Evaluation of Pyrazolyl-Indolizine Derivatives as Antimicrobial Agents: Synthesis, In vitro, In silico ADMET and Molecular Docking Studies.

Herein, we report analogues of s-indacene by the synthesis of novel indolizine derivatives. Using chloroform as an appropriate solvent, sixteen derivatives of pyrazolyl-indolizine (4-19) were prepared by the reaction of 3-(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one with hydrazonoyl chloride derivatives in the presence of triethylamine in good to excellent yields. We used NMR spectra, IR, mass spectrometry, as well as elemental analyses to prove the chemical structures and the purity of the synthesized compounds. Among all tested compounds 5, 9, 13 and 19 had a potent antimicrobial efficiency against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aerginousea, Sallmonella typhemerium, and Candida albicans. Furthermore, a significant increase in lipid peroxidation (LPO) toward the Gram-negative bacteria, Pseudomonas aeruginosa when treated with compound 9 was observed, while compound 13 remarkably increased the cell membrane oxidation of Salmonella typhimurium. Additionally, we utilized docking studies and in silico methods to evaluate the drug-likeness, physicochemical properties, and ADMET profiles of the compounds. The results of the molecular docking simulation revealed that the synthesized compounds displayed decreased binding energy when interacting with the active sites of important enzymes, including Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of S. typhimurium, and Gyrase B of B. subtilis.

Toxicity and Repellency Efficacy of Benzyl Alcohol and Benzyl Benzoate as Eco-Friendly Choices to Control the Red Flour Beetle Tribolium castaneum (Herbst. 1797).

Tribolium castaneum is a damaging pest of stored grains, causing significant losses and secreting lethal quinones, which render the grains unfit for human consumption. Chemical insecticides are the most commonly used approach for control; however, they create insecticide resistance and affect the health of humans, animals, and the environment. As a result, it is critical to find an environmentally friendly pest-management strategy. In this study, two naturally occurring chemicals, benzyl alcohol (BA) and benzoyl benzoate (BB), were investigated for insecticidal activity against T. castaneum using different assays (impregnated-paper, contact toxicity, fumigant, and repellency assays). The results showed that BA had a significant insecticidal effect, with the LC50 achieved at a lower concentration in the direct-contact toxicity test (1.77%) than in the impregnated-paper assay (2.63%). BB showed significant effects in the direct-contact toxicity test, with an LC50 of 3.114%, and a lower toxicity in the impregnated-paper assay, with an LC50 of 11.75%. Furthermore, BA exhibited significant fumigant toxicity against T. castaneum, with an LC50 of 6.72 µL/L, whereas BB exhibited modest fumigant toxicity, with an LC50 of 464 µL/L. Additionally, at different concentrations (0.18, 0.09, 0.045, and 0.0225 µL/cm2), BA and BB both showed a notable and potent repelling effect. BA and BB significantly inhibited acetylcholinesterase, reduced glutathione (GSH), and increased malondialdehyde (MDA) in treated T. castaneum. This is the first report of BA insecticidal activity against the red flour beetle. Also, the outcomes of various assays demonstrated that the application of BA induces a potent bio-insecticidal effect. BA may be a promising eco-friendly alternative to control T. castaneum due to its safety and authorization by the EFSA (European Food Safety Authority).

A protocol for evaluating the entomological impact of larval source reduction on mosquito vectors at hotel compounds in Zanzibar.

There is an increasing awareness of the association between tourism activity and risks of emerging mosquito-borne diseases (MBDs) worldwide. In previous studies we showed that hotels in Zanzibar may play an important role in maintaining residual foci of mosquito vectors populations of public health concern. These findings indicated larval sources removal (LSR) interventions may have a significant negative impact on vector communities. However, a thorough analysis of the response vector species to potential LSM strategies must be evaluated prior to implementation of a large-scale area-wide control campaign. Here we propose a protocol for evaluation of the impact of LSR against mosquito vectors at hotel settings in Zanzibar. This protocol is set to determine the efficacy of LSR in a randomized control partial cross-over experimental design with four hotel compounds representing the unit of randomization for allocation of interventions. However, the protocol can be applied to evaluate the impact of LRS in more than four sites. Proposed interventions are active removal of disposed containers, and installation of water dispenser to replace single use discarded plastic water bottles, which were identified as the most important source of mosquitoes studied hotels. The ideal time for allocating intervention to the intervention arms the dry season, when the mosquito abundance is predictably lower. The possible impact of interventions on mosquito occurrence and abundance risks is then evaluated throughout subsequent rainy and dry seasons. If an appreciable reduction in mosquito abundance and occurrence risks is observed during the trial period, intervention could be extended to the control arm to determine whether any potential reduction of mosquito density is reproducible. A rigorous evaluation of the proposed LRS interventions will inspire large scale trials and provide support for evidence-based mosquito management at hotel facilities in Zanzibar and similar settings.

