Computational Design, Synthesis, and Pharmacological Evaluation of Naproxen-Guaiacol Chimera for Gastro-Sparing Anti-Inflammatory Response by Selective COX2 Inhibition.

The 4-allyl guaiacol is a natural phenolic molecule that has been widely studied for its antioxidant capacity against reactive-oxygen-species-mediated cellular damage. Therefore, we hypothesized that concomitant use of an antioxidant and NSAID may decrease the risk of gastrointestinal toxicity and make the therapy safer. To address the gastrointestinal toxicity of conventional NSAIDs, a new S-naproxen-4-allyl guaiacol chimera (MAS-1696) was computationally developed, chemically synthesized, and tested for anti-inflammatory effectiveness and gastrointestinal safety. The inhibitory potency of MAS-1696 tested against cyclooxygenase-2 (COX2), 15-lipoxygenase-2 (15-LOX2), and lipoxygenase-5 (5-LOX) in vitro revealed a stronger inhibition of COX2. Furthermore, the MAS-1696 chimera increased the COX selectivity index by 23% as compared to the parent compound naproxen, implying higher efficacy and gastric safety. In vivo data showed that MAS-1696 was less likely to cause gastrointestinal harm than naproxen while also exerting anti-inflammatory and analgesic effects equivalent to or superior to naproxen. In conclusion, MAS-1696 is orally active, bio-labile, and crystalline, making it a medication that may be administered orally.

Reversed-phase-HPLC enantioseparation and control of enantiomeric purity of duloxetine using a new chiral reagent and recovery of enantiomers.

This study reports a rapid and low-cost LC method for control of enantiomeric purity of duloxetine. Though duloxetine, as marketed and administered, is expected to be a single (S)-enantiomer, the analysis of a few commercial branded samples by the method developed and presented here showed that they contain a relatively high percentage of (R)-enantiomer (e.g., 2.71-5.42%, which is undesirable in drug formulations). A new chiral derivatizing reagent [isatinyl-(S)-naproxen amide] was synthesized on (S)-naproxen platform. Diastereomeric derivatives were synthesized under microwave irradiation and were separated using reversed-phase-HPLC on a C18 column. A combination of acetonitrile and triethylammonium phosphate buffer (9 mM, pH 4) as the mobile phase and detection at 273 nm were found successful. The diastereomeric derivatives at preparative scale were separated using open column chromatography, and the native enantiomers were obtained and characterized. The HPLC separation method was validated for detection limit, linearity, accuracy, and precision. The limits of detection of (S,R)-diastereomer and (S,S)-diastereomer were found to be 12 and 16 pg/mL, respectively, for the 20-µL injected volume. The method so developed has a practical significance and greater societal impact in establishing the control of enantiomeric purity and in ensuring the enantiomeric purity of the drug meant for human consumption.

Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives.

In this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, 1H NMR,13C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 µM anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 µM, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 µM, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy.

Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen.

A new series of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen ( 7a-m) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier-transform infrared spectroscopy, 1 H-nuclear magnetic resonance (NMR), 13 C-NMR, and high-resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase-2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU-145, and LNCaP) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU-145 and LNCaP cancer cell lines with IC50 values of 26.0, 34.5, and 48.8 µM, respectively. Compounds 7b, 7k, and 7m showed anticancer activity against cancer cell lines PC3 and DU-145 with IC50 values of 43.0, 36.5, 29.3 µM and 49.8, 49.1, 31.6 µM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC50 values of 43.4 and 34.5 µM, respectively. To assess the biodistribution in mice of IRDye800, dye-labeled compound 7a or 100 µM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.

Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivatives.

Current study is based on the biology-oriented drug synthesis (BIODS) of S-naproxen (NSAID) derivatives and the evaluation of their urease inhibitory potential. In this regard, a variety of S-naproxen derivatives 2-39 including hydrazide 1, Schiff bases 2-21, aroyl substituted hydrazides 22-24, sulfohydrazides 25-34, 2-mercapto oxadiazole 35, phenacyl substituted 2-mercapto oxadiazoles 36-39 were synthesized under the umbrella of BIODS by simple chemical transformation of its pharmacophoric carboxylic group. Compounds 1-39 were evaluated for in vitro urease inhibitory activity and most of them showed good to moderate inhibitory potential in the range of IC50 = 14.01 ±â€¯0.23-76.43 ±â€¯0.8 µM as compared to standard acetohydroxamic acid (IC50 = 27.0 ±â€¯0.5 µM). Limited structure-activity relationship (SAR) was established in order to rationalize the participation of varying groups (R) in the inhibitory potential of compounds. Molecular docking study on all active compounds was also carried out to decipher the interactions detail of the ligand with the receptors of active site of enzyme.

Enhanced molecular recognition for imprinted monolithic column containing polyhedral oligomeric silsesquioxanes by dendritic effect of mesoporous molecular sieve scaffolds.

