Geochemistry of Liquid Hydrocarbons and Natural Gases Combined with 1D Basin Modeling of the Oligocene Shale Source Rock System in the Offshore Nile Delta, Egypt.

The current study aims to integrate the geochemical characteristics of the Oligocene shale source rock system, oil, condensate, and natural gas samples in the Oligocene sandstone reservoirs from three exploration wells located in the offshore Nile Delta, East Mediterranean Sea, using organic geochemistry and a 1D basin modeling scheme. The Tineh shales exhibit total organic carbon values ranging between 0.90 and 1.89 wt %, along with hydrogen index values in the range of 54-240 mg hydrocarbon/g rock. The geochemical characterization suggests that the shale intervals of the Oligocene Tineh Formation contain type II-III and type III kerogens and, thereby, could be regarded as promising oil- and gas-prone source rocks with high contributions of gas generation potential. The study also reconstructs the 1D thermal and burial history models, showing that the Oligocene Tineh source rock system is in the main oil and wet gas generation phases from the late Miocene to the present time. The simulated basin models reveal the transformation (TR) of 10-50% kerogen to oil during the late Miocene-early Pliocene period and that the Oligocene Tineh source rock system has larger oil generation and expulsion competency, with a TR value of up to 65% during the early Pliocene-Pleistocene time period. The thermogenic gas was also formed during this time and continued to the present day. This study also investigated the presence of oil and condensate in the Oligocene sandstone reservoir samples and revealed that they were generated from mature source rock, ranging from moderately to highly mature stages. This source rock unit was deposited in fluvial to fluvial-deltaic environments under oxic mixed organic conditions and accumulated during the Tertiary time, as evidenced by the presence of the oleanane biomarker dating indicator. The molecular and isotope compositions of natural gases revealed that most of the natural gases in the Oligocene sandstone reservoir are mainly thermogenic methane gases that were generated from mainly mixed organic matter. The thermogenic methane gases were formed mainly from secondary cracking of oil and gas, with small contributions of primary kerogen cracking. The properties of natural gases together with oil and condensate in the Oligocene reservoir rocks suggest that most of the thermogenic methane gases and associated liquid hydrocarbons are derived primarily from the Oligocene shale source rock system and formed by primary kerogen cracking and secondary oil and oil/gas cracking in different thermal maturity stages. Therefore, the Oligocene Tineh Formation can be regarded as self-source generation and self-reservoir rock; hence, an intensive oil exploration and production program can be recommended whenever the Tineh source rock system is is well developed and deeply buried.

Assessment of Performance, Microbial Community, Bacterial Food Quality, and Gene Expression of Whiteleg Shrimp (Litopenaeus vannamei) Reared under Different Density Biofloc Systems.

Biofloc shrimp culture, as a way of improving shrimp production, gains worldwide consideration. However, the effects of the biofloc system on shrimp culture at high densities could be a challenge. Here, this study is aimed at identifying a better stocking density of whiteleg shrimp (Litopenaeus vannamei) between two intensive biofloc systems of 100 and 300 org./m2. Achieving that was done by comparing growth performance, water quality, feed utilization, microbial loads from water and shrimps, and gene expression of growth, stress, and immune-related genes. Shrimp postlarvae with a mean weight of 35.4 ± 3.7 mg were reared in six indoor cement tanks (36 m3 total capacity each) at two stocking densities (3 replicates each) for a rearing period of 135 days. Better final weight, weight gain, average daily weight gain, specific growth rate, biomass increase percentage, and survival rate were associated with lower density (100/m2), whereas high-density showed significantly higher total biomass. Better feed utilization was found in the lower density treatment. Lower density treatment enhanced water quality parameters, including higher dissolved oxygen and lower nitrogenous wastes. Heterotrophic bacterial count in water samples was recorded as 5.28 ± 0.15 and 5.11 ± 0.28 log CFU/ml from the high- and low-density systems, respectively, with no significant difference. Beneficial bacteria such as Bacillus spp. were identified in water samples from both systems, still, the Vibrio-like count was developed in the higher density system. Regarding shrimp food bacterial quality, the total bacterial count in the shrimp was recorded as 5.09 ± 0.1 log CFU/g in the 300 org./m2 treatment compared to 4.75 ± 0.24 log CFU/g in the lower density. Escherichia coli was isolated from the shrimps in a lower density group while Aeromonas hydrophila and Citrobacter freundii were associated with shrimps from a higher density system. Immune-related genes including prophenoloxidase, superoxide dismutase (SOD), and lysozyme (LYZ) expressions were all significantly higher expressed in the shrimp from the lower density treatment. Toll receptor (LvToll), penaiedin4 (PEN4), and stress-related gene (HSP 70) showed a decreased gene expression in the shrimp raised in the lower density. Significant upregulation of growth-related gene (Ras-related protein-RAP) expression was associated with the lower stocking density system. In conclusion, the current study found that applying high stocking density (300 org./m2) contributes negatively to performance, water quality, microbial community, bacterial food quality, and gene expression of immune, stress, and growth-related genes when compared with the lower stocking density system (100 org./m2) under biofloc system.

