Synthesis, Antimicrobial Evaluation, DFT, and Molecular Docking Studies of Pyrano [4,3-b] Pyranone and Pyrano[2,3-b]Pyridinone Systems.

Dehydroacetic acid (DHA) was utilized as a fundamental precursor in the synthesis of novel pyrano [4,3-b] pyran and pyrano [2,3-b] pyridine systems. Whereas, a new series of fused polyheteronuclear systems was achieved through the reaction of DHA with active methylene compounds such as malononitrile and pyrazolone. Whereas, the treatment of DHA 1 with cyclic ketones involving cyclohexanone and cyclododecanone afforded annulated tricyclic system 6 and spiro hybrid molecule 7. Also, the reaction of DHA 1 with cyanoacetamide derivatives 8 and 11 yielded their corresponding novel pyrano [2,3-b] pyridine-6-carbonitrile frameworks 9 and 12, respectively. Also, in silico predictive theoretical molecular docking studies for bioactive synthesized scaffolds against both HER2 and 6BBP displayed an optimistic result for compounds 2 b, 5, 9, and 12 highlighting their expediency as up-and-coming candidates for future preclinical trials. Additionally, all compounds were assessed as antibacterial agents against various types of four candidates of bacteria in the presence of ampicillin as a reference. Notably, compounds 6, 7, and 12 showed promising antibacterial potential against Bacillus subtilis with activity indexes (69.6, 91.3, and 82.6 %), respectively.

An Efficient Approach for the Synthesis and Antitumor Evaluation of Novel Azo- and Anil-Linked with 3-Aminopyrazolo[3,4-b]pyridine.

In this project, an effective procedure for constructing a new combination of pyrazolo[3,4-b]pyridine was depicted through the coupling of diazonium salt 2 of heterocyclic amine 1 with active methylene, enamine, and amidine moieties such as 3, 5, 7, and 9 at 0-5 °C in pyridine to afford hydrazinylhydrazonoyl derivatives 4, and diazenylheterocyclic derivatives 6, 8, and 10, respectively. Also, aminopyrazolo[3,4-b]pyridine 1 condensed with different aryl or heteroaryl aldehydes in EtOH/AcOH gave the corresponding aldimine 14, 15, 16. Compound 15 was cyclized via refluxing in DMF for 6 h to afford 18, while the transformation of compound 16 with an alkyl halide afforded 19a, b. The synthesized compounds, explicated by spectral data and elemental analysis, were examined for their antitumor activities. The in vitro cytotoxic activity of new pyrazolo[3,4-b]pyridines against the A2780CP, MCF-7, and HepG-2 cell lines was evaluated using the reference doxorubicin. Compounds 15 and 19a exhibited high reactivity against the A2780CP cell lines, with IC50 values of 35 and 17.9 µM, respectively. Also, compound 28 had the cytotoxic potential for A2780CP and MCF-7 cell lines, with IC50 values of 14.5, and 27.8 µM, respectively.

Conversion of Sewage Water into H2 Gas Fuel Using Hexagonal Nanosheets of the Polyaniline-Assisted Deposition of PbI2 as a Nanocomposite Photocathode with the Theoretical Qualitative Ab-Initio Calculation of the H2O Splitting.