The dendritic effect of nano mesoporous molecular sieve was first used to enhance molecular recognition of molecularly imprinted polymers (MIPs)-based polyhedral oligomeric silsesquioxanes (POSS). In this study, the MIPs were made using S-naproxen (S-NAP) as template molecule, 4-vinylpyridine (4-VP) as functional monomer, ethylene glycol dimethacrylate as cross-linker, 1-butyl-3-methylimidazoliumtetrafluoroborate ([BMIM]BF4)/DMSO as binary porogens, 1-propylmethacrylate-heptaisobutyl substituted as POSS monomer, and mesoporous molecular sieve (Mobil composition of matter No. 41, MCM-41) as dendritic scaffold. The influence of synthesis parameters on the imprinting effect, including the content of POSS monomer and derivatized MCM-41-MPS, the ratio of template to monomer, and the ratio of binary porogens were also investigated, respectively. The morphology of the polymers was characterized by scanning electron microscopy, nitrogen adsorption, and X-ray powder diffraction. The results showed that POSS&MCM-41-MPS MIP had a stronger imprinting effect with an imprinting factor 6.86, which is approximately 2.4, 2.3, and 3 times than that of POSS MIP, MCM-41-MPS MIP, and conventional MIP, respectively. The increase of affinity might be attributed to impediment of the chain motion of polymer due to improved POSS aggregation and the dipole interaction between the POSS units by introduce of MCM-41-MPS as scaffolds. The resulting POSS&MCM-41-MPS MIP was used as adsorbent for the enrichment of S-NAP in solid-phase extraction with a high recovery of 97.65% and the value of RSD was 0.94%.

Development of liquid chromatographic methods for enantioseparation and sensitive detection of ß-adrenolytics/ß2-agonists in human plasma using a single enantiomer reagent.

Enantioseparation of four commonly used ß-adrenolytics (bisoprolol, salbutamol, and carvedilol, marketed as racemic mixtures) has been achieved by both TLC and RPHPLC via an indirect approach. A new chiral reagent, (S)-naproxen benzotriazole ester, was synthesized and it was characterized by UV, IR, 1HNMR, elemental analysis and polarimetry. It was used to synthesize diastereomeric derivatives of the three ß-adrenolytics under microwave irradiation. TLC separation of diastereomeric derivatives was achieved which were then isolated by preparative approach; these were characterized and were used as standard reference for determining absolute configuration of diastereomeric derivatives and for establishing validated HPLC method for enantioseparation and sensitive detection of the three ß-adrenolytics in human plasma. Mobile phase in gradient mode containing methanol and aqueous triethylaminephosphate (TEAP) was successful for HPLC separation; conditions with respect to pH, flow rate, and buffer concentration were optimized. The method is capable to accurately quantitate ß-adrenolytics in human plasma with minimal sample clean-up and rapid separation by TLC and RPHPLC. The limit of detection values were 0.97 and 0.87ng/mL for diastereomeric derivatives of (S)- and (R)-bisoprolol, respectively, which are very low in comparison to literature reports.

Enantiomeric Resolution of (RS)-Naproxen and Application of (S)- Naproxen in the Direct and Indirect Enantioseparation of Racemic Compounds by Liquid Chromatography: A Review.

(S)-Naproxen (Npx), an α-aryl propionic acid derivative, belongs to the class of Non-Steroidal Anti-Inflammatory Drugs and is easily available in pure (S)-form. (S)-Npx has been used as a chiral selector for chromatographic separation of a variety of racemates, using both direct and indirect methods, and has been found to be useful and successful as a basic chiral moiety. This review article describes methods for enantioseparation of (RS)-Npx, development of chiral stationary phases based on (S)-Npx and preparation of novel chiral derivatizing reagents synthesized from (S)-Npx along with their application for enantioseparation of several pharmaceutically important racemates.

Efficient Synthesis of ß-Aryl-γ-lactams and Their Resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen.

An efficient synthesis of enantiomerically-pure ß-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of ß-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

Liquid chromatographic enantioseparation of (RS)-mexiletine and (RS)-fluoxetine using chiral derivatizing reagents synthesized with (S)-naproxen moiety.

Enantiomeric separation of racemic mexiletine and fluoxetine was achieved using three chiral derivatizing reagents (CDRs) based on (S)-naproxen. Diastereomers were synthesized by reaction of mexiletine or fluoxetine with the CDRs and were separated on a C18 column under reversed-phase conditions using a binary mixture of acetonitrile and triethylammonium phosphate/water, with UV detection at 230 and 226 nm. The results obtained for enantioseparation of the two drugs using the three CDRs were compiled and compared. The conditions for derivatization and chromatographic separation were optimized. The method was validated for linearity, repeatability, limit of detection and limit of quantification.

Indirect enantioseparation of selenomethionine by reversed-phase high-performance liquid chromatography using a newly synthesized chiral derivatizing reagent based on (S)-naproxen moiety.

(S)-Naproxen was reacted with N-hydroxyphthalimide in the presence of coupling reagent dicyclohexylcarbodiimide, and a new chiral derivatizing reagent, phthalimidyl-(S)-naproxen ester, was synthesized. It was characterized and was used for synthesis of diastereomers of selenomethionine via microwave irradiation or vortexing. The reaction conditions were optimized. Diastereomeric pairs synthesized by two approaches were successfully separated by reversed-phase high-performance liquid chromatography using binary mixtures of aqueous triethylammonium phosphate and acetonitrile. Detection was carried out at 231 nm. The limit of detection was found to be 0.11 and 0.10 pmol/mL for diastereomers of d- and l-SeMet, respectively. The method was validated for accuracy, precision and limit of detection. The new chiral derivatizing reagent was capable of enantioseparation of dl-SeMet in the form of diastereomers having higher stability, enhanced resolution and lower limits of detection in comparison to the diastereomers prepared with other chiral derivatizing reagents reported in the literature. Optimized structures of the two diastereomers were drawn using the Gaussian 09 Rev. A.02 program and hybrid density functional B3LYP with 6-31G basis set to explain the separation mechanism.