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The main aim is to develop a simple, rugged, and sensitive method for determining the Montelukast Sodium-related impurities in a tablet dosage form using reverse-phase high-performance liquid chromatography (RP-HPLC) method. Chromatographic separation on the Agilent Eclipse XDB C18 (octadecylsilane) column of the dimension (100 mm × 4.6 mm, 5 µm) was carried out in the gradient mode with triethylamine and acetonitrile in various combinations and adjusted to a pH of 6.60 using phosphoric acid. The mobile phase was pumped at a flow rate of 1.0 mL min−1 and the analyte was monitored with a UV detector at a wavelength of 220 nm. The method was developed and validated under the stress conditions such as acidic, basic, peroxide, thermal, photolytic, and humidity degradation, respectively. Under the above conditions, oxidative degradation was performed which served as the system suitability solution providing a resolution of 2.5 between the Impurity 3 (retention time = 13.8 min) and Montelukast Sodium (retention time = 24.2 min). The method was validated with respect to specificity, linearity, precision, accuracy, limit of detection, and limit of quantification provided by the ICH guidelines. Results of linear regression analysis of the calibration plot revealed a good linear relationship between response and concentration with a correlation coefficient value of r2 = 0.9999. The accuracy of known impurities was obtained in the range of 94–108%. From the analysis, their LOD and LOQ values for impurities were measured and found to be 0.007 and 0.025 μg g−1, respectively. Chromatographic interference was not found during the degradation and excipients were detected from the tablet. The proposed method was successfully used to estimate the Montelukast Sodium-related impurities in a tablet dosage form.

Chemoselective catalytic oxidation of olefin derivatives containing alcoholic and olefinic groups is important in organic synthesis. In the present study, Co–Salen immobilized on SBA-15 was synthesized and characterized to study its chemoselective catalytic activity towards the oxidation of cinnamyl alcohol and cinnamaldehyde, with tert-butyl hydroperoxide as the oxidant at 60, 70 and 80 oC. Cinnamyl alcohol selectively yielded cinnamaldehyde at the reactant ratio of cinnamyl alcohol tert-butyl hydroperoxide equal to 1:0.5. Cinnamaldehyde selectively yielded 2,3-epoxy-cinnamaldehyde at the ratio of cinnamaldehyde tert-butyl hydroperoxide equal to 1:0.5. The catalyst yielded epoxide with many styrene derivatives and benzaldehyde with benzyl alcohol, but only cinnamaldehyde with cinnamyl alcohol, thus proving its applicability for chemoselective catalytic oxidation of olefin derivatives. The cinnamaldehyde conversion and selectivity to 2,3-epoxy-cinnamaldehyde increased with the increase in the content of tert-butyl hydroperoxide. So, this study establishes that the catalyst can be applied to selective oxidation of primary alcoholic function without affecting olefinic double bonds. The conversion was maximum at 70 oC. The conversion and product selectivity remained the same for 5 cycles thus endorsing stability of the catalysts. Based on the activity and selectivity of the catalysts, it is inferred that the same catalyst can be exploited for selective oxidation of multifunctional olefin derivatives.

Our recent investigations for the radiosynthesis of [18 F]fluoromethyl tosylate have highlighted that choice of quaternary methyl ammonium (QMA) cartridge used during the radiosynthesis can significantly impact the radiochemical yields. Often the details of the QMA cartridge used in fluourine-18 syntheses are not fully described. However, our studies demonstrate that the type, the size, and nature (method by which it has been conditioned) of the QMA cartridge used during the radiosynthesis can make a significant impact in the labelling efficiency. This paper investigates the use of three QMA cartridges and demonstrates that radiochemical yield (decay corrected) of [18 F]fluoromethyl tosylate can increase from 46% to 60% by simply changing the QMA cartridge (and leaving all other reagents and labelling conditions exactly the same). These learnings may be applied to improve the radiochemical yields of a number of [18 F]-fluorinated tracers (and synthons), where the labelling step is base-sensitive to increase the radiochemical yield, thereby significantly benefiting the radiochemistry and nuclear medicine community. This paper also highlights the necessity of the radiochemistry community to ensure the details of QMA cartridges used in fluorine-18 chemistry are fully and accurately described, since this will improve the translation of radiochemical methods from one laboratory to another.

18 F-radiolabeled diphenyl gallium thiosemicarbazone was prepared by [18 F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).