This study is very promising for providing a renewable enrgy (H2 gas fuel) under the elctrochemical splitting of the wastwater (sewage water). This study has double benefits: hydrogen generation and contaminations removel. This study is carried out on sewage water, third stage treated, from Beni-Suef city, Egypt. Antimony tin oxide (ATO)/polyaniline (PANI)/PbI2 photoelectrode is prepared through the in situ oxidative polymerization of PANI on ATO, then PANI is used as an assistant for PbI2 deposition using the ionic adsorption deposition method. The chemical structural, morphological, electrical, and optical properties of the composite are confirmed using different analytical tools such as X-ray diffreaction (XRD), scanning electron microscope (SEM), transmision electron microscope (TEM), Fourier-transform infrared spectroscopy (FTIR), and UV-Vis spectroscopy. The prepared PbI2 inside the composite has a crystal size of 33 nm (according to the peak at 12.8°) through the XRD analyses device. SEM and TEM confirm the hexagonal PbI2 sheets embedded on the PANI nanopores surface. Moreover, the bandgap values are enhanced very much after the composite formation, in which the bandgap values for PANI and PANI/PbI2 are 3 and 2.51 eV, respectively. The application of ATO/PANI/PbI2 nanocomposite electrode for sewage splitting and H2 generation is carried out through a three-electrode cell. The measurements carreid out using the electrocehical worksattion under th Xenon lamp (100 mW.cm-2). The produced current density (Jph) is 0.095 mA.cm-2 at 100 mW.cm-2 light illumination. The photoelectrode has high reproducibility and stability, in which and the number of H2 moles is 6 µmole.h-1.cm-1. The photoelectrode response to different monochromatic light, in which the produced Jph decreases from 0.077 to 0.072 mA.cm-2 with decreasing of the wavelengths from 390 to 636 nm, respectively. These values confirms the high response of the ATO/PANI/PbI2 nanocomposite electrode for the light illuminaton and hydrogen genration under broad light region. The thermodynamic parameters: activation energy (Ea), enthalpy (ΔH*), and entropy (ΔS*) values are 7.33 kJ/mol, -4.7 kJ/mol, and 203.3 J/mol.K, respectively. The small values of ΔS* relted to the high sesnivity of the prepared elctrode for the water splitting and then the hydrogen gneration. Finally, a theoretical study was mentioned for calculation geometry, electrochemical, and thermochemistry properties of the polyaniline/PbI2 nanocomposite as compared with that for the polyaniline.

Antibodies to extractable nuclear antigens (ENAS) in systemic lupus erythematosus patients: correlations with clinical manifestations and disease activity.

The aim was to explore possible correlations of antibodies to extractable nuclear antigens (ENA) with clinical manifestations and disease activity indices in systemic lupus erythematosus (SLE) patients. A total of 70 consecutive SLE patients (64 females) were included. Disease activity was assessed by SLE activity index (SLEDAI), and British Isles Lupus Assessment Group (BILAG). Anti-Ro/SSA correlated positively with, headache (r=0.24, p=0.04), blurring of vision (r=0.25, p=0.03) and SLEDAI (r=0.25, p=0.04) and negatively with C3 (r=-0.35, p=0.003). Anti-Ro/SSA correlated with anti La/SSB antibodies (r=0.69, p<0.001), but not with anti-DNA, anti-RNP and anti-Sm antibodies. Anti-La/SSB antibodies correlated with headache (r=0.26, p=0.03), SLEDAI (r=0.25, p=0.03) and negatively with C3 (r=-0.34, p=0.004). Anti-La/SSB did not correlate with anti-RNP or anti-Sm antibodies. Anti-Sm antibodies correlated with disease duration (r=0.34, p=0.003), 24 hours urinary proteins (r=0.31, p=0.008), SLEDAI (r=0.31, p=0.009), BILAG renal score (r=0.29, p=0.02) and negatively with age at onset (r=-0.27, p=0.02), WBCs (r=-0.29, p=0.014) and C4 (r=-0.25, p=0.049). In multivariate analyses, anti-Ro/SSA antibodies remained associated with headache, blurring of vision and C3 and anti-La/SSB antibodies remained associated with C3 and with headache. Anti-Sm antibodies were independently associated with disease duration and total SLEDAI scores, while anti-RNP antibodies remained significantly associated with BILAG mucocutaneous scores only. Antibodies to ENAs are associated with clinical aspects of SLE and may play a role in the assessment of disease activity. Insight into these ENAs may lead to new approaches to diagnostic testing, accurate evaluation of disease activity and lead to target approach for SLE.

Recent advances in the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs.

This review highlights the recently cited research data in the literature on the chemistry of 2-chloroquinoline-3-carbaldehyde and related analogs and their applications over the period from 2013 to 2017. It covers: synthesis of quinoline ring systems and reactions adopted to construct fused or binary quinoline-cord heterocyclic systems. The biological evaluation and the synthetic applications of the target compounds were illustrated.

Eyelid Merkel cell carcinoma in a patient treated with golimumab.

