Synthesis, antiproliferative activity, and molecular modeling of novel 4-methylcoumarin derivatives and/or nitric oxide donor hybrids.

Two new 4-methylcoumarin derivatives (3a-f and 4a-f) were designed, synthesized, and evaluated for their cytotoxic activity. Different spectroscopic methods and elemental analyses confirmed all the synthesized derivatives' characterization. All the prepared compounds were biologically screened against four cancer cell lines (hepatocellular carcinoma HepG-2, colon cancer cell lines HCT-116, breast cancer cell lines MCF-7, and prostate cancer cell lines PC3). The in vitro antiproliferative activity of the target analogues 4b, 4c, 4f, 3b, and 3d against the MCF-7 cancer cell line was significant, with IC50 values of 3.98, 7.80, 10.94, 17.7, and 24.07 µM, respectively. Furthermore, the potent cytotoxic oxime derivative 4b was evaluated for cell cycle analysis showing a significant substantial disruption in cell cycle profile and cell cycle arrest at the S phase boundary with a time-dependent rise in a pre-G cell population, as well as a 22-fold increase in MCF-7 apoptosis compared to control cells. Accordingly, the Bax/Bcl-2 ratio, a critical ratio in controlling cell sensitivity to apoptosis, increased upon treatment with the oxime analog 4b. A docking investigation was conducted within the BcL-2 binding site to explore and anticipate the binding modes of the synthesized compounds. Thus, synthesizing these novel coumarin/nitric oxide hybrids may aid in developing promising antiproliferative agents.

Isatin derivatives as broad-spectrum antiviral agents: the current landscape.

In recent decades, several viruses have resulted in large outbreaks with serious health, economic and social consequences. The current unprecedented outbreak of the new coronavirus, SARS-COV-2, necessitates intensive efforts for delivering effective therapies to eradicate such a deadly virus. Isatin is an opulent heterocycle that has been proven to provide tremendous opportunities in the area of drug discovery. Over the last fifty years, suitably functionalized isatin has shown remarkable and broad-spectrum antiviral properties. The review herein is an attempt to compile all of the reported information about the antiviral activity of isatin derivatives with an emphasis on their structure-activity relationships (SARs) along with mechanistic and molecular modeling studies. In this regard, we are confident that the review will afford the scientific community a valuable platform to generate more potent and cost-effective antiviral therapies based on isatin templates.

Current development of 5-nitrofuran-2-yl derivatives as antitubercular agents.

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB) and still remains one of the foremost fatal infectious diseases, infecting nearly a third of the worldwide population. The emergencies of multidrug-resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) prompt the efforts to deliver potent and novel anti-TB drugs. Research aimed at the development of new anti-TB drugs based on nitrofuran scaffold led to the identification of several candidates that were effective against actively growing as well as latent mycobacteria with unique modes of action. This review focuses on the recent advances in nitrofurans that could provide intriguing potential leads in the area of anti-TB drug discovery.

Synthesis and Antimicrobial Activity of Nitrobenzyl-oxy-phenol Derivatives.

Two hydroquinone derivatives were prepared and their antimicrobial activity evaluated. Their minimum inhibitory concentrations (MICs) were determined using a broth dilution method. Gentamycin and ciprofloxacin were used as reference antibiotics. The antimicrobial activity of 4-(benzyloxy)phenol (monobenzone) was also evaluated based on its structural similarity to the new compounds; activity was comparable to that of 3,5-dimethyl-4-((4-nitrobenzyl)oxy)phenol (4a). 2,3,5-Trimethyl-4-((4-nitrobenzyl)oxy)phenol (4b) exhibited the best antibacterial activity against both clinical isolates and type strain of Moraxella catarrhalis (M. catarrhalis), with a MIC value of 11 µM, comparable to ciprofloxacin 9 µM.

Ziziphus spina-christi L. extract attenuates bleomycin-induced lung fibrosis in mice via regulating TGF-ß1/SMAD pathway: LC-MS/MS Metabolic profiling, chemical composition, and histology studies.

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-ß1/SMAD pathway.

A First Report on Side-Effects of COVID-19 Vaccines among General Population in Sudan: A Cross-Sectional Analysis.