[18F]Fluoroethyl tosylate was synthesized using an automated “Synthra” module using ethylene di-tosylate and [18F]fluoride/K222/K2CO3 in acetonitrile. [18F]Fluoroethyl tosylate was purified by semi-preparative HPLC followed by reformulation using a C18 Sep-Pak cartridge and eluted with DMF. Using this [18F]fluoroethyl tosylate, we attempted to alkylate protected tryptophan aiming to obtain the N-[18F]fluoroethyl-t-Boc-tryptophan methyl ester. Initial attempts resulted in the formation of the O-alkylated, rather than N-alkylated product. Manual removal of the cartridge from the automated module, followed by an extended drying of the cartridge under high flow nitrogen, was required to form the desired N-alkylated product. This demonstrates that the drying process in automated modules requires modification for sensitive N-alkylation of compounds and may be essential for compounds like tryptophan methyl ester that have multiple potential sites of alkylation in their chemical structure.

The organic crystal 4-aminopyridinium 4-hydroxy benzoate hydrate was grown using slow evaporation method. Various characterization techniques such as single crystal X-ray diffraction, powder X-ray diffraction, FTIR, UV–visible–NIR spectroscopy and thermal analysis (TG-DSC) were employed to assay the structure and properties of the grown crystal. The antimicrobial evaluation of 4-aminopyridinium 4-hydroxy benzoate hydrate crystal was also performed against some bacteria and fungi. The minimum inhibitory concentration (MIC) values of 4-aminopyridinium 4-hydroxy benzoate hydrate were determined for bacterial and fungal strains. The assessment of optimized structure of the molecule and vibrational frequencies were done using DFT/B3LYP method with 6-31 G (d, p) basis set. The stability of the molecule, hyperconjugative interactions, delocalization of charges and intermolecular hydrogen bond were studied by applying natural bond orbital (NBO) analysis. TD-DFT method employing polarizable continuum model (PCM) was used to examine the electronic absorption spectrum. Evaluation of molecular electrostatic potential (MEP), Mulliken population charges and nonlinear optical (NLO) properties were also carried out. In addition, from the optimized geometry, frontier molecular orbitals analysis was executed.

The Surface modifications of Fe3O4/rGO/ZnSnO3 nanocomposites showed good dye degradation performance with Methylene blue dye under the halogen lamp (visible) 500 nm light source. The Fe3O4/rGO/ZnSnO3 composite was synthesized by in-situ method and characterized with techniques like XRD, Raman, morphological studies and electrochemical sensing performance also investigated. The ternary composite showed remarking ability and an enhanced degradation with charge separation. The Fe3O4/rGO/ZnSnO3 nanocomposite materials enhanced the electrochemical sensing of uric acid for the modified electrode, this result are more satisfying. The electrochemical sensing and the photocatalytic properties of Fe3O4/rGO/ZnSnO3 nanocomposites are synergism owing to the amazing morphological results and diameter size of the materials. We conclude that the Fe3O4/rGO/ZnSnO3 composite shows 64% degradation at 1 h in the visible light. Fe3O4/rGO/ZnSnO3 modified electrodes have a diffusion-controlled process with the two-electron transfer for the sensing of uric acid.

The charge-transfer interactions between n-electron donor, atorvastatin calcium (ATC) and the electron acceptors, 2,5-dihydroxy-1,4-benzoquinone (DHBQ), 1,2,5,8-tetrahydroxy-9,10-anthraquinone (quinalizarin, Quiz), and 2,4,6-trinitrophenol (picric acid, PA) as π-acceptors have been studied spectrophotometrically in methanol by giving highly colored charge transfer complexes. The isolated solid charge-transfer complexes were characterized by elemental, IR, NMR, mass and thermal analysis to elucidate the chemical structure of the obtained solid CT complexes. The stoichiometry of the complexes was found to be 1:2 in [ATC]:[reagent] at DHBQ, quinalizarin, picric acid. This ratio gave the formed charge-transfer complexes in the formulas [(ATC)(DHBQ)2], [(ATC)(Quiz)2], and [(ATC)(PA)2] which was also confirmed by elemental and mass analysis. Their biological activities were also screened against various bacterial organisms. The obtained results are suitable for the estimation of antihyperlipidemic drug, ATC in pharmaceutical dosage forms.