PURPOSE: To describe a clinical case of biopsy-proven Merkel cell carcinoma of the eyelid following golimumab therapy for rheumatoid arthritis (RA). METHODS: Interventional case report. RESULTS: A 73-year-old woman with a history of chronic RA presented with a right upper eyelid mass. She had been treated with golimumab (tumor necrosis factor (TNF) inhibitors) injection therapy for the past 6 months. A biopsy showed findings suggestive of a Merkel cell carcinoma of the eyelid. CONCLUSIONS: Merkel cell carcinoma may be associated with anti-TNF treatment and should be included in the differential diagnosis of an eyelid tumor in patients treated with TNF inhibitors.

Synthesis, characterization and RHF/ab initio simulations of 2-amino-1,3,4-thiadiazole and its annulated ring junction pyrimidine derivatives.

Michael addition reaction of the 2-amino-1,3,4-thiadiazole to chalcone as biselectrophile afforded 5,7-diphenyl-6-[1,3-diphenylpropan-1-on-3-yl][1,3,4]thiadiazolo[3,2-a]pyrimidine (3) instead of 5,7-diphenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine (5) via further Michael addition at C5 in pyrimidine moiety. The structure 3 was established through the aspect of ab initio calculations, elemental analysis and spectral data.

Facile construction of substituted pyrimido[4,5-d]pyrimidones by transformation of enaminouracil.

The reaction of 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1) as a binucleophile with primary aromatic or heterocyclic amines and formaldehyde or aromatic (heterocyclic) aldehydes in a molar ratio (1:1:2) gave the pyrimido[4,5-d]pyrimidin-2,4-dione ring systems 2-5. Treatment of 1 with diamines and formalin in molar ratio (2:1:4) gave the bis-pyrimido[4,5-d]pyrimidin-2,4-diones 6-8. Furthermore, substituted pyrimido[4,5-d]pyrimidin-2,4-diones with uracil derivative 11 or spiro indole 16 were synthesized. Synthesis of pyrimido[4,5-d]pyrimidin-2,4-diones with different substitution at C-5 and C-7 was achieved to give 13 and 18, respectively.

The potential distribution of Phlebotomus papatasi (Diptera: Psychodidae) in Libya based on ecological niche model.

The increased cases of cutaneous leishmaniasis vectored by Phlebotomus papatasi (Scopoli) in Libya have driven considerable effort to develop a predictive model for the potential geographical distribution of this disease. We collected adult P. papatasi from 17 sites in Musrata and Yefern regions of Libya using four different attraction traps. Our trap results and literature records describing the distribution of P. papatasi were incorporated into a MaxEnt algorithm prediction model that used 22 environmental variables. The model showed a high performance (AUC = 0.992 and 0.990 for training and test data, respectively). High suitability for P. papatasi was predicted to be largely confined to the coast at altitudes <600 m. Regions south of 300 degrees N latitude were calculated as unsuitable for this species. Jackknife analysis identified precipitation as having the most significant predictive power, while temperature and elevation variables were less influential. The National Leishmaniasis Control Program in Libya may find this information useful in their efforts to control zoonotic cutaneous leishmaniasis. Existing records are strongly biased toward a few geographical regions, and therefore, further sand fly collections are warranted that should include documentation of such factors as soil texture and humidity, land cover, and normalized difference vegetation index (NDVI) data to increase the model's predictive power.

Efficient regioselective synthesis and potential antitumor evaluation of isoxazolo[5,4-b]pyridines and related annulated compounds.

The reaction of 5-amino-3-methylisoxazole with appropriate α,ß-unsaturated ketones gave the corresponding isoxazolo[5,4-b]pyridines. Treatment of 1 with 2,6-dibenzylidenecyclohexanone or 2-benzylidenedimedone afforded the corresponding isoxazolo[5,4-b]quinoline derivatives. 4,6,8,9-Tetrahydroisoxazolo[5,4-b]quinolin-5-one derivative was also obtained by multicomponent condensation reaction of 1 with dimedone and benzaldehyde. Heterocyclic annulation of the isoxazolo[5,4-b]pyridine system was achieved via reaction of 1 with benzylidene derivatives of indandione, quinuclidone, pyrazolone, and oxazolone. A representative of some newly synthesized compounds was evaluated as antitumor agents.

