Communicated by Ramaswamy H. Sarma.

Does follistatin gene have any direct role in the manifestation of polycystic ovary syndrome in Indian women?

BACKGROUND: Out of a panel of 37 candidate genes tested for linkage with polycystic ovary syndrome (PCOS), the strongest evidence of linkage was reported in the follistatin (FST) gene region. Subsequently, a couple of studies outside India investigated the FST gene for the presence of any mutations and its association with PCOS and the results were found to be largely inconsistent probably due to differences in the ethnic backgrounds and small sample sizes. AIMS: To screen the FST gene for mutations and to establish their association pattern with PCOS among a large cohort of South Indian women. SETTINGS AND DESIGN: Case-control study. MATERIALS AND METHODS: PCOS cases were recruited according to the 2003 Rotterdam diagnostic criteria. All the exons of the FST gene were amplified and analyzed in all the cases and controls for the presence of mutations using polymerase chain reaction (PCR) and direct DNA sequencing. RESULTS: A total of 549 women consisting of 250 PCOS cases and 299 controls were recruited for the study. No mutations were found in any of the exons of the FST gene in our Indian sample which is consistent with an earlier finding among the Asian women from Singapore. Although three of the four cohorts of Caucasian background studied earlier reported variants, none of them could establish a strong association with PCOS. CONCLUSIONS: The occurrence of the exonic variants of FST gene seems to be dependent on the ethnic background of the subjects under study and its role in the PCOS pathophysiology cannot be established with hitherto available evidence.

Crystallography, in Silico Studies, and In Vitro Antifungal Studies of 2,4,5 Trisubstituted 1,2,3-Triazole Analogues.

A series of 2,4,5 trisubstituted-1,2,3-triazole analogues have been screened for their antifungal activity against five fungal strains, Candida parapsilosis, Candida albicans, Candida tropicalis, Aspergillus niger, and Trichophyton rubrum, via a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) microdilution assay. Compounds GKV10, GKV11, and GKV15 emerged as promising antifungal agents against all the fungal strains used in the current study. One of the highly active antifungal compounds, GKV10, was selected for a single-crystal X-ray diffraction analysis to unequivocally establish its molecular structure, conformation, and to understand the presence of different intermolecular interactions in its crystal lattice. A cooperative synergy of the C-H···O, C-H···N, C-H···S, C-H···π, and π···π intermolecular interactions was present in the crystal structure, which contributed towards the overall stabilization of the lattice. A molecular docking study was conducted for all the test compounds against Candida albicans lanosterol-14α-demethylase (pdb = 5 tzl). The binding stability of the highly promising antifungal test compound, GKV15, from the series was then evaluated by molecular dynamics studies.

Synthesis of one-dimensional gold nanostructures and the electrochemical application of the nanohybrid containing functionalized graphene oxide for cholesterol biosensing.

This manuscript reports a new approach for the synthesis of one dimensional gold nanostructure (AuNs) and its application in the development of cholesterol biosensor. Au nanostructures have been synthesized by exploiting ß-diphenylalanine (ß-FF) as an sacrificial template, whereas the Au nanoparticles (AuNPs) were synthesized by ultrasound irradiation. X-ray diffractometer (XRD), scanning electron microscope (SEM) and energy dispersive analysis of X-rays (EDAX) have been employed to characterize the morphology and composition of the prepared samples. With the aim to develop a highly sensitive cholesterol biosensor, cholesterol oxidase (ChOx) was immobilized on AuNs which were appended on the graphite (Gr) electrode via chemisorption onto thiol-functionalized graphene oxide (GO-SH). This Gr/GO-SH/AuNs/ChOx biosensor has been characterized using cyclic voltammetry (CV), electrochemical impedance spectroscopy and chronoamperometry. CV results indicated a direct electron transfer between the enzyme and the electrode surface. A new potentiostat intermitant titration technique (PITT) has been studied to determine the diffusion coefficient and maxima potential value. The proposed biosensor showed rapid response, high sensitivity, wide linear range and low detection limit. Furthermore, our AuNs modified electrode showed excellent selectivity, repeatability, reproducibility and long term stability. The proposed electrode has also been used successfully to determine cholesterol in serum samples.