Newly Synthesized Arylazo Derivatives Induce Apoptosis and G2/M Cell Cycle Arrest With Molecular Docking Validation in Human Cancer Cell Lines.

OBJECTIVE: We reported herein the synthesis of novel arylazo derivatives 3a-e incorporating isoquinoline moiety. METHODS: A coupling reaction of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile 1 with diazotized heterocyclic amines 2 in ethanol in the presence of sodium acetate to give arylazo derivatives 3a-e. RESULTS: Cytotoxic effect of five arylazo derivatives on breast carcinoma MCF7 and hepatocellular carcinoma HepG2 was carried out, followed by molecular and functional-based assays, to estimate the anticancer effect of these compounds. The fibroblast growth factor receptor (FGFR) and epithelial growth factor receptor (EGFR) were found to interact and bind with the compounds 3a and 3d through several hydrophobic and hydrogen bonds, which were validated by molecular docking. CONCLUSION: The two promising compounds 3a and 3d demonstrated various anticancer potential activities on tumorigenesis, cytotoxicity, and apoptotic effects, exhibited in the deregulation of the expression of different genes involved in apoptotic and anti-apoptotic mechanisms, cell cycle arrest at G2/M, and induction of apoptosis in both cell lines.

Production of natural flavor compounds using Bacillus subtilis-fermented soybean meal extract and their biological potential: a comprehensive in vitro study.

This study aims to investigate the production of natural flavor compounds through the utilization of Bacillus subtilis-fermented soybean meal extract and evaluate their biological potential. The experiment involved a comprehensive in vitro investigation to assess the capabilities and effects of the produced flavor compounds. The resulting flavor compounds were subjected to various in vitro tests to assess their properties, including cytotoxicity, antioxidant activity, anticancer potential, antiviral activity, and antimicrobial activity. To enhance the fermentation process, soybean meal extract was fortified with a combination of L-Lysine and L-Threonine. Gas chromatography-mass spectrometry (GC/MS) analysis was conducted on the fermented soybean meal using two strains of Bacillus subtilis, namely NRCH123 and NRCZ144. This analysis revealed the presence of various volatile compounds in all extracts, including Butylated hydroxytoluene. The fermented soybean extract with bacillus subtilis NRCZ144 (B2) fortified with a combination of 2.5% (w/w) L-Lysine and 2.5% w/w L-threonine (SLT2) exhibited a rich profile of flavor compounds, with Eucalyptol being identified as the predominant compound. The antioxidant activity of the SLT2 extract was found to be 72.04% at a concentration of 100 µg/mL, indicating significant antioxidant potential. Furthermore, when tested against the human liver cancer cell line HepG2, the extract demonstrated anticancer activity with an IC50 value of 2.26 µg/mL. The extract exhibited potent cytotoxicity, with an IC50 value of 1.02 µg/mL. Importantly, the SLT2 extract displayed strong antibacterial and antifungal activity, even at very low concentrations. The extract's antimicrobial properties indicate its potential for inhibiting the growth of bacteria and fungi.

Application of Gurma Melon (Citrullus lantus var. colocynthoides) Pulp-Based Gel Fat Replacer in Mayonnaise.