Efficacy of light and nonlighted carbon dioxide-baited traps for adult sand fly (Diptera: Psychodidae) surveillance in three counties of Mesrata, Libya.

ABSTRACT. Sand flies are important vectors of cutaneous leishmaniasis, especially along coastal towns of northwestern Libya where an estimated 20,000 cases have occurred from 2004 to 2009. Host-seeking traps are an important tool for sampling sand fly populations and surveying the incidence of Leishmania major and L. tropica within a given population. We evaluated the capture efficiency of CO2-baited BG-Sentinel, Centers for Disease Control and Prevention (CDC) light, CDC ultraviolet light, and nonbaited CO2 CDC light traps in 3 coastal townships during June, August, September, and November 2010. A total of 3,248 sand flies, representing 8 species from 2 genera, were collected; most sand flies were identified as either Phlebotomus papatasi or P. longicuspis. Three of the traps captured significantly more sand flies compared to the BG-Sentinel baited with CO2 (P < 0.001). Three of 456 DNA pools extracted from sand flies were positive for Leishmania DNA, indicating a minimum estimated infection rate of 0.83% and 0.47% for P. papatasi and P. longicuspis, respectively.

Comparison of three carbon dioxide sources on phlebotomine sand fly capture in Egypt.

Lighted Centers for Disease Control and Prevention (CDC) light traps were baited with carbon dioxide (CO2) produced from three different sources to compare the efficacy of each in collecting phlebotomine sand flies in Bahrif village, Aswan Governorate, Egypt. Treatments consisted of compressed CO2 gas released at a rate of 250 ml/min, 1.5 kg of dry ice (replaced daily) sublimating from an insulated plastic container, CO2 gas produced from a prototype FASTGAS (FG) CO2 generator system (APTIV Inc., Portland, OR), and a CDC light trap without a CO2 source. Carbon dioxide was released above each treatment trap's catch opening. Traps were placed in a 4 x 4 Latin square designed study with three replications completed after four consecutive nights in August 2007. During the study, 1,842 phlebotomine sand flies were collected from two genera and five species. Traps collected 1,739 (94.4%) Phlebotomus papatasi (Scopoli), 19 (1.0%) Phlebotomus sergenti, 64 (3.5%) Sergentomyia schwetzi, 16 (0.9%) Sergentomyia palestinensis, and four (0.2%) Sergentomyia tiberiadis. Overall treatment results were dry ice (541) > FG (504) > compressed gas (454) > no CO2 (343). Total catches of P. papatasi were not significantly different between treatments, although CO2-baited traps collected 23-34% more sand flies than the unbaited (control) trap. Results indicate that the traps baited with a prototype CO2 generator were as attractive as traps supplied with CO2 sources traditionally used in sand fly surveillance efforts. Field-deployable CO2 generators are particularly advantageous in remote areas where dry ice or compressed gas is difficult to obtain.

Efficacy of commercial mosquito traps in capturing phlebotomine sand flies (Diptera: Psychodidae) in Egypt.

Four types of commercial mosquito control traps, the Mosquito Magnet Pro (MMP), the Sentinel 360 (S360), the BG-Sentinel (BGS), and the Mega-Catch Ultra (MCU), were compared with a standard Centers for Disease Control and Prevention (CDC) light trap for efficacy in collecting phlebotomine sand flies (Diptera: Psychodidae) in a small farming village in the Nile River Valley 10 km north of Aswan, Egypt. Each trap was baited with either carbon dioxide (CO2) from combustion of butane gas (MMP), dry ice (CDC and BGS traps), light (MCU and S360), or dry ice and light (CDC). Traps were rotated through five sites in a5 x 5 Latin square design, repeated four times during the height of the sand fly season (June, August, and September 2007) at a site where 94% of sand flies in past collections were Phlebotomus papatasi (Scopoli). A total of 6,440 sand flies was collected, of which 6,037 (93.7%) were P. papatasi. Of the CO2-baited traps, the BGS trap collected twice as many P. papatasi as the MMP and CDC light traps, and at least three times more P. papatasi than the light-only MCU and S360 traps (P < 0.05). Mean numbers (+/- SE) of P. papatasi captured per trap night were as follows: BGS 142.1 (+/- 45.8) > MMP 56.8 (+/- 9.0) > CDC 52.3 (+/- 6.1) > MCU 38.2 (+/- 6.4) > S360 12.6 (+/- 1.8). Results indicate that several types of commercial traps are suitable substitutes for the CDC light trap in sand fly surveillance programs.

