Modeling climate change adaptation for sustainable coastal zones using GIS and AHP.

The world is currently confronting one of its biggest environmental challenges: combating climate change. Coastal zones are one of the areas thought to be most sensitive to current and future climate change threats. The paper integrates Remote Sensing (RS), Geographic Information System (GIS) techniques, and Multi-Criteria Decision Analysis (MCDA) to detect vulnerable areas from climate change impacts in coastal zones in order to recommend adaptation systems in new coastal zones that can withstand various climatic changes. The proposed decision-making framework was developed in three phases: 1) climate data collection and processing; 2) Coastal Climate Impact Assessment (CCIA) model development; and 3) implementation and adaptation system selection. The climate data collection and processing phase involves determining the most significant climate change parameters and their indicators that affect coastal zone stability, extracting climatic data indicators from different climate database sources, and prioritizing the selected indicators. The indicators' weights were estimated using the Analytical Hierarchy Process (AHP) through a questionnaire survey shared with experts in climate change impacts. A CCIA model development phase involves the formulation of the proposed model using GIS technique to discover the vulnerable areas according to the most dominant impact. The implementation and adaptation system selection phase involves the application of the framework to Al-Alamein New City in Egypt. A sensitivity analysis was conducted to measure the behavior of several climate change parameters to identify the most critical parameter for climate change in Al-Alamein New City. The results showed that the geology of the region is the most crucial component influenced by climate change. It is capable of producing a very sensitive area in the coastal zone while also taking other factors into account. When creating new urban neighborhoods, the erosion of the shoreline is the least important factor to consider. This is because coastal deterioration is caused by both the influence of metrological data on the region and the impact of human activity. Shoreline deterioration will be reduced if climate conditions are maintained while limiting the impact of human activities. To adapt to the long-term effects of climate change on coastal zones, a combination of soft and hard protection systems should be considered.

The use of lidocaine infusion in laparoscopic cholecystectomy: An updated systematic review and meta-analysis.

ABSTRACT: Being one of the most common abdominal surgical procedures, numerous techniques have been adapted to decrease post-operative pain post cholecystectomy. However, the efficacy of intravenous (IV) lidocaine in managing post operative pain after LC is still controversial, according to many recent studies. This study aims to detect the effectiveness of IV lidocaine compared to other medications in managing post-operative pain. PubMed, Scopes, Web of Science and Cochrane Library were searched for eligible studies from inception to June 2023, and a systematic review and meta-analysis was done. According to eligibility criteria, 14 studies (898 patients) were included in our study. The pooled results of the included studies showed that the pain score after 6, 12 and 24 h after the surgery was significantly lower in those who received IV lidocaine as a painkiller (Visual Analogue Scale [VAS] 6H, mean difference [MD] = -1.20, 95% confidence interval [CI] = -2.20, -0.20, P = 0.02; I2 = 98%, VAS 12H, MD = -0.90, 95% CI = -1.52, -0.29, P = 0.004; I2 = 96% and VAS 24H, MD = -0.86, 95% CI = -1.48, -0.24, P = 0.007; I2 = 92%). In addition, IV lidocaine is associated with a significant decrease in the opioid requirement after the surgery (opioid requirements, MD = -29.53, 95% CI = -55.41, -3.66, P = 0.03; I2 = 98%). However, there was no statistically significant difference in the incidence of nausea and vomiting after the surgery between the two groups (nausea and vomiting, relative risk = 0.91, 95% CI = 0.57, 1.45, P = 0.69; I2 = 50%). Lidocaine infusion in LC is associated with a significant decrease in post operative pain and in opioid requirements after the surgery.

Evaluation of Some Benzo[g]Quinazoline Derivatives as Antiviral Agents against Human Rotavirus Wa Strain: Biological Screening and Docking Study.

Globally, rotavirus (RV) is the most common cause of acute gastroenteritis in infants and toddlers; however, there are currently no agents available that are tailored to treat rotavirus infection in particular. Improved and widespread immunization programs are being implemented worldwide to reduce rotavirus morbidity and mortality. Despite certain immunizations, there are no licensed antivirals that can attack rotavirus in hosts. Benzoquinazolines, chemical components synthesized in our laboratory, were developed as antiviral agents, and showed good activity against herpes simplex, coxsackievirus B4 and hepatitis A and C. In this research project, an in vitro investigation of the effectiveness of benzoquinazoline derivatives 1-16 against human rotavirus Wa strains was carried out. All compounds exhibited antiviral activity, however compounds 1-3, 9 and 16 showed the greatest activity (reduction percentages ranged from 50 to 66%). In-silico molecular docking of highly active compounds, which were selected after studying the biological activity of all investigated of benzo[g]quinazolines compounds, was implemented into the protein's putative binding site to establish an optimal orientation for binding. As a result, compounds 1, 3, 9, and 16 are promising anti-rotavirus Wa strains that lead with Outer Capsid protein VP4 inhibition.