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation.

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2'-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators.

Despite the achieved progress in developing efficient MDM2-p53 protein-protein interaction inhibitors (MDM2 inhibitors), the acquired resistance of tumor cells to such p53 activators posed an argument about the druggability of the pathway. Combination studies disclosed that concomitant inhibition of MDM2 and BCL2 functions can sensitize the tumor cells and synergistically induce apoptosis. Herein, we employed a rapid combinatorial approach to generate a novel series of hybrid spirooxindole-based MDM2 inhibitors (5a-s) endowed with BCL2 signaling attenuation. The adducts were designed to mimic the thematic features of the chemically stable potent spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones MDM2 inhibitors while installing a pyrrole ring on the core via a carbonyl spacer inspired by the natural product marinopyrrole A that efficiently inhibits BCL2 family functions by various mechanisms. NCI 60 cell-line panel screening revealed their promising broad-spectrum antiproliferative activities. The NCI-selected derivatives were screened for cytotoxic activities against normal fibroblasts, MDA-MB 231, HepG-2, and Caco-2 cells via MTT assay, subjected to mechanistic apoptosis studies for assessment of p53, BCL2, p21, and caspase 3/7 status, then evaluated for potential MDM2 inhibition utilizing MST assay. The most balanced potent and safe derivatives; 5i and 5q were more active than 5-fluorouracil, exhibited low µmrange MDM2 binding (KD=1.32and 1.72 µm, respectively), induced apoptosis-dependent anticancer activities up to 50%, activated p53 by 47-63%, downregulated the BCL2 gene to 59.8%, and reduced its protein level (13.75%) in the treated cancer cells. Further downstream p53 signaling studies revealed > 2 folds p21 upregulation and > 3 folds caspase 3/7 activation. Docking simulations displayed that the active MDM2 inhibitors resided well into the p53 binding sites of MDM2, and shared key interactions with the co-crystalized inhibitor posed by the indolinone scaffold (5i, 5p, and 5q), the halogen substituents (5r), or the installed spiro ring (5s). Finally, in silico ADMET profiling predicted acceptable drug-like properties with full accordance to Lipinski's, Veber's, and Muegge's bioavailability parameters for 5i and a single violation for 5q.

Synthesis, molecular modeling, selective aldose reductase inhibition and hypoglycemic activity of novel meglitinides.

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.

Multifunctional Hydroxyapatite/Silver Nanoparticles/Cotton Gauze for Antimicrobial and Biomedical Applications.