Susceptibility of sand flies to selected insecticides in North Africa and the Middle East.

The purpose of this study was to determine the baseline susceptibility of 4 species of phlebotomine sand flies from North Africa and the Middle East to various insecticides. Susceptibility was determined using the World Health Organization test kits for measuring resistance in mosquitoes exposed to insecticide-impregnated papers. Fifty, 90, and 99% lethal doses were calculated for bendiocarb, cyfluthrin, DDT, malathion, permethrin, and resmethrin on Phlebotomus bergeroti, P. langeroni, P. papatasi. and P. sergenti. The least toxic insecticide to all species was DDT, followed by malathion and permethrin in order of increasing toxicity. Cyfluthrin was the most toxic to P. langeroni and P. papatasi, followed by resmethrin and bendiocarb in order of decreasing toxicity. Resmethrin exhibited the highest toxicity to P. bergeroti followed by cyfluthrin and bendiocarb, whereas bendiocarb was most toxic to P. sergenti, followed by cyfluthrin and resmethrin in order of decreasing toxicity. An attempt was made to obtain data for deltamethrin, but close response data were insufficient to determine regression lines for this insecticide on these species. However, analysis of preliminary data indicated that deltamethrin is highly toxic to these sand flies.

New record of Phlebotomus sergenti, the vector of Leishmania tropica, in the southern Nile valley of Egypt.

We report the 1st collection of Phlebotomus sergenti, a vector of the cutaneous and visceralizing forms of Leishmania tropica, from southern Egypt. Four female and 1 male P. sergenti were collected from unlit Centers for Disease Control light traps placed in a village on the Nile River, 6 km north of Aswan, Egypt, during studies conducted from 1998 to 1999. This extends the known distribution of this species farther south in Egypt than previously recorded.

Molecular systematics of the phlebotomine sandflies of the subgenus Paraphlebotomus (diptera, psychodidae, phlebotomus) based on ITS2 rDNA sequences. Hypotheses Of dispersion and speciation.

Phylogenetic Paraphlebotomus relationships are inferred by a study based on the sequences of ITS2, which has been sequenced in nine Paraphlebotomus species: P. alexandri, P. andrejevi, P. jacusieli, P. kazeruni, P. mireillae, P. mongolensis, P. saevus, P. sergenti and P. similis and in two out-groups species of the subgenus Phlebotomus: P. papatasi and P. duboscqi. Paraphlebotomus alexandri appears as the sister group of all other Paraphlebotomus sandflies. Among the other species, three groupings are clearly highlighted: andrejevi and mongolensis; mireillae and saevus; jacusieli, kazeruni, sergenti and similis. These groupings are related to speculations about the migration of Paraphlebotomus from a centre of dispersion located in the Middle East sometime from the early Eocene to the late Miocene.

The effect of Leishmania major on some biological parameters of Phlebotomus papatasi (Diptera: Psychodidae) from endemic and non-endemic areas in Egypt.

Biological activities of two populations of Phlebotomus papatasi collected from two different areas in Egypt (Sinai and Aswan) and the effect of Leishmania major on such activities were investigated under insectary conditions. A significant reduction (P < 0.05) was observed in the number of eggs laid by the infected females when compared to the non-infected females of the tested populations. The immatures of the Aswan population required a longer period (P < 0.05) to complete larval development. Life expectancy at emergence for infected and non-infected females was almost 13 days for the two populations. No significant difference was observed for the effect of L. major on the survivorship of tested populations. The mean generation time for the non-infected and infected females of Sinai and Aswan were 47.5, 49.8, 50.8, 49.5 days, respectively. Mean productivity (the number of females produced by one female) of the non-infected females of the Sinai population (18.1 female female/female) was significantly higher (P < 0.05) than the Aswan population (12.3 female female/female) while the productivity for infected females for both Sinai and Aswan populations (10.8 and 7.3 female female/female) was significantly reduced (P < 0.05). These results show Leishmania infection affects the fertility and productivity of both populations and may be a factor in controlling the insect population size in nature.