Efficacy of weekly compared with daily iron supplementation.

A reduction in the frequency of iron supplement administration to once or twice weekly is being widely examined in developing countries on the assumption that the side effects of oral iron will decrease and that the reduction in administered iron will be offset by a lesser inhibition in absorption from iron taken on the previous day. We examined this premise by measuring iron absorption from 50 mg radiolabeled ferrous sulfate in 23 female volunteer subjects divided into two groups. In the first group, a labeled ferrous sulfate supplement was given with water, and in the second group it was given with a rice-based meal. In both groups, absorption was measured in a randomized fashion twice in each subject, once with daily and once with weekly supplementation. Those tested for daily supplementation were given an iron supplement daily for 6 d before testing whereas those tested for weekly supplementation were given no iron for 6 d before testing. When the labeled iron supplement was given with water only, absorption averaged 8.5% with daily and 9.8% with weekly administration compared with 2.3% and 2.6%, respectively, when given with food. The 13% lower absorption observed with daily administration in both groups was not statistically significant (P > 0.20). These results indicate that there is no significant absorptive advantage in giving iron less often than once daily.

Effect of calcium intake on nonheme-iron absorption from a complete diet.

Recent studies based on radioiron measurements from single meals have suggested that calcium has a strongly inhibitory influence on nonheme-iron absorption. In view of evidence that the importance of various dietary enhancers and inhibitors of absorption is greatly diminished when assessed by labeling a complete diet, the present study evaluated the effect of variations in calcium intake on total dietary nonheme-iron absorption. Nonheme-iron absorption was measured in 14 healthy volunteers during three periods in which the diet was freely chosen or modified to decrease or increase dietary calcium intake maximally. The diet was labeled during each 5-d period by including with each of the two main meals of the day a small bread roll tagged extrinsically with radioiron. Carefully maintained dietary records indicated that 69-78% of the daily iron intake was labeled by this method. The basal calcium intake of 684 mg/d varied from 280 to 1281 mg/d when calcium intake was reduced or increased, respectively. Geometric mean iron-absorption values of 5.01%, 4.71%, and 5.83% for the three dietary periods were not significantly different from one another. No significant relation was observed between nonheme-iron absorption and dietary factors known to influence iron absorption. We conclude that calcium intake had no significant influence on nonheme-iron absorption from a varied diet.

Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet.

BACKGROUND: Ascorbic acid has a pronounced enhancing effect on the absorption of dietary nonheme iron when assessed by feeding single meals to fasting subjects. This contrasts with the negligible effect on iron balance of long-term supplementation with vitamin C. OBJECTIVE: Our goal was to examine the effect of vitamin C on nonheme-iron absorption from a complete diet rather than from single meals. DESIGN: Iron absorption from a complete diet was measured during 3 separate dietary periods in 12 subjects by having the subjects ingest a labeled wheat roll with every meal for 5 d. The diet was freely chosen for the first dietary period and was then altered to maximally decrease or increase the dietary intake of vitamin C during the second and third periods. RESULTS: There was no significant difference in mean iron absorption among the 3 dietary periods despite a range of mean daily intakes of dietary vitamin C of 51-247 mg/d. When absorption values were adjusted for differences in iron status and the 3 absorption periods were pooled, multiple regression analysis indicated that iron absorption correlated negatively with dietary phosphate (P = 0.0005) and positively with ascorbic acid (P = 0.0069) and animal tissue (P = 0.0285). CONCLUSIONS: The facilitating effect of vitamin C on iron absorption from a complete diet is far less pronounced than that from single meals. These findings may explain why several prior studies did not show a significant effect on iron status of prolonged supplementation with vitamin C.