Medical textiles have played an increasingly important protection role in the healthcare industry. This study was aimed at improving the conventional cotton gauze for achieving advanced biomedical specifications (coloration, UV-protection, anti-inflammation, and antimicrobial activities). These features were obtained by modifying the cotton gauze fabrics via in-situ precipitation of hydroxyapatite nanoparticles (HAp NP), followed by in-situ photosynthesis of silver (Ag) NPs with ginger oil as a green reductant with anti-inflammation properties. The HAp-Ag NPs coating provides good UV-protection properties. To further improve the HAp and Ag NPs dispersion and adhesion on the surface, the cotton gauze fabrics were modified by cationization with chitosan, or by partial carboxymethylation (anionic modification). The influence of the cationic and anionic modifications and HAp and Ag NPs deposition on the cotton gauze properties (coloration, UV-protection, antimicrobial activities, and water absorption) was thoroughly assessed. Overall, the results indicate that chemical (anionic and cationic) modification of the cotton gauze enhances HAp and Ag NPs deposition. Chitosan can increase biocompatibility and promotes wound healing properties of cotton gauze. Ag NP deposition onto cotton gauze fabrics brought high antimicrobial activities against Candida albicans, Gram-positive and Gram-negative bacteria, and improved UV protection.

Discovery of Potent Dual EGFR/HER2 Inhibitors Based on Thiophene Scaffold Targeting H1299 Lung Cancer Cell Line.

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

Anterior Lamellar Recession versus Posterior Lamellar Tarsal Rotation for Lower Lid Trachomatous Trichiasis: A Randomized Controlled Trial.

PURPOSE: To compare the outcomes of anterior lamellar recession (ALR) versus posterior lamellar tarsal rotation (PLTR) procedure for the repair of lower eyelid trachomatous trichiasis (TT). DESIGN: Prospective randomized comparative trial. METHODS: Study Population and Interventions: Patients with lower eyelid TT were enrolled. Patients with a history of lower lid surgery, marked horizontal lid laxity, another evident cause for the trichiasis, and those under 18 years were excluded. Participants were randomized to either PLTR or ALR. The sequence was computer-generated by an independent statistician, and the allocation sequence was concealed in sealed opaque envelops. Patients were evaluated at 1 week and 1, 3, 6, and 12 months. Main Outcome Measures: postoperative trachomatous trichiasis (PTT) and cosmetic satisfaction. RESULTS: A total of 60 patients were randomly assigned with 30 patients in each group. Two (3.3%) participants in PLTR group did not follow up and were excluded from the analysis. At 1, 3, and 6 months, PTT was significantly more frequent in the PLTR group than the ALR group (14.3% vs 0%; p= 0.048, 25% vs 0%; p= 0.004, 35.7% vs 10%; p= 0.019, respectively). In the ALR group, 6 patients (20%) had PTT at their 12-month follow-up visit compared with 15 patients (53.6%) in the PLTR group (P = 0.008) with absolute risk reduction of 33.6% (95% (CI= 9% -58%)). Cosmetic dissatisfaction was significantly more frequent in the ALR group at the initial follow-up visits compared to the PLTR group. However, this difference was no longer significant at 6 and 12 months follow-up. CONCLUSION: These data provide strong evidence that ALR is more effective in correction of lower eyelid trachomatous trichiasis with acceptable cosmesis compared with PLTR.

Garlic alters the expression of putative virulence factor genes SIR2 and ECE1 in vulvovaginal C. albicans isolates.

Vulvovaginal candidiasis causes sufferers much discomfort. Phytotherapy with garlic has been reported to be a possible alternative form of treatment; however, it is unknown why patients report varying success with this strategy. Fresh garlic extract has been shown to down-regulate the putative virulence gene, SIR2 in C. albicans. Our study aimed to see if previous observations were reproducible for the gene responsible for Candidalysin (ECE1). Two clinical strains from patients with reported variable efficacy of using garlic for the treatment of vulvovaginal candidiasis were compared through biofilm assays and antimicrobial susceptibility. Real-time PCR was used to assess changes in gene expression when exposed to garlic. Treatment with fresh garlic extract and pure allicin (an active compound produced in cut garlic) resulted in a decrease in SIR2 expression in all strains. In contrast, ECE1 expression was up-regulated in a reference strain and an isolate from a patient unresponsive to garlic therapy, while in an isolate from a patient responsive to garlic therapy, down-regulation of ECE1 occurred. Future studies that investigate the effectiveness of phytotherapies should take into account possible varying responses of individual strains and that gene expression may be amplified in the presence of serum.