The present study deals with the synthesis, characterization and photocatalytic activity of g-C3N4/ZnO composite towards the degradation of significant dyes like Malachite green (MG), Rhodamine-B (Rh–B), Congo red (Con-R), and Red ink (RI) solution. For the synthesis of the g-C3N4/ZnO composite, we have adopted the chemical precipitation method where the composite was thoroughly analyzed for the crystallinity, optical performance, and morphology by making use of the instrumental methods like powdered X-ray diffraction (PXRD), Fourier transform–infrared spectroscopy (FTIR), UV–Vis diffuse reflection spectroscopy (UV–Vis), Transmission electron microscopy (TEM), Atomic force microscopy (AFM), and thermogravimetric (TGA) analysis. It was found from the PXRD and TEM analysis that the composite maintains hexagonal wurtzite phases for the ZnO and g-C3N4 compounds, while the UV–Vis spectrum confirmed that the composite's absorption edge is getting shifted to the lower energy and wavelength region as compared to ZnO. On testing the photocatalytic activity under the UV light towards the dye degradation, the g-C3N4/ZnO composite is indicated to have significant performance and thereby supporting the synergistic impact of each component. The observation of such activity in the g-C3N4/ZnO composite can be investigated to be due to the composite's enhanced stability in the aqueous solution (supported by the lower amounts of Zn2+), in addition to the improved electron-hole separations and synergistic photocatalytic mechanism between ZnO and g-C3N4.

A comparative study of experimental and calculated NMR chemical shifts of six compounds comprising 2-amino and 2-hydroxy phenyl benzoxazoles/benzothiazoles/benzimidazoles in four solvents is reported. The benzimidazoles showed interesting spectral characteristics, which are discussed. The proton and carbon chemical shifts were similar for all solvents. The largest chemical shift deviations were observed in benzene. The chemical shifts were calculated with density functional theory using a suite of four functionals and basis set combinations. The calculated chemical shifts revealed a good match to the experimentally observed values in most of the solvents. The mean absolute error was used as the primary metric. The use of an additional metric is suggested, which is based on the order of chemical shifts. The DP4 probability measures were also used to compare the experimental and calculated chemical shifts for each compound in the four solvents. Copyright © 2015 John Wiley & Sons, Ltd.

Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging β-amyloid in Alzheimer's disease. These precursors were radiolabeled with 11C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring.

The synthesis and spectroscopic characterization of four new 2-(4-aminophenyl)benzothiazole substituted 1,4,7-triazacyclononane derivatives with and without appended pyridyl groups on the macrocycle is reported: 1-(2-(4-aminophenyl)benzothiazolyl)-2-oxoethyl)-1,4,7-triazacyclononane (L1), 1-(2-(4-aminophenyl)benzothiazolyl)-2-oxoethyl)-4-(2-pyridylmethyl)-1,4,7-triazacyclononane (L2), 1-(2-(4-N-methylaminophenyl)benzothiazolyl)-2-oxoethyl)-4-(2-pyridylmethyl)-1,4,7-triazacyclononane (L3), 1,4-bis(2-pyridylmethyl)-7-(2-(4-aminophenyl)benzothiazolyl)-2-oxoethyl)-1,4,7-triazacyclononane (L4). The ligands have been applied in the synthesis of a series of copper (II) complexes, [Cu(L1)(OH2)](ClO4)2·0.5ACN (C1), [Cu(L3)](ClO4)2·ACN (C2) and [Cu(L4)(OH2)](ClO4)2·0.5THF (C4) whose structures have been determined by X-ray crystallography. As commonly observed for Cu(II) complexes of 1,4,7-triazacyclononane derivatives, the geometry of the metal centre ranges from distorted square pyramidal to pseudo-octahedral. Notably, the amide carbonyl coordinates to the copper(II) centre in C1 and C2 but not in C4 where the presence of an additional pyridyl group results in an N5 coordination sphere.

Al-MCM-48 molecular sieves (Si/Al molar ratios = 25, 50, 75, and 100) were synthesized hydrothermally using cetyltrimethylammonium bromide as the structure directing template. The orderly arrangement of mesopores was evident from the low angle X-ray diffraction patterns and transmission electron microscopy images. The catalytic performance of the materials was evaluated in the vapor phase isopropylation of phenol with isopropyl acetate. Phenol conversion decreased with the increase in the Si/Al ratio of the catalysts. The major reaction product was 4-isopropyl phenol with 78% selectivity. The delocalization of phenolic oxygen electron pair over the aromatic ring promoted para -selective alkylation. Such delocalization could be aided by the hydrophilic surface of the molecular sieves. Although an ester was used as the alkylating agent, phenyl isopropyl ether was not formed in the reaction.