Assessment of dietary determinants of nonheme-iron absorption in humans and rats.

Prior investigations have shown that rats are less sensitive than humans to dietary factors that influence the absorption of nonheme iron. This investigation was undertaken to determine whether this disparity is due to differences in the methods used to measure absorption in the two species. By use of identical methodology and test meals, absorption studies were performed in rats and humans to compare the effect of known dietary enhancers (ascorbic acid and meat) and inhibitors (tea, bran, and soy protein) on nonheme-iron absorption. Meat and tea had a marked effect on absorption in humans but did not influence absorption in rats. Although the effect of ascorbic acid, soy protein, and bran on absorption was statistically significant in rats, the absorptive response was far less than it was in humans. Our studies indicate that rodents cannot be used to assess the quantitative importance of dietary factors in human iron nutrition.

Estimation of nonheme-iron bioavailability from meal composition.

BACKGROUND: Considerable data are available on the individual effects of dietary factors on nonheme-iron absorption, but their combined effect when they are present in the same meal is not known. OBJECTIVE: Our objective was to predict the bioavailability of iron from complex meals that are consumed commonly in the United States on the basis of the contents of factors that are known to promote or inhibit food iron absorption. DESIGN: Radioisotopic measurements of nonheme-iron absorption from 25 meals were made in 86 volunteer subjects by using extrinsic radioiron labeling. The meal contents of nonheme iron, calcium, ascorbic acid, polyphenols, and phytic acid were determined by biochemical analysis; energy and protein contents were estimated from food-composition tables. Animal tissue content was based on weight or was obtained from the manufacturer. RESULTS: After adjusting iron absorption for differences in iron status, the significant biochemical predictors of iron absorption as determined by multiple regression analysis were the contents of animal tissue (P = 0.0001), phytic acid (P = 0.0001), and ascorbic acid (P = 0. 0441). Collectively, these 3 variables accounted for 16.4% of the variation in absorption. On the basis of the multiple regression analysis, we developed the following equation to estimate iron absorption: Ln absorption, % (adjusted to serum ferritin concentration of 30 microg/L) = 1.9786 + (0.0123 x animal tissue in g) - (0.0034 x phytic acid in mg) + (0.0065 x ascorbic acid in mg). CONCLUSION: For the 25 meals evaluated, only the contents of animal tissue, phytic acid, and ascorbic acid were useful for estimating nonheme-iron absorption.

The effect of red and white wines on nonheme-iron absorption in humans.

The effect of the phenolic compounds in wine was examined in this study by performing radioiron-absorption measurements from extrinsically labeled test meals in 33 human subjects. In four separate studies we observed that absorption was 2- to 3-fold higher from white wine containing a low concentration of polyphenols than from two red wines containing a 10-fold higher concentration of polyphenols. The interaction between the polyphenols and alcohol in wine was evaluated by reducing the alcohol content of the wines by approximately 90%. When the alcohol concentration was reduced, there was a significant 28% decrease in nonheme-iron absorption with red wine but no effect with white wine. The inhibitory effect of red wines with reduced alcohol content was about twofold greater when they were consumed with a small bread roll than when taken without food. Our findings indicate that the inhibitory effect of phenolic compounds in red wine is unlikely to affect iron balance significantly.

The influence of different protein sources on phytate inhibition of nonheme-iron absorption in humans.

The inhibiting effect of phytate on nonheme-iron absorption from different protein sources was examined in human subjects using extrinsic radioiron labeling. A drink containing maltodextrose and corn oil was used as a control meal to which was added sufficient sodium phytate to provide 300 mg phytic acid and/or various protein sources. The proteins were selected to cover a broad range of effects on bioavailability and included egg white, meat, and phytate-free soy protein. When sodium phytate alone was added, there was a pronounced 83-90% reduction in mean absorption in separate studies with a composite average decline of 86%. Despite a wide range in absorption from meals containing the three protein sources, a remarkably similar relative inhibition was observed when sodium phytate was added. No significant difference in the inhibiting effect of phytate could be detected with additions ranging from the equivalent of 50-300 mg phytic acid to a meal containing egg white as the protein source. Our studies found no evidence that the inhibiting effect of phytate depends on the protein composition of the meal.

