Utilization of α‐halocarbonyl compounds in the synthesis of thiazole,thiadiazole, and thiophene derivatives

The behavior of ethyl 2‐phenylthiocarb‐ amoyl acetate 1 toward a variety of several α‐halo‐ carbonyl compounds was investigated. Thus, reaction of 1 with α‐bromoketones, hydrazonoyl bromides, and 2‐chloro‐N‐arylacetamides afforded the corresponding dihydrothiazole, 1,3,4‐thiadiazole, and thiophene derivatives, respectively. The synthesis of thiazolidin‐4‐one 11 , thiazolidin‐5‐one 12 , and some azo derivatives of thiazolidin‐5‐one were described. 5‐Arylazothiazoles 17 and 19 were synthesized by condensation of hydrazonoyl bromides 3 with different thiourea derivatives. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:299–305, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20206     

Two Green Micellar HPLC and Mathematically Assisted UV Spectroscopic Methods for the Simultaneous Determination of Molnupiravir and Favipiravir as a Novel Combined COVID-19 Antiviral Regimen

Following the spread of the COVID-19 pandemic crisis, a race was initiated to find a successful regimen for postinfections. Among those trials, a recent study declared the efficacy of an antiviral combination of favipiravir (FAV) and molnupiravir (MLP). The combined regimen helped in a successful 60% eradication of the SARS-CoV-2 virus from the lungs of studied hamster models. Moreover, it prevented viral transmission to cohosted sentinels. Because both medications are orally bioavailable, the coformulation of FAV and MLP can be predicted. The developed study is aimed at developing new green and simple methods for the simultaneous determination of FAV and MLP and then at their application in the study of their dissolution behavior if coformulated together. A green micellar HPLC method was validated using an RP-C18 core-shell column (5 μm, 150 × 4.6 mm) and an isocratic mixed micellar mobile phase composed of 0.1 M SDS, 0.01 M Brij-35, and 0.02 M monobasic potassium phosphate mixture and adjusted to pH 3.1 at 1.0 mL min⁻¹ flow rate. The analytes were detected at 230 nm. The run time was less than five minutes under the optimized chromatographic conditions. Four other multivariate chemometric model methods were developed and validated, namely, classical least square (CLS), principal component regression (PCR), partial least squares (PLS-1), and genetic algorithm–partial least squares (GA–PLS-1). The developed models succeeded in resolving the great similarity and overlapping in the FAV and MLP UV spectra unlike the traditional univariate methods. All methods were organic solvent-free, did not require extraction or derivatization steps, and were applied for the construction of the simultaneous dissolution profile for FAV tablets and MLP capsules. The methods revealed that the amount of the simultaneously released cited drugs increases up until reaching a plateau after 15 and 20 min for FAV and MLP, respectively. The greenness was assessed on GAPI and found to be in harmony with green analytical chemistry concepts.     

In Vitro Anti-Inflammatory Activity of Cotula anthemoides Essential Oil and In Silico Molecular Docking of Its Bioactives

The genus Cotula (Asteraceae) comprises about 80 species, amongst them Cotula anthemoides L. It is a wild plant growing in Egypt that possesses many traditional uses as a headache, colic, and chest cold remedy. In our study, the chemical composition of C. anthemoides essential oils was analyzed using GC-MS spectroscopy. Sixteen components of leave and stem oils and thirteen components of flower oils were characterized. The main components in both essential oil parts were camphor (88.79% and 86.45%) and trans-thujone (5.14% and 10.40%) in the leaves and stems and the flowers, respectively. The anti-inflammatory activity of the oils in lipopolysaccharide-stimulated RAW 264.7 macrophage cells was evaluated. The flower oil showed its predominant effect in the amelioration of proinflammatory cytokines and tumor necrosis factor-α, as well as cyclooxygenase-2. The bornyl acetate showed the highest affinity for the cyclooxygenase-2 receptor, while compound cis-p-menth-2-ene-1-ol had the best affinity for the tumor necrosis factor receptor, according to the results of molecular docking. In addition, the molecule cis-β-farnesene showed promising dual affinity for both studied receptors. Our findings show that essential oils from C. anthemoides have anti-inflammatory properties through their control over the generation of inflammatory mediators. These findings suggest that C. anthemoides essential oils could lead to the discovery of novel sources of anti-inflammatory treatments.     

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460–1047 nm) and entrapment efficiency ranging from 36.4–44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan^®). Observed bacterial suppression was detected in rabbit’s eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.     