Enzyme polymorphism and genetic variability of laboratory populations of Phlebotomus papatasi, P. bergeroti, P. langeroni, and P. perniciosus.

Enzyme allomorph frequency and electrophoretic mobility were evaluated to clearly separate between morphologically similar sandfly species and to yield quantitative measures of their genetic similarity. Twelve enzyme systems were studied in laboratory colonies of Phlebotomus perniciosus, P. langeroni, P. papatasi, and P. bergeroti. Phlebotomus perniciosus and P. langeroni confirmed vectors of visceral leishmaniasis, were found to have fixed diagnostic allomorph differences at 3 enzyme loci (ICD-2, FUM, XDH). Phlebotomus papatasi, a known vector of cutaneous leishmaniasis and phleboviruses and P. bergeroti, a newly colonized suspected vector, were clearly differentiated from each other by a fixed allomorph at the MPI locus. Polymorphism at loci in these sandfly colonies ranged from 6.7% (P. perniciosus) to 43.7% (P. papatasi), with lowest levels seen in the older colonies. Expected heterozygosity was highest in P. papatasi, despite 33 generations of inbreeding, and comparable to that of P. bergeroti in its 7th generation. Against a scale of 0 for completely different, and 1.0 for identical genotypes, the enzyme data yielded indices of genetic identity (I) between P. perniciosus and P. langeroni and between P. papatasi and P. bergeroti of 0.783 and 0.737, respectively. These relatively high levels of genetic identity, paralleling similarities between species in morphology, inbreeding compatibility, and vectorial attributes, provide evidence of comparable and recent evolutionary divergence.

Colonization and bionomics of the sandfly Phlebotomus kazeruni from Sinai, Egypt.

Phlebotomuius kazeruni (Diptera: Psychodidae) females were collected by light-trap in southern Sinai, Egypt, and this sandfly species was colonized for the first time as a laboratory strain, maintained by the procedures of Modi & Tesh (1983). Laboratory-reared females did not lay eggs autogenously; they blood-fed more readily (P=0.02) on a hamster (37%) than a human (22%) during 1 h exposure. Fecundity of hamster-fed females was significantly greater than for those fed on human blood: 69.4 +/- 5.8 vs. 45.2 +/- 8.1 eggs/female from the first gonotrophic cycle. Pre-oviposition and egg incubation periods were significantly less for females fed on hamster compared with human blood, but the larval development and pupation periods were not affected by this difference in bloodmeal source. Egg to adult survival was equivalent (38%) for progeny of females blood-fed on hamster or human. The mean generation time of progeny from females fed on hamster (51.9 +/- 1.0 days) or human (53.3 +/- 1.7 days) was not significantly different. The sex ratio of adult male:female progeny was similar (P=0.2) for both hosts: 42:58% from hamster, 46:54% from human blood-fed female parents. Evidently P. kazeruni from Sinai is sufficiently anthropophagic to be a potential vector of Leishmania from rodents to humans.

Response of mosquitoes (Diptera: Culicidae) to carbon dioxide and octenol in Egypt.

Carbon dioxide and 1-octen-3-ol (octenol were evaluated individually, and in combination, as adult mosquito attractants at two sites in Qara, Matruh Governorate, Egypt. Four mosquito species were collected during the study: Aedes caspius, Anopheles multicolor, An. sergenti and Culex pipiens. Anopheles multicolor and Cx. pipiens were collected in insufficient numbers to allow statistical analysis. Significantly greater numbers of Ae. caspius and An sergenti were collected in CO2 and CO2 + octenol traps than octenol alone or the control at both locations (P < 0.05). Traps baited with octenol + CO2 resulted in greater capture of these two species at both locations; but results were not significant when compared with CO2 alone. There were no significant differences in number of mosquitoes collected between the octenol alone and control traps at both locations. At the release rate tested (0.5 mg/h at 21 degrees C), octenol was not an effective attractant for the mosquito species collected during the course of this study.