Gurma melon pulp-based gel (GMPG) was examined as a fat replacement in mayonnaise. GMPG was used to partially replace fat in quantities of 25, 50, and 70%, abbreviated as GMPG-25, GMPG-50, and GMPG-70, respectively. Mayonnaise's physicochemical and sensory properties were studied. The data demonstrated that all low-fat mayonnaises had much lower energy value but significantly higher water content than their full-fat equivalents and that these differences developed as GMPG replacement levels increased. A microstructure analysis revealed compact the packing structures of big droplets in the whole fat sample and a baggy structure network of aggregated tiny droplets in the GMPG-25, GMPG-50, and GMPG-70 samples. There were no significant differences in pH or water activity after one day of storage between the full-fat and low-fat mayonnaises. Mayonnaises with GMPG-50 and GMPG-70 exhibited the same hardness as full-fat, whereas mayonnaises with GMPG-25 were harder than the other samples. Increased mayonnaise whiteness (L* increase and a* and b* reduction) was seen with reductions in fat. All samples had good sensory approval, with the 50% oil mayonnaise appearing to be the most appealing. It has been demonstrated that GMPG is an effective fat replacement agent.

High DDT resistance without apparent association to kdr and Glutathione-S-transferase (GST) gene mutations in Aedes aegypti population at hotel compounds in Zanzibar.

Global efforts to control Aedes mosquito-transmitted pathogens still rely heavily on insecticides. However, available information on vector resistance is mainly restricted to mosquito populations located in residential and public areas, whereas commercial settings, such as hotels are overlooked. This may obscure the real magnitude of the insecticide resistance problem and lead to ineffective vector control and resistance management. We investigated the profile of insecticide susceptibility of Aedes aegypti mosquitoes occurring at selected hotel compounds on Zanzibar Island. At least 100 adults Ae. aegypti females from larvae collected at four hotel compounds were exposed to papers impregnated with discriminant concentrations of DDT (4%), permethrin (0.75%), 0.05 deltamethrin (0.05%), propoxur (0.1%) and bendiocarb (0.1%) to determine their susceptibility profile. Allele-specific qPCR and sequencing analysis were applied to determine the possible association between observed resistance and presence of single nucleotide polymorphisms (SNPs) in the voltage-gated sodium channel gene (VGSC) linked to DDT/pyrethroid cross-resistance. Additionally, we explored the possible involvement of Glutathione-S-Transferase gene (GSTe2) mutations for the observed resistance profile. In vivo resistance bioassay indicated that Ae. aegypti at studied sites were highly resistant to DDT, mortality rate ranged from 26.3% to 55.3% and, moderately resistant to deltamethrin with a mortality rate between 79% to and 100%. However, genotyping of kdr mutations affecting the voltage-gated sodium channel only showed a low frequency of the V1016G mutation (n = 5; 0.97%). Moreover, for GSTe2, seven non-synonymous SNPs were detected (L111S, C115F, P117S, E132A, I150V, E178A and A198E) across two distinct haplotypes, but none of these were significantly associated with the observed resistance to DDT. Our findings suggest that cross-resistance to DDT/deltamethrin at hotel compounds in Zanzibar is not primarily mediated by mutations in VGSC. Moreover, the role of identified GSTe2 mutations in the resistance against DDT remains inconclusive. We encourage further studies to investigate the role of other potential insecticide resistance markers.

Ethosomal gel for rectal transmucosal delivery of domperidone: design of experiment, in vitro, and in vivo evaluation.

Despite high efficiency of domperidone (DOM) in prophylaxis of emesis accompanied with radiotherapy and chemotherapy, it still can bother cancer patients by its powerful side effects and difficulty of its oral administration. The study was designed to develop and optimize DOM loaded ethosomal gel for rectal transmucosal delivery. Ethosomal formulations were prepared using a 21, 51 full-factorial design where the impact of lecithin concentration and additives were investigated. The optimum ethosomal vesicles were subsequently incorporated in Carbopol gel base where rheological behavior, spreadability, mucoadhesion, and in vivo pharmacokinetic parameters were studied. Based on Design Expert® software (Stat Ease, Inc., Minneapolis, MN), the optimum formulation illustrated entrapment efficiency of 70.02%±5.52%, and vesicular size of 112 ± 3.3 nm, polydispersity index of 0.32 ± 0.01, zeta potential of -59 ± 0.28 mV, and % drug released after 6 h of 76.30%±2.45%. Moreover, ex vivo permeation through rabbit intestinal mucosa increased four times compared to free DOM suspension. The gel loaded with ethosomes showed excellent mucoadhesion to rectal mucosa. DOM ethosomal gel showed a raise in Cmax and AUC0-48 of DOM by twofolds compared to free DOM gel. The study suggested that ethosomes incorporated in gels could be an efficient candidate for rectal transmucosal delivery of DOM.