Biological Investigation of 2-Thioxo-benzo[g]quinazolines against Adenovirus Type 7 and Bacteriophage Phi X174: An In Vitro Study.

Mortality and morbidity caused by viruses are a global health problems. Therefore, there is always a need to create novel therapeutic agents and refine existing ones to maximize their efficacy. Our lab has produced benzoquinazolines derivatives that have proven effective activity as antiviral compounds against herpes simplex (HSV 1 and 2), coxsackievirus B4 (CVB4), and hepatitis viruses (HAV and HCV). This in vitro study was aimed at investigating the effectiveness of benzoquinazoline derivatives 1-16 against adenovirus type 7 and bacteriophage phiX174 using a plaque assay. The cytotoxicity against adenovirus type 7 was also performed in vitro, using a MTT assay. Most of the compounds exhibited antiviral activity against bacteriophage phiX174. However, compounds 1, 3, 9, and 11 showed statistically significant reductions of 60-70% against bacteriophage phiX174. By contrast, compounds 3, 5, 7, 12, 13, and 15 were ineffective against adenovirus type 7, and compounds 6 and 16 had remarkable efficacy (50%). Using the MOE-Site Finder Module, a docking study was carried out in order to create a prediction regarding the orientation of the lead compounds (1, 9, and 11). This was performed in order to investigate the activity of the lead compounds 1, 9, and 11 against the bacteriophage phiX174 by locating the ligand-target protein binding interaction active sites.

Optimizing Sanitation Network Upgrading Projects in Slum Areas.

Infrastructure upgrading projects are a key element in enhancing the livelihood of residents in slum areas. These projects face significant constructability challenges common to dense-urban construction coupled with the unique socioeconomic challenges of operating in slums. This research focuses on sanitation network upgrading projects in slum areas and proposes a novel methodology capable of (1) accounting for the unique constructability challenges for these projects, (2) accelerating the provision of sanitation services, and (3) optimizing construction decisions. The key contribution of this research to the body of knowledge is in developing a comprehensive construction planning framework capable of achieving these three objectives. The proposed framework focuses specifically on sewer lines upgrading within the larger sanitation networks upgrading projects. This framework consists of five main models that can guide planners in selecting the appropriate equipment sizes, trench system configuration, and optimal equipment routing, in addition to identifying all possible execution sequences along with the corresponding construction cost and duration of each sequence. Most notably, this framework proposes an approach to assess the serviceability of different construction plans measured by how fast sanitary services can be provided to slum dwellers. A multi-objective, genetic algorithms optimization model is developed to identify the optimal construction plans that accelerate the sanitary service provision to residents while minimizing construction costs. A real-world example is presented to demonstrate the model capabilities in optimizing construction plans.

Superior vena cava tear during transvenous lead extraction: Medical management in hemodynamically stable patients.

INTRODUCTION: Superior vena cava (SVC) tear is the most lethal complication during transvenous lead extraction (TLE) with a mortality rate as high as 50%. Treatment involves aggressive attempts to maintain cardiac output and immediate sternotomy to localize and repair the vascular tear. Occlusion balloons have been developed to provisionally occlude the lacerated SVC and to provide hemodynamic stability allowing time for surgery. In case of mediastinal hematoma without hemodynamic instability, the strategy remains unclear. METHODS AND RESULTS: We describe two cases of SVC tear during TLE. The first case was a 60-year-old man who presented with a right ventricular single-chamber defibrillator lead fracture and innominate vein stenosis. The RV lead was removed using a laser sheath causing a mediastinal hematoma with no active bleeding during surgical exploration few hours later. The second case was a 28-year-old man that presented with a right atrial (RA) lead fracture and RV lead insulation failure in a dual-chamber defibrillator (ICD). CONCLUSION: Both the RA and RV leads were removed with mechanical sheaths, and a mediastinal hematoma was medically managed.

LC/HRESI-MS/MS screening, phytochemical characterization, and in vitro antioxidant and cytotoxic potential of Jatropha integerrima Jacq. extracts.