Production,Partial Purification,and Biochemical Characterization of a Thermotolerant Alkaline Metallo-protease from Staphylococcus sciuri

Applied Biochemistry and Biotechnology - (R)-[3,5-bis(trifluoromethyl) phenyl] ethanol [(R)-3,5-BTPE] is a crucial chiral intermediate for the synthesis of the NK-1 receptor antagonists aprepitant,...     

Molecular and Biological Characterization of a Prepared Recombinant Human Interferon Alpha 2b Isoform

Recombinant human interferon alpha2b (rhIFN-α2b) protein is FDA approved for treatment of many tumors and viral diseases. A rhIFN-α2b isoform has been produced and purified from the refolding reaction using high-resolution anion ion exchange chromatography. This isoform has a proper MW (19 kDa) and high purity and homogeneity. The conservation of native linear and conformational epitopes in this isoform was immunologically confirmed by Western blot and ELISA. Mass spectrometry assessment of its intact mass showed average mass (19,337 Da) equivalent to that of the expressed rhIFN-α2b protein without any chemical modification and without the first methionine. Peptide mapping of rhIFN-α2b through tryptic digestion of reductive/alkylated protein using urea as a denaturing agent gave the best pattern. The rhIFN-α2b had a high specific antiviral activity (2.5?×?10⁸?±?1.1?×?10⁸IU/mg protein). In vivo clearance study of rhIFN-α2b in female SD rats (500 μg/kg, intramuscularly) revealed rapid clearance (elimination half-life 0.54 h with a maximum plasma concentration of 33,792 pg/ml) compared with the commercial rhIFN-α2 (elimination half-life 0.75–0.96 h). In conclusion, the prepared rhIFN-α2b isoform has high purity, homogeneity, native like chemical and structural composition, high antiviral activity, and proper biological stability, which reduce its immunogenicity and raise its therapeutic efficiency.

     

Bio-analytical methods for investigating the effect of age,body mass index and gender on the PK/PD ratio of antibiotics

The effectiveness of antibiotics (ABs) is governed by achieving the adequate pharmacokinetic (PK)/pharmacodynamics (PD) ratio. In this study, fast LC–MS/MS methods were developed and validated for the bioanalysis of cefaclor (CFC), ciprofloxacin (CFC), roxithomycin (RXM) and clindamycin (CLD). Chromatographic separation was performed on a C₁₈ Zorbax-Eclipse Plus (3.5 μm, 100 × 4.6 mm) using isocratic elution. Detection was performed by positive electrospray ionization. The methods were applied for the assessment of PK parameters in volunteers (n = 101, 64 male and 37 female) and the effects of age, body mass index (BMI) and gender were investigated. Good linearity (r ² ≥ 0.99), accuracy (>86%), precision (CV% ≤ 11) and extraction recovery (>83%) were observed for CFC, CFX, RXM and CLD. Application to PK studies revealed that age and BMI affected the T_half and the AUC of RXM and CLD (p < 0.023). Gender difference affected the critical PK parameters of the four ABs (T_half (U = 18; P = 0.036) of CFC, the C_max of CFX (U = 30; P = 0.017), the T_half (U = 23; P = 0.009) and AUC (U = 26; P = 0.008) of RXM and CLD), respectively. These results highlight the significance of age and BMI variations for RXM and CLD dosing. Furthermore, it indicates that the gender difference may be considered when adjusting the AB dose.     

Dendronephthols A–C,new sesquiterpenoids from the Red Sea soft coral Dendronephthya sp.

Three new ylangene-type sesquiterpenoids: dendronephthol A (7,13-dihydroxy-3,4-dihydro-α-ylang-5-one) (1), dendronephthol B (6,7,13-trihydroxy-3,4-dihydro-α-ylangene) (2), and dendronephthol C (6,7,13-trihydroxy-α-ylang-5-one) (3), together with two known compounds: dendronesterone A and cholesterol were isolated from the CHCl₃ fraction of Red Sea soft coral Dendronephthya sp. (Nephtheidae). The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic studies (¹H, ¹³C, DEPT, COSY, HSQC, HMBC, and NOESY) as well as MS spectroscopy and by comparison of the spectral data with those of related known compounds. Compounds 1 and 3 showed cytotoxic activity against the murine lymphoma L5187Y cancer cell line with ED₅₀ values of 8.4 and 6.8 μg/mL, respectively.