Al-SBA-1 (Si/Al = 40, 80 and 120) and Al,Mg-SBA-1 (Si/(Al + Mg) = 40 and 80) molecular sieves were synthesized and characterized. Acetalization of n -heptanal with methanol was studied under autogenous pressure between 80 and 150 °C. Since protonation of n -heptanal was fast, addition of methanol to the same formed hemiacetal slowly whereas conversion of hemiacetal to acetal was fast. The catalysts exhibited nearly similar conversion irrespective of their difference in acidity, and all of them showed more than 80% conversion either at 80 or 100 °C. Hence, it is evident that the difference in acidity is not so important in differentiating the activity of the catalysts. The large pore size and hydrophilic and hydrophobic properties are suggested to be the main factors that control acetalization.

Synthesis of piperazinyl-substituted oxazolopyridine and benzoxazole was achieved in three steps starting from aminophenol and carbon disulfide. Condensation of aminophenols with carbon disulfide in ethanol using potassium hydroxide as catalyst gave the required benzoxazole thiol in one step. Treatment of the thiol with piperazine and substituted piperazine derivatives in toluene furnished the titled compounds in good yield. We introduced halogen substitution in the pendant arm of the piperazine derivatives for versatile functionalization. We report the synthesis and characterization of these compounds using high resolution NMR techniques.

The synthesis of 1- and 2-cinnamoyloxyacetonaphthones was achieved in one step using hydroxyl acetonaphthones and substituted cinnamic acids in the presence of a catalytic amount of phosphoroxychloride. Structural characterization was accomplished using high-resolution nuclear magnetic resonance (NMR) spectroscopy. Chemical shifts of the compounds were compared and the change in the chemical shifts relative to electron-donating and -withdrawing groups is presented. Introduction of a thiophene ring instead of phenyl-substituted analogs caused shielding of the olefinic proton. © 2010 John Wiley & Sons, Ltd.

New Schiff bases containing a hydroxynaphthyl ring and substituted benzothiazolyl groups have been synthesized. High-resolution NMR spectra confirmed that these anils exist as enol–keto tautomers in solution. The results from NMR data demonstrated that the proportion of enol tautomer exceeded 90% in these substituted anils. Some compounds exhibited thermochromism in solid state. Copyright © 2010 John Wiley & Sons, Ltd.

MCM-22 materials (Si/Al ratios 24, 50 and 75) were synthesized and characterized. The catalytic activity was examined in the vapour phase isopropylation of ethylbenzene with isopropyl alcohol. Based on ethylbenzene conversion, the order of activity of the catalysts is found to be MCM-22(50) > MCM-22(24) = MCM-22(75). The selective formation of p-isopropyl ethylbenzene (p-IPEB) suggests that the reaction occurs mainly inside the 10-membered ring channel. The time on stream study over MCM-22(50) showed steady conversion for 6 h with nearly the same selectivity to p-isopropyl ethylbenzene (p-IPEB) and o-isopropyl ethylbenzene (p-IPEB).

Al-MCM-41 (Mobil Composition Mater) (Si/Al = 25) molecular sieve was synthesized hydrothermally and 20 and 40 wt% phosphotungstic acid (PW) was supported on it. The materials were characterized using XRD, pyridine adsorbed FT-IR, 31P and 1H MAS NMR techniques. Catalytic performance of the materials was examined in the liquid phase condensation of resorcinol and ethyl acetoacetate. 7-Hydroxy-4-methylcoumarin was the only product observed in this reaction. The results revealed that 20 wt% PW/Al-MCM-41 is found to be more active than other catalysts. The reaction parameters were optimized to obtain high selectivity of the desired product at maximum resorcinol conversion. The reaction was also performed with substituted phenolic derivatives and ethyl acetoacetate in order to realize the substituent effect.

Several substituted terphenyl derivatives were prepared following two synthetic routes with five steps. Condensation of 4‐amino‐3‐bromo‐benzotrifluoride with 4‐(methylthio) phenyl boronic acid in the presence of sodium carbonate and palladium triphenylphosphine in toluene gave 4‐amino‐3‐(4‐methylthiophenyl)‐benzotrifluoride. Treatment of this compound with osmium tetroxide in the presence of 4‐methyl morpholine‐N‐oxide yielded the corresponding sulfone, which was converted into the iodo derivative using sodium nitrite. The iodo derivative thus obtained was treated first with propylmagnesium chloride and triethylborane and subsequently with hydroxylamine‐O‐sulfonic acid to furnish the target compounds.

The pharmacokinetics, metabolism, and toxicity of Zidampidine, an aryl phosphate derivative of AZT, 3'-azidothymidine-5'-[p-bromophenyl methoxyalaninyl phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24h prior, 1h prior, and 24, 48, 72, and 96h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value0.0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus.