Avoiding the probable dangerous side effects of synthetic drugs, this study aims the identification of natural antioxidant and antitumor agents from J. integerrima leaf and floral extracts. A highly efficient and fast UPLC/ESI-qTOF-HRMS/MS screening has led to characterization of 30 flavonoids, i.e. 12 flavonols, 6 flavones, 3 dihydroflavonols, 4 anthocyanins (flower), 2 dihydroflavonols, and 3 isoflavones from both J. integerrima extracts. In addition, six major polyphenols were identified for the first time from leaf extract, and their structures were established as apigenin 7-O-ß-d-neohesperidoside (rhoifolin, 1), apigenin 8-C-ß-D-4C1-glucopyranoside (vitexin, 2), luteolin 6-C-ß-D-4C1-glucopyranoside (isoorientin, 3), 6,6″-di-C-ß-D-4C1-glucopyranosyl-methylene-biapigenin (Jatrophenol-I, 4), (E)-p-coumaric acid methyl ester (5), and (E)-ferulic acid methyl ester (6) with HRESI-MS and NMR analyses. The in vitro antioxidant activity of both extracts and major pure isolates was decided using DPPH, reducing power capability, FRAP, and ABTS radical scavenging assays, and their in vitro cytotoxicity was evaluated on Ehrlich ascites carcinoma cells (EACC), as well.The flower extract and compound 3 have shown the strongest antioxidant and cytotoxic effects. At low concentrations (25 µg/mL), they showed the highest DPPH radical scavenging ability (79.63 ± 0.42 and 76.20 ± 0.35%) regarding BHA (91.44 ± 0.29% at 100 µg/mL). In the parameter of absorbance, they exhibited higher reducing power ability (1.402 ± 0.025 and 1.178 ± 0.019%) than that of BHA (0.975 ± 0.013 at 100 µg/mL). Similarly, they proved superior FRAP (1427 ± 9.61 and 1377 ± 13.61 µmol Trolox/ 100 g) and highest ABTS activity (80.19 ± 0.55 and 68.38 ± 0.19%), which are higher activities compared to BHA (88.42 ± 0.24% at 100 µg/mL). Furthermore, all samples gave noticeable cytotoxicity at the same concentration (100 µg/mL), especially the flower extract and compound 3 which showed a relatively high effect on the viability of EACC (81.12 ± 0.24 and 77.21 ± 0.76 %, respectively) relative to vincristine reference drug (90.64 ± 0.39 %). Based on the findings, the extracts and isolates can be considered as potent antioxidant and cytotoxic natural agents, especially flower extract and isoorientin (3), which may supply novel insight into their likely application in pharmaceutical industries.

Ultra-Wideband Compact Fractal Antenna for WiMAX, WLAN, C and X Band Applications.

In this paper, a compact dual-wideband fractal antenna is created for Bluetooth, WiMAX, WLAN, C, and X band applications. The proposed antenna consists of a circularly shaped resonator that contains square slots and a ground plane where a gap line is incorporated to increase the gain and bandwidth with a small volume of 40 × 34 × 1.6 mm3. The patch was supported by the FR4 dielectric, which had a permittivity of 4.4 and tan δ = 0.02. A 50 Ω microstrip line fed this antenna. The antenna was designed by the HFSS program, and after that, the simulated results were validated using the measured results. The measurement results confirm that the suggested antenna achieves dual-band frequencies ranging from 2.30 to 4.10 GHz, and from 6.10 GHz to 10.0 GHz, resonating at 2.8, 3.51, 6.53, and 9.37 GHz, respectively, for various applications including commercial, scholarly, and medical applications. Moreover, the antenna's ability to operate within the frequency range of 3.1-10.6 GHz is in accordance with the FCC guidelines for the use of UWB antennas in breast cancer detection. Over the operational bands, the gain varied between 2 and 9 dB, and an efficiency of 92% was attained. A good agreement between the simulation and the measured results was found.

UWB Circular Fractal Antenna with High Gain for Telecommunication Applications.