Hydrazonoyl chlorides possess promising antitumor properties.

AIMS: the main purpose of this study was to identify new selective antitumor agents. MAIN METHODS: several hydrazonoyl chlorides (HCs) were synthesized and human tumor cell line viability was determined using the MTT assay. Tumor development was assessed using Ehrlich ascites carcinoma (EAC)-bearing mice. KEY FINDINGS: our results showed that 2-oxo-N-phenyl-2-(phenylamino)acetohydrazonoyl chloride (compound 4; CPD 4) and 2-oxo-2-(phenylamino)-N-(p-tolyl)acetohydrazonoyl chloride (CPD 5) were the most cytotoxic HCs to human cervical tumor HeLa (IC50: 20 and 25 µM for CPD 4 and 5 respectively), breast MCF7 (IC50: 29 and 34 µM for CPD 4 and 5 respectively) and colon HCT116 cancer cells (IC50: 26 and 25 µM for CPD 4 and 5 respectively) with the least cytotoxicity to human non-tumor CCD-18Co colon fibroblasts as well as murine splenocytes. The active compounds significantly inhibited colony formation as well as tumor development in EAC-bearing mice. We also observed that PTEN-deficient cells displayed greater sensitivity than cells expressing wild type PTEN. At the molecular level, comet and cell cycle analyses indicated that the active compounds generate DNA damage. In light of the PTEN-dependent sensitivity and genomic instability we examined the influence of HCs on the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) and the PI3K/AKT/mTOR pathway, which are each known to be synthetic lethal with PTEN. We found that both PNKP and the PI3K/AKT/mTOR pathway to be adversely affected by the HCs, which may partially account for their toxicity. SIGNIFICANCE: hydrazonoyl chlorides can be considered as hit compounds for the development of new antitumor agents.

Anticancer activity of novel 3-(furan-2-yl)pyrazolyl and 3-(thiophen-2-yl)pyrazolyl hybrid chalcones: Synthesis and in vitro studies.

Twelve novel chalcone derivatives were prepared using the Claisen-Schmidt condensation reaction. The reaction of 4-acetyl-5-furan/thiophene-pyrazole derivatives 5 with the corresponding aldehydes 6 afforded the targeted chalcone derivatives 7a-l in good yields. The newly synthesized chalcones were fully characterized by spectrometric and elemental analyses. The in vitro anticancer activities of the novel compounds 7a-l were evaluated against four human cancer cell lines: HepG2 (human hepatocellular carcinoma), MCF7 (human Caucasian breast adenocarcinoma), A549 (lung carcinoma), and BJ1 (normal skin fibroblasts). Compound 7g emerged as the most promising compound, with IC50 = 27.7 µg/ml against A549 cells compared to the reference drug doxorubicin (IC50 = 28.3 µg/ml), and IC50 = 26.6 µg/ml against HepG2 cells compared to the reference drug doxorubicin (IC50 = 21.6 µg/ml). The gene expression and DNA damage values and the DNA fragmentation percentages for compound 7g were determined on the lung and liver cell lines. The expression levels of the AMY2A and FOXG1 genes increased significantly (p < 0.01) in the negative samples of lung cancer cells compared with treated cells. Also, the expression values of the PKM and PSPH genes improved significantly (p < 0.01) in the negative samples compared with treated samples of liver cancer cells. The DNA damage values increased significantly (p < 0.01) in treated lung cell line samples (7g) and the positive control. The results showed a significant decrease (p < 0.05) in DNA damage values in the negative samples of liver cancer cells compared to those treated with 7g. However, the DNA fragmentation values increased significantly (p < 0.01) in the treated lung and liver cell line samples compared with the negative control.

Risk factors for occurrence and abundance of Aedes aegypti and Aedes bromeliae at hotel compounds in Zanzibar.