Mammalian proteases have not been implicated in the metabolism of any nucleoside phosphoramidate prodrug. The results presented herein provide unprecedented and conclusive experimental evidence that mammalian proteases are capable of hydrolyzing stavudine phosphoramidates. Specifically, cathepsin B and Proteinase K are able to metabolize stampidine and other phosphoramidate derivatives of stavudine. Additionally, cathepsin B exhibits chiral selectivity at the phosphorus center. The elucidation of the metabolic pathways leading to activation of stampidine may provide the basis for pharmacologic interventions aimed at modulating the metabolism and thereby improving the therapeutic window of stampidine as an anti-HIV agent.

Stampidine and other halogen substituted stavudine phosphoramidates can be activated by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D-amino acid substituted isomers {Rp or Sp}are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that the L-amino acid configured isomers {Rp or Sp} are preferred in the lipase binding pocket.

Polyhydroxylated stilbene analogs of piceatannol are shown to possess protein‐tyrosine kinase (PTK) inhibitory activity. We have developed a novel approach to introduce an amide moiety into the structure of piceatannol. The amido substituted stilbene derivative was synthesized in 10 steps with an overall yield of 30%.

A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of these two types of d4T derivatives indicated that replacement of oxygen with sulfur decreases the rate of hydrolysis by twofold. Additionally, the activation energy ( E a ) for the sulfur analogs is comparatively higher than that of the oxygen analogs. Notably, an intermediate was formed in the hydrolysis reaction of the sulfur analogs of d4T that was absent in the case of the oxygen analog, and the tentative structure of the intermediate was proposed based on LC/mass spectroscopy data. Using both HPLC and 31 P-NMR techniques, we identified the hydrolysis product of the phosphoramidate derivatives and were able to show in in vitro studies that porcine liver esterase can hydrolyze the methyl ester portion of the phosphoramidate derivatives. Aryl phosphoramidate derivatives of d4T were 1000-fold more active than the corresponding aryl thiophosphoramidate derivatives, indicating that the energy of activation of hydrolysis of these phosphoramidate derivatives plays a significant role in their biological potency.

Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme (NNRTI) of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the NNRTI binding pocket, the R stereoisomers would fit the NNRTI binding pocket of the HIV-1 RT much better than the corresponding S stereoisomers, as reflected by their 10(4)-fold lower K1 values. The R stereoisomers of several PETT derivatives inhibited recombinant RT in vitro with lower IC(50) values than their enantiomers. The active compounds were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). All the R isomers once again showed potent anti-HIV activity and inhibited the replication of the HIV-1 strain HTLVIIIB in peripheral blood mononuclear cells (PBMC) at nanomolar concentrations whereas their enantiomers were substantially less potent. The lead compounds in the respective groups were further tested against the NNRTI-resistant HIV strains, A17 (Y181C mutant), and A17Var (Y181C+K103N mutant) and RT MDR (V106N). The results showed that the lead compounds were several logs more potent than the standard NNRTI nevirapine. Structure-activity relationship studies also revealed a preference for the pyridyl unit with halo substitutions primarily at 5-position demonstrating the importance of regiochemistry. Our data provides experimental evidence that the stereochemistry as well as regiochemistry of NNRTI can profoundly affect their anti-HIV activity.

Adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, nephritis, and gastroenteritis in immunocompromised patients, including HIV-infected individuals. Here we report the identification of halo-substituted stavudine phenyl phosphoramidate derivatives as a new class of dual-function anti-HIV agents with potent and selective anti-adenovirus (ADV) activity. We examined the investigational stavudine phenyl phosphoramidate derivative stampidine and 12 structurally similar stavudine derivatives for anti-ADV activity. All 13 derivatives of stavudine, including stampidine, were substantially more potent than stavudine and inhibited ADV-induced plaque formation at nanomolar IC 50 values. Compounds with halo substitutions in the phenyl ring as well as the unsubstituted compound 607 were more potent than compounds with methoxy, methyl, or cyano substitutions. Compound 113 (stampidine) with a 4-Br substitution and compound 609 with a 4-Cl substitution were identified as the most potent lead anti-ADV agents. Compound 113/ Stampidine inhibited ADV-induced plaque formation in skin fibroblasts in a concentration-dependent fashion with a mean (±S.E.M.) IC 50 value of 17 ± 2 nM without any evidence of cytotoxicity even at 100 μM. Similarly, compound 609 inhibited ADV-induced plaque formation with an IC 50 value of 27 ± 3 nM. We next sought to determine if the lead compounds 113 and 609 can also inhibit other viruses. Both compounds exhibited potent anti-HIV activity at nanomolar concentrations. However, neither compound exhibited any antiviral activity against non-HIV viruses, including Cytomegalovirus (CMV), Type I or Type II herpes simplex viruses (HSV-1, HSV-2), enterovirus ECHO 30, or respiratory syncytial virus (RSV) (IC 50 > 100 μM). The remarkable anti-ADV potency of the lead compounds stampidine and compound 609 warrants the further development of these promising new antiviral agents for possible clinical use in ADV infected patients.