The present study proposes a new, highly efficient fractal antenna with ultra-wideband (UWB) characteristics. The proposed patch offers a wide simulated operating band that reaches 8.3 GHz, a simulated gain that varies between 2.47 and 7.73 dB throughout the operating range, and a high simulated efficiency that comes to 98% due to the modifications made to the antenna geometry. The modifications carried out on the antenna are composed of several stages, a circular ring extracted from a circular antenna in which four rings are integrated and, in each ring, four other rings are integrated with a reduction factor of 3/8. To further improve the adaptation of the antenna, a modification of the shape of the ground plane is carried out. In order to test the simulation results, the prototype of the suggested patch was built and tested. The measurement results validate the suggested dual ultra-wideband antenna design approach, which demonstrates good compliance with the simulation. From the measured results, the suggested antenna with a compact volume of 40 × 24.5 × 1.6 mm3 asserts ultra-wideband operation with a measured impedance bandwidth of 7.33 GHz. A high measured efficiency of 92% and a measured gain of 6.52 dB is also achieved. The suggested UWB can effectively cover several wireless applications such as WLAN, WiMAX, and C and X bands.

Reactivity of 4,5-Dichlorophthalic Anhydride towards Thiosemicarbazide and Amines: Synthesis, Spectroscopic Analysis, and DFT Study.

The cyclic anhydrides are broadly employed in several fields, such as the chemical, plastic, agrochemical, and pharmaceutical industries. This study describes the chemical reactivity of 4,5-dichlorophthalic anhydride towards several nucleophiles, including thiosemicarbazide and different amines, to produce the carboxylic acid derivatives resulting from anhydride's opening, namely, phthalimide and dicarboxylic acid (1-12) products. Their chemical structures are confirmed by NMR, IR and MS spectra analyses. Density-functional theory (DFT) studies are performed using (DFT/B3LYP) with the 6-311G(d, p) basis sets to recognize different chemical and physical features of the target compounds.

Anti-Obesity Evaluation of Averrhoa carambola L. Leaves and Assessment of Its Polyphenols as Potential α-Glucosidase Inhibitors.

Averrhoa carambola L. is reported for its anti-obese and anti-diabetic activities. The present study aimed to investigate its aqueous methanol leaf extract (CLL) in vivo anti-obese activity along with the isolation and identification of bioactive compounds and their in vitro α-glucosidase inhibition assessment. CLL improved all obesity complications and exhibited significant activity in an obese rat model. Fourteen compounds, including four flavone glycosides (1-4) and ten dihydrochalcone glycosides (5-12), were isolated and identified using spectroscopic techniques. New compounds identified in planta included (1) apigenin 6-C-(2-deoxy-ß-D-galactopyranoside)-7-O-ß-D-quinovopyranoside, (8) phloretin 3'-C-(2-O-(E)-cinnamoyl-3-O-ß-D-fucopyranosyl-4-O-acetyl)-ß-D-fucopyranosyl-6'-O-ß-D fucopyranosyl-(1/2)-α-L arabinofuranoside, (11a) phloretin3'-C-(2-O-(E)-p-coumaroyl-3-O-ß-D-fucosyl-4-O-acetyl)-ß-D-fucosyl-6'-O-(2-O-ß-D-fucosyl)-α-L-arabinofuranoside, (11b) phloretin3'-C-(2-O-(Z)-p-coumaroyl-3-O-ß-D-fucosyl-4-O-acetyl)-ß-D-fucosyl-6'-O-(2-O-ß-D-fucosyl)-α-L-arabinofuranoside. Carambolaside M (5), carambolaside Ia (6), carambolaside J (7), carambolaside I (9), carambolaside P (10a), carambolaside O (10b), and carambolaside Q (12), which are reported for the first time from A. carambola L. leaves, whereas luteolin 6-C-α-L-rhamnopyranosyl-(1-2)-ß-D-fucopyranoside (2), apigenin 6-C-ß-D-galactopyranoside (3), and apigenin 6-C-α-L-rhamnopyranosyl-(1-2)-ß-L-fucopyranoside (4) are isolated for the first time from Family. Oxalidaceae. In vitro α-glucosidase inhibitory activity revealed the potential efficacy of flavone glycosides, viz., 1, 2, 3, and 4 as antidiabetic agents. In contrast, dihydrochalcone glycosides (5-11) showed weak activity, except for compound 12, which showed relatively strong activity.

In silico study and biological screening of benzoquinazolines as potential antimicrobial agents against methicillin-resistant Staphylococcus aureus, carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans.