BACKGROUND: A field survey was performed to investigate local environmental factors promoting occurrence and abundance of Aedes aegypti and Ae. bromeliae mosquitoes at hotel compounds in the south-east coastal region of Zanzibar Island. METHODS: The potential risk factors were determined using generalized linear mixed models. Aedes (Stegomyia) spp. indices such as container index (CI) and pupae per container (PPC) index were also estimated. RESULTS: Aedes aegypti and Ae. bromeliae were the most abundant vector species, accounting for 70.8% of all Aedes mosquitoes collected. The highest CI was observed for plastic containers irrespective of the season, whereas the highest PPC was observed for coconut shells and aluminium containers in the rainy and dry seasons, respectively. The risk of Aedes mosquito occurrence and abundance were significantly associated with presence of plastic containers, coconut shells, used tyres and steel containers. These were discarded in shaded places, in the open and gardens, or found in plant nurseries. CONCLUSION: This study shows that Aedes species of global health significance occur at hotel compounds on this part of Zanzibar Island. The occurrence and abundance are sustained by the presence of abundant and poorly managed solid wastes and containers used for gardening tasks. This highlights an urgent need for the adoption of area-wide environmentally sustainable Aedes mosquito management interventions that also integrate solid waste management and ornamental plant production practices for reducing the risk of arboviral disease epidemics.

Survey of Dental Implant and Restoration Selection by Prosthodontists in Dubai.

BACKGROUND: With various surgical and prosthetic component designs being introduced in dental implants, decisions have to be made when choosing a system and a certain prosthodontic protocol. A survey of implant prosthodontic specialists has not been previously performed in the Middle East. AIM: This study aimed to determine selection criteria and choice of dental implants and restorations by prosthodontic specialists in the Emirate of Dubai, United Arab Emirates. MATERIALS AND METHODS: A validated 16-item questionnaire was used in the survey which included demographic information, implant training and experience, implant treatment planning, implant restoration, and implant system preference. The research protocol was approved by the Research and Ethics Committees of Hamdan Bin Mohammed College of Dental Medicine and Dubai Health Authority. Prosthodontists were identified from regulatory authority websites and contacted by e-mail with the questionnaire attached. RESULTS: A total of 84.6% (77) of the registered prosthodontists in Dubai completed the questionnaire with 66.2% reported practicing implant dentistry. Out of which, 54.9% reported surgically placing dental implants and 45.1% restore them only prosthetically. Prefabricated metal abutments were the most commonly selected abutments for single crowns (76.0%) and for fixed dental prostheses (66.7%). Screw retention is preferred mostly for single crowns (68.0%) and fixed dental prostheses (74.0%). Locators were the most commonly selected type of attachment for implant-retained/supported overdentures (49.0%). Conventional loading was the most selected type of loading in all oral conditions. CONCLUSION: Within the limitations of this study, it can be concluded that most prosthodontists in Dubai practice implant dentistry and more than half surgically place dental implants. Prefabricated metal abutments are the most selected type of abutments. Most prosthodontists use screw-retained implant restorations and prefer locator attachments for implant-retained/supported overdentures. Conventional loading is the most preferred implant loading method in all oral conditions. Implant company/system selections are various and there is no major preference for a certain system. The majority of prosthodontists select implant systems based on implant features, literature review, and simplicity of restorative kit.

Emerging epidemics: is the Zanzibar healthcare system ready to detect and respond to mosquito-borne viral diseases?

BACKGROUND: Effective control of emerging mosquito-borne viral diseases such as dengue, chikungunya, and Zika requires, amongst other things, a functional healthcare system, ready and capable of timely detection and prompt response to incipient epidemics. We assessed the readiness of Zanzibar health facilities and districts for early detection and management of mosquito-borne viral disease outbreaks. METHODS: A cross-sectional study involving all 10 District Health Management Teams and 45 randomly selected public and private health facilities in Zanzibar was conducted using a mixed-methods approach including observations, document review, and structured interviews with health facility in-charges and District Health Management Team members. RESULTS: The readiness of the Zanzibar healthcare system for timely detection, management, and control of dengue and other mosquito-borne viral disease outbreaks was critically low. The majority of health facilities and districts lacked the necessary requirements including standard guidelines, trained staff, real-time data capture, analysis and reporting systems, as well as laboratory diagnostic capacity. In addition, health education programmes for creating public awareness and Aedes mosquito surveillance and control activities were non-existent. CONCLUSIONS: The Zanzibar healthcare system has limited readiness for management, and control of mosquito-borne viral diseases. In light of impending epidemics, the critical shortage of skilled human resource, lack of guidelines, lack of effective disease and vector surveillance and control measures as well as lack of laboratory capacity at all levels of health facilities require urgent attention across the Zanzibar archipelago.