The regiospecific synthesis of 5‐halothiophenethylamines and halo‐substituted phenylethyl thioureas was accomplished with an overall yield of 45–60%. Condensation of t‐boc protected 2‐thiophenethylamine with N‐halo succinamide in dimethylformamide furnished the desired halo‐substituted thiophenethylamines. These thiophenethyl amines were further converted into biologically active thiourea compounds using thiocarbonyldiimidazole chemistry. Several of the halo‐substituted thiophene pyridyl thiourea compounds inhibited HIV‐1 reverse transcriptase (RT) at nanomolar concentrations.

Synthesis of β‐fluorophenethylamines was accomplished in three steps with an overall yield of 50%. Condensation of β‐fluorophenethylamine hydrochloride with thiocarbonylimidazole derivative derived from halopyridyl amines in dimethylformamide furnished the desired thiourea compounds as crystalline solids. Several of the β‐fluorophenethyl thiourea compounds inhibited HIV‐1 reverse transcriptase (RT) at nanomolar to low micromolar concentrations.

We developed a novel approach to introduce a carbohydrate moiety into the structure of thiourea compounds targeting the NNI binding pocket of the HIV-1 reverse transcriptase. The described method involves the synthesis of an amino-substituted carbohydrate moiety which is then condensed with various thiocarbonylimidazole derivatives of substituted aromatic amines.

The regiospecific synthesis of 5-bromothiophenethyl thioureas was accomplished in four steps with an overall yield of 40–60%. The requisite regioselectivity for bromination of the thiophene ring was achieved using bromine in acetic acid at low temperatures. The resulting 5-bromothiophenethylamine hydrobromide is an important precursor for the preparation of substituted thioureas. The X-ray crystal structure demonstrates that the bromine atom is indeed located at the 5-position of the thiophene ring.

Several thiazolyl thiourea derivatives were designed and synthesized as non-nucleoside inhibitors (NNRTI) of HIV-1 reverse transcriptase. Six lead compounds were identified that showed subnanomolar IC50 values for the inhibition of HIV replication, were minimally toxic to human peripheral blood mononuclear cells (PBMC) with CC50 values ranging from 28 to >100 μM, and showed remarkably high selectivity indices ranging from 28,000 to >100,000. The most promising compound was N-[1-(1-furoylmethyl)]-N′-[2-(thiazolyl)]thiourea (compound 6), which showed potency against two NNRTI-resistant HIV-1 isolates (A17 and A17 variant) at nanomolar to low micromolar concentrations, exhibited much greater potency against both wild-type as well as NNRTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244, was minimally toxic to PBMC, and had a selectivity index of >100,000. The potency and minimal cytotoxicity of these aromatic/heterocyclic thiourea compounds suggest that they may be potentially useful as anti-AIDS drugs.

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two α-methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized as nonnucleoside inhibitors (NNI) of human immunodeficiency virus (HIV) reverse transcriptase (RT). The R stereoisomers of all five compounds inhibited the recombinant RT in vitro with 100-fold lower IC 50 values. HI-509 R , HI-510 R , HI-511 R , HI-512 R and HI-513 R were active anti-HIV agents and inhibited HIV-1 replication in human peripheral blood mononuclear cells at nanomolar concentrations, whereas their enantiomers were inactive. Each of these five compounds was also active against NNI-resistant HIV-1 strains, with HI-511 R being the most active agent. When tested against the NNI-resistant HIV-1 strain A17 with a Y181C mutation in RT, HI-511 R was found to be 10,000-times more active than nevirapine, 5000-times more active than delavirdine, and 50-times more active than trovirdine. HI-511 R inhibited the HIV-strain A17 variant, containing RT mutations Y181C plus K103N, with an IC 50 value of 2.7 μM, whereas the IC 50 values of nevirapine, delavirdine, and trovirdine against this highly NNI-resistant HIV-1 strain were >100 μM.