Globally, antibiotic-resistant pathogens have become a serious threat to public health. The use of drugs having structures different from those applied in the clinical treatments of bacterial infections is a well-known potential solution to the antibiotic resistance crisis. Benzo-[g]-quinazolines were identified by our research group as a new class of antimicrobial agents. Herein, to follow-up the research on such compounds, three benzo-[g]-quinazolines (1-3) were studied, as in vitro antibacterial candidates against methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Klebsiella pneumoniae, and fluconazole-resistant Candida albicans, as well. The minimum inhibitory concentration (MIC) assay for benzoquinazolines was carried out via the calorimetric broth microdilution method using the XTT assay in comparison with vancomycin, ciprofloxacin, and ketoconazole as reference drugs. The target compounds 1-3 revealed high variation in their activity against the examined resistant microbial strains. Benzoquinazoline 3 exhibited a more potent effect against the resistant strains compared with the reference drugs. A docking study was performed to identify the interactions between the benzoquinazolines 1-3 and ligand proteins (OXA-48 carbapenemase, ß-lactamase, and sterol 14-alpha demethylase (CYP51)) at the active sites. Benzoquinazolines 1-3 showed very weak cytotoxicity against human lung fibroblast normal cells (WI-38). The targets showed promising antimicrobial effects against the three resistant strains. These findings may inform future inhibitor discoveries targeting penicillin-binding proteins.

Early to midterm survival of patients with deep sternal wound infection managed with laparoscopically harvested omentum.

OBJECTIVE: The optimal management of deep sternal wound infection (DWSI) remains controversial. Our objective was to evaluate outcomes of patients with DSWI managed with transposition of laparoscopically harvested omentum (LHO). METHODS: Between 2000 and 2020, a total of 38,623 adult patients who underwent full median sternotomy for cardiac surgery were analyzed retrospectively at our institution. DSWI occurred in 455 (1.2%), of whom 364 (93.2%) were managed with pectoralis myocutaneous flap (PMF) and 33 (7.2%) with LHO. Univariate and multivariate analysis models were used to determine predictors of cumulative late mortality and adjusted survival curves were generated. RESULTS: Among patients who received LHO, average age was 65.7 ± 9.7 years and a larger proportion of patients were male. A majority of patients (88%) had coronary bypass surgery, with bilateral internal mammary arteries use in only 21.2%. Mean length of stay (LOS) was 58.90 days and early hospital mortality occurred in 4 patients (12.1%). Patients who received LHO compared to only PMF had larger body mass index and had more heart failure. Furthermore, the hospital LOS was also significantly prolonged in the LHO group (58.9 vs. 27.4 days, p = .002), with a slightly higher in-hospital mortality (12.1% vs. 3.3%, p = .03). Late survival for LHO patients at 5 and 10 years was 71.9% and 44.8%, respectively. CONCLUSION: Use of LHO is a safe and viable alternative to traditional myocutaneous flaps to manage complex DSWI. Early and late survival were favorable in this high-risk population.

Transitioning to Del Nido cardioplegia for all-comers: the next switching gear?

BACKGROUND: Exclusive use of Del Nido cardioplegia administration in all adult patients undergoing cardiac surgery has been studied for operative, postoperative and myocardial protection outcomes. METHODS: From November 2016 to October 2017, Del Nido cardioplegia was used in 131 consecutive patients (DN group). Using a propensity score, DN group was compared to 251 patients having received intermittent cold blood cardioplegia (CB group). RESULTS: Preoperative characteristics were similar in DN and CB groups. Operative outcomes were statistically different (p < 0.0001): cardiopulmonary bypass (CPB) time (DN 105.9 ± 46.5, CB 131.2 ± 38.8); aortic cross-clamp time (DN 80.8 ± 35.5, CB 102.2 ± 31.3); operative time (DN 203.1 ± 65.0, CB 241.5 ± 54.7); total cardioplegia volume (DN 1328 ± 879, CB 3773 ± 1226); and peak glycemia on CPB (DN 8.2 ± 2.3, CB 9.0 ± 1.8). No statistical differences were noted in intensive care unit stay, hospital stay and hospital death. Myocardial protection outcomes were similar: discharge left ventricular ejection fraction (DN 52 ± 11, CB 51 ± 10); Troponin levels at the end of the surgery (DN 871 ± 1623, CB 1958 ± 854), day 1 (DN 853 ± 1139, CB 993 ± 8234) and day 4 (DN 442 ± 540, CB 463 ± 317). CONCLUSION: Del Nido cardioplegia use in all adult cardiac surgeries is associated with improved surgical efficiency. The design of larger trials including adults combined cardiac procedures and emergencies is needed.

Exploiting the 4-hydrazinobenzoic acid moiety for the development of anticancer agents: Synthesis and biological profile.