The influence of different cereal grains on iron absorption from infant cereal foods.

Iron absorption from various cereal grains was evaluated in the present study to identify possible preferences for the preparation of infant weaning foods. In six separate studies, four radioiron absorption tests were performed in each of 57 volunteer subjects by using a sequential double-isotopic method. Serum ferritin concentration was used to adjust for the effect of differences in the iron status of subjects participating in separate studies. Identical commercial processing and test meal composition were used to evaluate iron absorption from 50 g cooked cereal prepared from rice, wheat, maize, oats, millet, and sweet or bitter quinoa. In an initial evaluation of cereals fortified with 2.5 mg Fe as FeSO4, geometric mean absorption values were uniformly < 1% for all cereals and were not significantly different. In subsequent studies, percentage iron absorption was enhanced by either eliminating the fortifying iron or adding 50 mg ascorbic acid to the test meal. The effect was similar for most of the cereals tested with a composite mean increase in absorption of 37% when fortifying iron was removed and 270% when ascorbic acid was added. There was a strong inverse correlation between iron absorption and the phytate content of different cereals. Except for a modestly lower absorption of iron from quinoa and a remarkably higher absorption from one lot of maize, we conclude that the type of cereal grain has little influence on iron bioavailability of infant cereals. On the other hand, modification in the milling and processing methods for cereal grains that reduce their content of phytic acid is likely to improve iron availability significantly.

Soy protein, phytate, and iron absorption in humans.

The effect of reducing the phytate in soy-protein isolates on nonheme-iron absorption was examined in 32 human subjects. Iron absorption was measured by using an extrinsic radioiron label in liquid-formula meals containing hydrolyzed corn starch, corn oil, and either egg white or one of a series of soy-protein isolates with different phytate contents. Iron absorption increased four- to fivefold when phytic acid was reduced from its native amount of 4.9-8.4 to less than 0.01 mg/g of isolate. Even relatively small quantities of residual phytate were strongly inhibitory and phytic acid had to be reduced to less than 0.3 mg/g of isolate (corresponding to less than 10 mg phytic acid/meal) before a meaningful increase in iron absorption was observed. However, even after removal of virtually all the phytic acid, iron absorption from the soy-protein meal was still only half that of the egg white control. It is concluded that phytic acid is a major inhibitory factor of iron absorption in soy-protein isolates but that other factors contribute to the poor bioavailability of iron from these products.

Physiologically relevant one-compartment pharmacokinetic models for skin. 2. Comparison of models when combined with a systemic pharmacokinetic model.

Transport of chemicals through skin is best modeled as passive diffusion through a membrane, but mathematical solutions for realistic conditions are cumbersome. Compartment models, representing skin as a stirred tank, are mathematically simpler but less physiologically relevant. In a previous paper, several different compartment models were developed assuming constant blood and vehicle concentrations. Here, five skin models (four of the previously described compartment models and one membrane model) are combined with a one-compartment systemic pharmacokinetic (PK) model to examine the effects of changing vehicle and blood concentrations and to clarify how differences between skin models affect the predicted systemic response. The skin-PK models were solved with the same input parameters (i.e., permeability coefficients, partition coefficients, skin thickness, and cutaneous blood flow rates) and compared for five different exposure scenarios. Because the models have different underlying assumptions, they do predict different results. For many exposure situations compartment models give acceptable results, with the most pronounced differences from the membrane model during short exposure times. Generally, the compartment model that most closely represents the membrane model was developed by forcing it to match the membrane model for conditions similar to those of the given exposure scenario.