A series of novel phenethylthiazolylthiourea (PETT) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of HIV reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket. The structure-based design and synthesis of these new PETT derivatives were complemented by biological assays of their anti-HIV activity. Modeling studies for rational drug design included the construction of a composite NNI binding pocket from nine RT-NNI crystal structures, the analyses of surface complementarity between NNI and RT, and application of Ki calculations combined with a docking procedure involving the novel PETT derivatives. The use of the composite NNI binding pocket allowed the identification and structure-based design of three promising PETT derivatives with ortho-F (2), ortho-Cl (3), and meta-F (5) substituents on the phenyl ring. These novel PETT derivatives were more active than AZT or trovirdine and showed potent anti-HIV activity with IC50[p24] values of1 nM and selectivity indices of100,000.

A novel computer model of the HIV reverse transcriptase (RT) non-nucleoside inhibitor (NNI) binding pocket, which was generated using high resolution crystal structure information from 9 individual RT/NNI complexes, revealed previously unrecognized ligand derivatization sites for phenethylthiazolylthiourea (PETT) derivatives. Spatial gaps surrounding the pyridyl ring of the active PETT derivative trovirdine were discovered during modeling procedures. Docking studies using the computer-generated model of the binding pocket (composite binding pocket) suggested that the replacement of the planar pyridyl ring of trovirdine with a nonplanar piperidinyl or piperazinyl ring, which occupy larger volumes, would better fill the spacious Wing 2 region of the butterfly-shaped NNI binding pocket. The anti-HIV activity of the synthesized heterocyclic compounds N-[2-(1-piperidinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-[2-(5-bromopyridyl)]-thiourea was examined in HTLV iiib -infected peripheral blood mononuclear cells. Both compounds were more potent than trovirdine and abrogated HIV replication at nanomolar concentrations without any evidence of cytotoxicity.

Novel dihydroalkoxybenzyloxopyrimidine (S-DABO) derivatives targeting the non-nucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been synthesized using a novel computer model for the NNI binding pocket and tested for their RT inhibitory activity in cell-free assays using purified recombinant HIV RT as well as for their anti-HIV activity in HTL VIIIB-infected peripheral blood mononuclear cells. Our computational approach allowed the identification of several ligand derivatization sites for the generation of more potent S-DABO derivatives. Our lead S-DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-one (compound 3), elicited potent anti-HIV activity with an IC50 value of less than 1nM for inhibition of HIV replication without any evidence of cytotoxicity and an unprecedented selectivity index of > 100,000.

When photolysis of arylchlorodiazirines is performed in the presence of either alkyl- or allyl-substituted amines, either N-alkyl- or N-allyl-substituted amines result as the sole high-yield (64-93%) products. Photolysis in the presence of phenylallylamine produces a rearranged product in poor yield (11–15%) whereas the reaction of allyl alcohol with arylchlorocarbene gives exclusively diallyl acetals in high yield (70%). The rate constants for these reactions were obtained by laser flash photolysis. Allyl phenyl ether forms a cyclopropanated product when treated with arylchlorocarbene. The different behaviour of these compounds may be attributed to the nucleophilicity at the nitrogen and oxygen centres of these compounds, when the latter are subjected to the substitutions described above. The formation of a cyclopropanated product when allyl phenyl ether is used differs from the reaction of bis (methoxycarbonyl) carbene with allyl ethers, as reported in the literature. The formation of this cyclopropanated product demonstrates the absence of an oxonium ylide intermediate during the reaction.

The title compounds were synthesized starting from dimethyl (2S,3aR,8aS)-(+)-8-(phenylsulfonyl)hexahydrophyrrolo[2,3-b]indole-1,2-dicarboxylate. This compound on treatment with LDA followed by reaction with [14C]methyl iodide or [3H]methyl iodide gave the methyl substituted derivative which on treatment with trifloroacetic acid followed by hydrolysis with alkali gave the desired α-[14C]methyl- or [3H]methy-L-tryptophan, respectively, in 50-60% radiochemical yield.

Comparative acidity measurements have been performed between triphenylsilylpotassium and a series of arylmethanes by 1 H-NMR in tetrahydrofuran: Ph 3 SiK + Ar n CH 4 − n ⇆Ph 3 SiH + Ar n CH 3 − n K Metalation of the arylmethane was complete in the case of Ph 3 CH (p K a 31.4) and Ph 2 CH 2 (p K a 33.4) but with ( p -CH 3 ·C 6 H 4 ) 2 CH 2 (p K a 35.1) ∼50% metalation of the di- p -tolymethane occurred, indicating that the two acids have equal p K a . No reaction occurred with 4-Ph·C 6 H 4 ·CH 3 (p K a 38.7). Thus p K a Ph 3 SiH≈35.1 in THF. This represents the first solution measurement of the acidity of an organosilane.

A binuclear Co(III) complex has been prepared that shows greater reactivity towards bis(p-nitrophenyl)phosphate than two equivalents of the parent mononuclear Co(III) complex.