Assessment of the core and support functions of the integrated disease surveillance and response system in Zanzibar, Tanzania.

BACKGROUND: Disease surveillance is a cornerstone of outbreak detection and control. Evaluation of a disease surveillance system is important to ensure its performance over time. The aim of this study was to assess the performance of the core and support functions of the Zanzibar integrated disease surveillance and response (IDSR) system to determine its capacity for early detection of and response to infectious disease outbreaks. METHODS: This cross-sectional descriptive study involved 10 districts of Zanzibar and 45 public and private health facilities. A mixed-methods approach was used to collect data. This included document review, observations and interviews with surveillance personnel using a modified World Health Organization generic questionnaire for assessing national disease surveillance systems. RESULTS: The performance of the IDSR system in Zanzibar was suboptimal particularly with respect to early detection of epidemics. Weak laboratory capacity at all levels greatly hampered detection and confirmation of cases and outbreaks. None of the health facilities or laboratories could confirm all priority infectious diseases outlined in the Zanzibar IDSR guidelines. Data reporting was weakest at facility level, while data analysis was inadequate at all levels (facility, district and national). The performance of epidemic preparedness and response was generally unsatisfactory despite availability of rapid response teams and budget lines for epidemics in each district. The support functions (supervision, training, laboratory, communication and coordination, human resources, logistic support) were inadequate particularly at the facility level. CONCLUSIONS: The IDSR system in Zanzibar is weak and inadequate for early detection and response to infectious disease epidemics. The performance of both core and support functions are hampered by several factors including inadequate human and material resources as well as lack of motivation for IDSR implementation within the healthcare delivery system. In the face of emerging epidemics, strengthening of the IDSR system, including allocation of adequate resources, should be a priority in order to safeguard human health and economic stability across the archipelago of Zanzibar.

Novel [l,2,4]triazolo[3,4-a]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis.

Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis. Graphical abstract Novel chalcones were prepared and confirmed by different spectral tools. Docking simulations were done to detect the mechanism of action. In vitro cytotoxicity indicated a strong effect against different cancer cell lines and low toxic effects against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies that include Real-time PCR, Flow-cytometry, Cytochrome c oxidase, and ELISA assay. SEM and TEM tool were used to follow the morphological changes occurred on the cell surface.

Epidemic risk of arboviral diseases: Determining the habitats, spatial-temporal distribution, and abundance of immature Aedes aegypti in the Urban and Rural areas of Zanzibar, Tanzania.

BACKGROUND: In Zanzibar, little is known about the arboviral disease vector Aedes aegypti in terms of abundance, spatio-temporal distribution of its larval habitats or factors associated with its proliferation. Effective control of the vector requires knowledge on ecology and habitat characteristics and is currently the only available option for reducing the risk of arboviral epidemics in the island nation of Zanzibar. METHODOLOGY: We conducted entomological surveys in households and surrounding compounds from February to May 2018 in the urban (Mwembemakumbi and Chumbuni) and rural (Chuini and Kama) Shehias (lowest government administrative unit) situated in the Urban-West region of Unguja island, Zanzibar. Larvae and pupae were collected, transported to the insectary, reared to adult, and identified to species level. Characteristics and types of water containers were also recorded on site. Generalized linear mixed models with binomial and negative binomial distributions were applied to determine factors associated with presence of Ae. aegypti immatures (i.e. both larvae and pupae) or pupae, alone and significant predictors of the abundance of immature Ae. aegypti or pupae, respectively. RESULTS: The survey provided evidence of widespread presence and abundance of Ae. aegypti mosquitoes in both urban and rural settings of Unguja Island. Interestingly, rural setting had higher numbers of infested containers, all immatures, and pupae than urban setting. Likewise, higher House and Breteau indices were recorded in rural compared to the urban setting. There was no statistically significant difference in Stegomyia indices between seasons across settings. Plastics, metal containers and car tires were identified as the most productive habitats which collectively produced over 90% of all Ae. aegypti pupae. Water storage, sun exposure, vegetation, and organic matter were significant predictors of the abundance of immature Ae. aegypti. CONCLUSIONS: Widespread presence and abundance of Ae. aegypti were found in rural and urban areas of Unguja, the main island of Zanzibar. Information on productive habitats and predictors of colonization of water containers are important for the development of a routine Aedes surveillance system and targeted control interventions in Zanzibar and similar settings.