Thirteen 4-hydrazinobenzoic acid derivatives were elaborated and characterized by spectral analyses (NMR and MS). Evaluation of their in vitro cytotoxic activity showed that some of the targets demonstrated potent inhibitory effects against HCT-116 and MCF-7 cancer cells. The IC50 values ranged between 21.3 ± 4.1 and 28.3 ± 5.1 µM, respectively, whereas those of doxorubicin (reference drug) ranged between 22.6 ± 3.9 and 19.7 ± 3.1 µM, respectively. The active targets 6, 7 and 9 exhibited very weak cytotoxicity on normal cells (RPE-1) and showed higher IC50 values against HCT-116 and MCF-7 cells in comparison to doxorubicin. Furthermore, compounds 7, 9 and 10 inhibited the proliferation of MCF-7 by the induction of apoptosis. The bioassay results in the regression plots generated in 3D QSAR models were in agreement and correlated with the anticancer results of the target molecules. The 4-hydazinobenzoic acid derivatives can be used as cornerstones for further structural modifications as future anticancer agents.

Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[g]quinazoline Derivatives (In Vitro).

A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[g]quinazolines (1-17) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[g]quinazolines demonstrated promising activity (IC50 = 8.8 ± 0.5-10.9 ± 0.9 µM) and (IC50 = 26.0 ± 2.5-40.4 ± 4.1 µM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds 13-15 showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of 13 and 14 against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound 15 showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, 14 and 15 showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, 13 and 15 were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[g]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2.

Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC50 = 4-8 µM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 µM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 = 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor κB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

Anti-HAV evaluation and molecular docking of newly synthesized 3-benzyl(phenethyl)benzo[g]quinazolines.

Synthesized 3-benzyl(phenethyl)benzo[g]quinazolines (1-17) were evaluated in vitro to determine their effects against the anti-hepatitis A virus (HAV) using a cytopathic effect inhibition assay. Of the synthesized compounds, 16 and 17 showed considerably high anti-HAV activity, as indicated by their EC50 values of 27.59 and 18 µM, respectively, when compared to that of amantadine (37.3 µM), the standard therapeutic agent. In addition, they exhibited low cytotoxicity as indicated by their CC50 values, 290.63 and 569.45 µM, respectively. Compounds 1, 2, and 5 exhibited remarkable activity compared to the active compounds (16, 17) and amantadine. The selectivity index (SI) values were calculated and applied as a parameter for classifying the activity of the targets. In addition, molecular docking was performed to rationalize the SAR of the target compounds and analyze the binding modes between the docked-selected compounds and amino acid residues in the active site of the HAV-3C proteinase enzyme.

11-Aminostrychnine and N-(Strychnine-11-yl)propionamide: Synthesis, Configuration, and Pharmacological Evaluation at Glycine Receptors.

(11S)-11-Aminostrychnine (1) and N-[(11S)-strychnine-11-yl]propionamide (2) were synthesized and characterized as antagonists of homomeric α1 and heteromeric α1ß glycine receptors in a functional fluorescence-based assay and a patch-clamp assay and in radioligand binding studies. The absolute configuration at C-11 of 1 was determined based on vicinal coupling constants and NOESY data. Docking experiments to the orthosteric binding site of the α3 glycine receptor showed a binding mode of compound 2 analogous to that of strychnine, explaining its high antagonistic potency. The findings identify the C-11 amide function of strychnine as a suitable linker group for the future development of dimeric strychnine analogues targeting glycine receptors. The findings extend the SAR of strychnine at glycine receptors.

Investigation the antioxidant activity of benzo[g]triazoloquinazolines correlated with a DFT study.

Previously, a series of 2-phenoxy-benzo[g]triazoloquinazolines 1-16 were synthesized and fully characterized. The antioxidant activity of the target molecules 1-16 was evaluated using three different assays namely 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging, ferric reduction antioxidant power (FRAP) and reducing power capability (RPC). The results revealed that some benzotriazoloquinazolines showed good activity and have the capacity to scavenge free radicals. In particular, compounds 1 and 14 have shown the highest activity. The butylated hydroxyl toluene (BHT) used as standard agent. Density functional theory was carried out to explain the relative importance of C[bond, double bond]O, C[bond, double bond]S and NH groups on the radical scavenging activity of the target benzotriazoloquinazolines. The finding in present study shows that the active compounds can be used as template for further development of more potent antioxidant agents.