Heterocyclic thioureas having an amino acid ester side chain were prepared in two steps with overall yields of 65–85%. Condensation of a substituted heterocyclic amine with thiocarbonyldiimidazole, followed by treatment with an amino acid methyl ester hydrochloride in DMF, yielded the desired heterocyclic thioureas as crystalline solids. Amino acid esters such as glycine, leucine, valine, phenyl alanine, and tryptophan were used to prepare these thioureas.

The synthesis of naphthylphosphoramidate derivatives of stavudine was achieved using a four-step procedure. The derivatives were subjected to several different enzymes including lipase, esterase, Subtilisin Carlsberg, and Carica papaya, and their hydrolysis rates were determined. Based on the rates of hydrolysis, we were able to differentiate between the chiralities at the phosphorus center of the phosphoramidate compounds. In addition, lipase was found to distinguish between both alpha and beta forms of the compounds. The superior chiral selectivity shown by lipase toward the naphthyl substituted phosphoramidate derivatives is attributed to the restrictive binding pocket of the lipase.

Synthesis of symmetrical and asymmetrical phenethyl thioureas was accomplished in two steps with an overall yield of 75–80%. Condensation of a substituted phenethyl amine with thiocarbonyldiimidazole, followed by treatment with one more equivalent of the phenethylamine in DMF, yielded the desired symmetrical phenethyl thiourea compound as a crystalline solid. In the case of asymmetrical thiourea derivatives, different amines were selected and condensed using a similar procedure. A series of 45 thioureas was synthesized.

Changing the nucleoside group of a series of phosphoramidate derivatives affects the enzyme mediated hydrolysis rate of the compounds. d4T and AZT-substituted analogs were activated by enzymes such as lipases, esterases, and proteases. On the other hand, 3dT-substituted derivatives were comparatively less prone to hydrolysis under similar experimental conditions. From the experimental results, we propose that the most preferable nucleoside group for enzyme activation is d4T rather than AZT or 3dT. Additionally, we also observed that depending on the enzymes used the chiral selectivity of the enzymes for the phosphorus center of these phosphoramidate derivatives differed, demonstrating the importance of the nucleoside structure for this class of compounds.

Several proteases are capable of hydrolyzing the aryl substituted phosphoramidate derivatives of stavudine resulting in the formation of the active metabolite, alaninyl d4T monophosphate. Subtilisin Protease A, Subtilisin Griseus, Subtilisin Carlsberg, Papaya, Bacillus were amongst the most effective proteases in hydrolyzing stavudine derivatives and specificity of their activity was confirmed using several protease inhibitors to block the hydrolysis of these phosphoramidate derivatives. We found that these proteases exhibit chiral selectivity at the phosphorus center of stavudine derivatives. Our results indicate that cellular proteases may be responsible for the activation of these phosphoramidate derivatives. In addition, we show that the enzymatic hydrolysis takes place at the carboxymethyl ester side chain of these pro-drugs and the direct attack on the phosphorus center by these enzymes does not occur. Finally, we describe a novel activation pathway hitherto unknown for the activation and viral inhibitory characteristic shown by these phosphoramidate derivatives of stavudine.

Enzymatic hydrolysis of stampidine and other aryl phosphate derivatives of stavudine were investigated using the Candida Antarctica Type B lipase. Modeling studies and comparison of the hydrolysis rate constants revealed a chiral preference of the lipase active site for the putative S-stereoisomer. The in vitro anti-HIV activity of these compounds correlated with their susceptibility to lipase- (but not esterase-) mediated hydrolysis. We propose that stampidine undergoes rapid enzymatic hydrolysis in the presence of lipase according to the following biochemical pathway: During the first step, hydrolysis of the ester group results in the formation of carboxylic acid. Subsequent step involves an intramolecular cyclization at the phosphorous center with simultaneous elimination of the phenoxy group to form a cyclic intermediate. In the presence of water, this intermediate is converted into the active metabolite Ala-d4T-MP. We postulate that the lipase hydrolyzes the methyl ester group of the l-alanine side chain to form the cyclic intermediate in a stereoselective fashion. This hypothesis was supported by experimental data showing that chloroethyl substituted derivatives of stampidine, which possess a chloroethyl linker unit instead of a methyl ester side chain, were resistant to lipase-mediated hydrolysis, which excludes the possibility of a direct hydrolysis of stampidine at the phosphorous center. Thus, our model implies that the lipase-mediated formation of the cyclic intermediate is a key step in metabolism of stampidine and relies on the initial configuration of the stereoisomers.