Synthesis, Cytotoxicity and Docking Simulation of Novel Annulated Dihydroisoquinoline Heterocycles.

OBJECTIVE: Coupling of ethyl 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate 2 with diazotized anilines in ethanol in the presence of sodium acetate yielded 2-(2-arylhydrazono)-2-(6,7- dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate (4a-f). METHODS: Treatment of 2 with α-bromoketones 6a-f in dry benzene at reflux gave the corresponding isoquinolinium bromides 7a-f. Refluxing of each of the salts 7a-f in dry benzene and in the presence of triethylamine yielded 2-arylpyrrolo-[2,1-a]isoquinoline structures 8a-f, that converted to ethyl (E)-8,9- dimethoxy-3-(phenyldiazen-yl)-2-(aryl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (9a-f) upon treatment with diazotized anilines 3 in ethanol in the presence of sodium acetate. RESULTS AND CONCLUSION: Cytotoxic assay was performed for in vitro antitumor screening against caucasian breast adenocarcinoma (MCF7), hepatocellular carcinoma (HepG2) and colorectal carcinoma (HCT-116) cell lines. The results were compared with the standard anticancer drug (doxorubicin). Molecular docking using MOE 2014.09 software was carried out for the most potent compound 4d, which showed the highest binding affinity towards the four tested proteins and thus initiated apoptosis of cancer cells.

Molecular Docking Study, Cytotoxicity, Cell Cycle Arrest and Apoptotic Induction of Novel Chalcones Incorporating Thiadiazolyl Isoquinoline in Cervical Cancer.

BACKGROUND: Chalcones are naturally occurring compounds found in various plant species which are widely used for the traditional popular treatments. Chalcones are distinguished secondary metabolites reported to display diverse biological activities such as antiviral, antiplatelet, anti-inflammatory, anticancer, antibacterial and antioxidant agents. The presence of a,ß-unsaturated carbonyl group in chalcones is assumed to be responsible for their bioactivity. In addition, heterocyclic compounds having nitrogen such as isoquinolines are of considerable interest as they constitute the core structural element of many alkaloids that have enormous pharmacological activities. OBJECTIVE: The objective of this study is the synthesis and biological activity of novel chalcones incorporating thiadiazolyl isoquinoline as potential anticancer candidates. Different genetic tools were used in an attempt to know the mechanism of action of this compound against breast cancer. METHODS: An efficient one pot synthesis of novel chalcones incorporating thiadiazolyl isoquinoline was developed. The cytotoxic activity of the novel synthesized compounds was performed against four different kinds of cancer cell lines. RESULTS: Among all the tested derivatives, chalcone 3 has the best cytotoxic profile against A549, MCF7, and HeLa cell lines, with IC50s 66.1, 51.3, and 85.1µM, respectively. Molecular docking studies for chalcone 3 revealed that CDK2, and EGFRTK domains have strong binding affinities toward the novel chalcone 3, while tubulin-colchicine-ustiloxin, and VEGFRTK domains illustrated moderate mode of binding. CONCLUSION: We have developed an efficient method for the synthesis of novel chalcones incorporating thiadiazolyl isoquinoline. All compounds showed better cytotoxicity results against four kinds of cancer cell lines (A549, MCF7, HCT116, and HELA cells). The results depicted that chalcone 3 has a high and promising cytotoxic effect against HELA cell line and the mechanism of cytotoxicity was widely studied through different theoretical and experimental tools. Thus, the newly synthesized derivative 3 can be utilized as a novel chemotherapeutic compound for cervical carcinoma.

Temporal Pattern of Mutations in the Knockdown Resistance (kdr) Gene of Aedes aegypti Mosquitoes Sampled from Southern Taiwan.