Pharmacophore modeling, 3D-QSAR, synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR.

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure-activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.

Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines.

Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 µM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 µM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.

Synthesis and molecular modeling of novel non-sulfonylureas as hypoglycemic agents and selective ALR2 inhibitors.

Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilities to discriminate in vitro between aldehyde reductase (ALR1) and aldose reductase (ALR2) were determined. The molecular docking and the in silico prediction studies were performed to rationalize the obtained biological results and to predict the physicochemical properties and drug-likeness scores of the new compounds. N-(2,4-Dichlorophenyl)-2-(2',4'-dioxospiro[fluorene-9,5'-imidazolidine]-3'-yl)acetamide (3e) displayed an 84% reduction in blood glucose level superior to that of repaglinide 66% and showed an IC50 value of 0.37 µM against ALR2 that is superior to that of sorbinil 3.14 µM. Compound (3e) was selective 96 fold towards ALR2 which is closely related to serious diabetic complications. Based on the identification of this hit candidate, a new generation of safe and effective antidiabetic agents could be designed.

Correction: Peripapillary retinal nerve fiber layer and ganglion cell complex degeneration in Egyptian patients with bipolar disorder.

Since the online publication of the above article, the authors have requested a change to the author list. The full correct author list is: Dalia H Khalil, Mohamed M. Said.

Peripapillary retinal nerve fiber layer and ganglion cell complex degeneration in Egyptian patients with bipolar disorder.

PURPOSE: To determine if changes in OCT parameters including peripapillary RNFL thickness and GCC thickness in Egyptian patients with bipolar disorder exist, and to correlate them with disease severity and clinical characteristics. METHODS: A case-control study conducted on 40 patients with bipolar disorder were compared to 40 matched healthy controls. Both patients and controls were subjected to ophthalmic examination including: BCVA, slit-lamp examination, fundus examination, and OCT imaging. Patients were also subjected to Young Mania Rating Scale (YMRS). RESULTS: Thinning of average (RNFL) and average (GCC) thickness of right and left eye in patients with BPD (whether received electroconvulsive therapy or not) when compared with control subjects. Number of episodes, age at onset and severity of disease showed insignificant correlation with OCT parameters. CONCLUSIONS: Significant degenerative changes were detected by OCT in patients with bipolar disorder that were not affected by receiving ECT and not related to disease severity or duration.

Molecular modelling and synthesis of spiroimidazolidine-2,4-diones with dual activities as hypoglycemic agents and selective inhibitors of aldose reductase.

Novel derivatives of spiroimidazolidinedione were synthesized and evaluated as hypoglycemic agents through binding to sulfonylurea receptor 1 (SUR1) in pancreatic beta-cells. Their selectivity index was calculated against both aldehyde reductase (ALR1) and aldose reductase (ALR2). Aldehyde reductase is a key enzyme in the polyol pathway that is involved in the etiology of the secondary diabetic complications. All structures were confirmed by microanalysis and by IR, 1H NMR, 13C NMR and EI-MS spectroscopy. The investigated compounds were subjected to molecular docking and an in silico prediction study to determine their free energy of binding (ΔG) values and predict their physicochemical properties and drug-likeness scores. Compound 1'-(5-chlorothiophene-2-ylsulfonyl)spiro[cyclohexane-1,5'-imidazolidine]-2',4'-dione showed IC50 0.47 µM and 79% reduction in blood glucose level with a selectivity index 127 for ALR2.

Regio- and stereoselective synthesis of new spirooxindoles via 1,3-dipolar cycloaddition reaction: Anticancer and molecular docking studies.

Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l­proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products. The new series of compounds with a high degree of stereo- and regioselectivity were evaluated against breast cancer cell lines (MCF-7) and leukemia (K562). Among them, compound 4g was identified as the most potent with IC50 values of 15.49 ±â€¯0.04 µM, against breast cancer cell lines (MCF-7) compared to standard drug 5-Fu (IC50 = 78.28 ±â€¯0.2 µM) and compound 4i IC50 values of 13.38 ±â€¯0.14 µM against leukemia (K562) compared to standard drug 5-fluorouracil (5-FU) (IC50 = 38.58 ±â€¯0.02). The selective apoptotic effects of 4g were investigated against MCF-12 normal mammary cell and the cytotoxicity of 4g was not associated with any induction of necrosis compared to untreated cells. Molecular docking studies were investigated. From the docking data, these compounds could be act as small molecules that inhibit the MDM2-p53 interaction.

Metabolic and process engineering for biodesulfurization in Gram-negative bacteria.

Microbial desulfurization or biodesulfurization (BDS) is an attractive low-cost and environmentally friendly complementary technology to the hydrotreating chemical process based on the potential of certain bacteria to specifically remove sulfur from S-heterocyclic compounds of crude fuels that are recalcitrant to the chemical treatments. The 4S or Dsz sulfur specific pathway for dibenzothiophene (DBT) and alkyl-substituted DBTs, widely used as model S-heterocyclic compounds, has been extensively studied at the physiological, biochemical and genetic levels mainly in Gram-positive bacteria. Nevertheless, several Gram-negative bacteria have been also used in BDS because they are endowed with some properties, e.g., broad metabolic versatility and easy genetic and genomic manipulation, that make them suitable chassis for systems metabolic engineering strategies. A high number of recombinant bacteria, many of which are Pseudomonas strains, have been constructed to overcome the major bottlenecks of the desulfurization process, i.e., expression of the dsz operon, activity of the Dsz enzymes, retro-inhibition of the Dsz pathway, availability of reducing power, uptake-secretion of substrate and intermediates, tolerance to organic solvents and metals, and other host-specific limitations. However, to attain a BDS process with industrial applicability, it is necessary to apply all the knowledge and advances achieved at the genetic and metabolic levels to the process engineering level, i.e., kinetic modelling, scale-up of biphasic systems, enhancing mass transfer rates, biocatalyst separation, etc. The production of high-added value products derived from the organosulfur material present in oil can be regarded also as an economically viable process that has barely begun to be explored.

Synthesis of Some Novel 2,6-Disubstituted Pyridazin-3(2H)-one Derivatives as Analgesic, Anti-Inflammatory, and Non-Ulcerogenic Agents.

Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 µM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti-inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening.

Synthesis and EPR-spectroscopic characterization of the perchlorotriarylmethyl tricarboxylic acid radical (PTMTC) and its 13C labelled analogue (13C-PTMTC).

A hydrophilic tris(tetrachlorotriaryl)methyl (tetrachloro-TAM) radical labelled 50% with 13C at the central carbon atom was prepared. The mixture of isotopologue radicals was characterised by continuous wave and pulsed X-band electron paramagnetic spectroscopy (EPS). For the pharmaceutical and medical applications planned, the quantitative influence of oxygen, viscosity, temperature and pH on EPR line widths was studied in aqueous buffer, DMSO, water-methanol and water-glycerol mixtures. Under in vivo conditions, pH can be disregarded. There is a clear oxygen dependence of the width of the 12C isotopologue single EPR line in aqueous solutions while changes in rotational motion (viscosity) are observable only in the doublet lines of the central carbon of the 13C isotopologue. The tetrachloro-TAM proved to be very stable as a solid. Its thermal decay was determined quantitatively by thermal annealing. Towards ascorbic acid as a reducing agent and towards an oocyte cell extract it had a half-life of approx. 60 and 10 min. Thus for in vivo applications, 50% 13C tetrachloro-TAMs are suitable for selective and simultaneous oxygen and macroviscosity measurements in a formulation, e.g. nanocapsules.