Aedes mosquitoes are the principal dengue vector in Taiwan, where the use of insecticides is a key element in the national control strategy. However, control efforts are constrained by the development of resistance to most insecticides, including pyrethroids. In this study, mutations in the voltage-gated sodium channel (VGSC) gene resulting in knockdown resistance (kdr) were examined in Aedes aegypti. Fragments of the VGSC gene were polymerase chain reaction (PCR)-amplified followed by restriction fragment length polymorphism analysis in samples from various settings in Southern Taiwan covering dry and wet seasons from 2013 to 2015. Three kdr mutations were identified: V1023G, D1794Y, and F1534C, with observed frequencies of 0.36, 0.55, and 0.33, respectively, in the dry season of 2013-2014. Exploring for temporal changes, the most important observation was the 1534C allele frequency increment in the following season to 0.60 (P < 0.05). This study suggests that continued insecticide pressure is driving the mutational changes, although the selection is ambiguous in the mosquito population.

Biological Activity, Apoptotic Induction and Cell Cycle Arrest of New Hydrazonoyl Halides Derivatives.

BACKGROUND: The hydrazonoyl halides are presently an important target in the field of medicinal chemistry. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to a myriad of both heterocyclic and acyclic compounds. In addition, they have diverse biological activities such as antiviral, anthelmintic, antiarthropodal, fungicidal, herbicidal, insecticidal, pesticidal, acaricidal and miticidal Activity correlated to the presence of hydrazonoyl halides. Moreover, many applications in both industrial and pharmaceutical fields have been found to be associated with these halides. Depending on the above facts and continuation to our work, we herein report on the evaluation of the anticancer activity of these two halides prepared according to the published work and trying to know their molecular mechanism that they proceed to stop proliferation and metastasis of tumor cells by molecular tools such as real time PCR using different apoptotic genes, and cell cycle assay. OBJECTIVE: The goal of this present study is to bring attention to the biological activities of hydrazonoyl halides and the molecular pathway they follow to exert their role in apoptotic death of cancer cell. METHODS: Synthesis of hydrazonoyl halides 2c and 2f. The cytotoxic effect against different human cancer cell lines PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines as MCF-10 and MCF-12 in a monolayer culture model was evaluated. Their mechanism of action inside cancer cell was evaluated using different molecular tools. CONCLUSION: Strong and promising chemotherapeutic hydrazonoyl halides (2a-2f) were evaluated for their different biological activities. As antimicrobial agents, results indicated that three compounds 2a, 2e and 2f exhibited high activity against two tested gram positive bacteria Staphylococcus aureus, Bacillus subtilis, and gram negative ones Escherichia coli, and Pseudomonas aeruginosa, the rest of the compounds were found to be moderately active against the tested microorganisms. Regarding their antifungal effect, compound 2c exhibited potent and promising effect against Candida albicans, while 2b was the most potent toward Aspergillus flavus Link. The compound 2f has repellent effect. With respect to the in vitro antitumor screening, this was done on different human cancer cell lines; namely PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines; as MCF-10 and MCF-12 (normal breast epithelial cell and non-tumorigenic breast epithelial cell line) in a monolayer culture model where screening has been conducted at 100µg/ml (single dose test). Single dose test (100µg/ml) showed that, in case of PC3, all compounds have cytotoxic activity over 90% inhibition, 4 compounds have cytotoxic activity with 100% inhibition with Human colon cancer cell line, 4 compounds showed over 90% inhibition with MCF7 cell line and 4 compounds showed cytotoxic activity over 90% inhibition with HepG-2. Results of IC50 values for most promising compounds showed compounds with values lower than 20µM for all tested human cancer cell line. The promising hydrazonoyl halide 2c and 2f were selected for molecular study to know how they could act inside cancer cell causing death. Two biochemical tests were performed using the two halides 2c and 2f to predict their mechanism of action against breast carcinoma. Real time PCR analysis indicates that the two compounds induced the apoptosis of MCF7 cells through the up regulation of caspase-3, BAX mediated P53 mechanism but unfortunately, they promote the expression of anti-apoptotic protein BCL2. Also, cell cycle assay was performed using two different cell lines MCF7 and HCT116 and data revealed that the two compounds 2c and 2f induced apoptotic cells death of both lines via cell growth arrest at G2/M phase. In addition, it was noted that 2c induced arrest in the two lines more efficiently than 2f at G2/M phase.