BACKGROUND: The process of mass immunization against COVID-19 may be impacted by vaccine reluctance despite intense and ongoing efforts to boost vaccine coverage. The COVID-19 vaccine is a crucial component for controlling the pandemic. To the best of our knowledge, we did not come across any study presenting the post-vaccination side-effect profile among the Sudanese population. Developing strategies to improve the vaccine acceptability and uptake necessitate evidence-based reports about vaccine's side effects and acceptance. In this regard, this study aimed at estimating the prevalence of COVID-19 vaccine side-effects among the general population in Sudan. METHODOLOGY: A cross-sectional web-based quantitative study was conducted among the general population aged ≥18 years and residing in the Khartoum state of Sudan. A 30-item survey tool recorded the demographics, chronic diseases, allergy to other vaccines and COVID-19 vaccine side-effects after the first, second and booster doses. The data on the onset and duration of side-effects after each dose were also recorded. The distribution of side-effect scores after each dose of COVID-19 vaccine was compared using appropriate statistical methods. RESULTS: A total of 626 participants were approached for this study. There was a preponderance of females (57.7%), and 19% of respondents had chronic diseases. The vaccination rate against COVID-19 was 55.8% (n = 349/626). The prevalence of side-effects after the first, second and booster doses were 79.7, 48 and 69.4%, respectively. Pain at the injection site, headache, fatigue, exhaustion and fever were the common side-effects after the first and second doses, while pain at the injection site, fatigue, headache and muscle pain were frequently reported after the booster dose. Most of these side-effects appeared within 6 h and resolved within one or two days following the administration of the vaccine dose. The average side-effects scores were 4.1 ± 4.4 (n = 349), 2.2 ± 3.6 (n = 202) and 3.5 ± 4.1 (n = 36) after the first, second and booster doses, respectively. The female gender had significantly higher side-effects after primary and booster doses. The age group 18-24 years indicated higher side-effects after the first dose compared to participants with ages ranging from 31 to 40 years (p = 0.014). Patients with chronic disease indicated significantly higher (p = 0.043) side-effects compared to those without any comorbid illness. CONCLUSIONS: This study showed a high prevalence of transient COVID-19 vaccine-related side-effects after primary and booster doses. However, these side-effects waned within 48 h. Pain at the injection site was the most common local side-effect, while fatigue, fever, headache and muscle pain were frequently reported systemic side-effects. The frequency of side-effects was more profound among females, young adults and those with comorbid conditions. These findings indicate that COVID-19 vaccines are safe and have side-effects as reported in the clinical trials of the vaccines. These results aid in addressing the ongoing challenges of vaccine hesitancy in the Sudanese population that is nurtured by widespread concerns over the safety profile.

Comparative Genomic Analysis of Multi-Drug Resistant Pseudomonas aeruginosa Sequence Type 235 Isolated from Sudan.

Pseudomonas aeruginosa (P. aeruginosa) is known to be associated with resistance to practically all known antibiotics. This is a cross-sectional, descriptive, laboratory-based analytical study in which 200 P. aeruginosa clinical isolates were involved. The DNA of the most resistant isolate was extracted and its whole genome was sequenced, assembled, annotated, and announced, strain typing was ascribed, and it was subjected to comparative genomic analysis with two susceptible strains. The rate of resistance was 77.89%, 25.13%, 21.61%, 18.09%, 5.53%, and 4.52% for piperacillin, gentamicin, ciprofloxacin, ceftazidime, meropenem, and polymyxin B, respectively. Eighteen percent (36) of the tested isolates exhibited a MDR phenotype. The most MDR strain belonged to epidemic sequence type 235. Comparative genomic analysis of the MDR strain (GenBank: MVDK00000000) with two susceptible strains revealed that the core genes were shared by the three genomes but there were accessory genes that were strain-specific, and this MDR genome had a low CG% (64.6%) content. A prophage sequence and one plasmid were detected in the MDR genome, but amazingly, it contained no resistant genes for drugs with antipseudomonal activity and there was no resistant island. In addition, 67 resistant genes were detected, 19 of them were found only in the MDR genome and 48 genes were efflux pumps, and a novel deleterious point mutation (D87G) was detected in the gyrA gene. The novel deleterious mutation in the gyrA gene (D87G) is a known position behind quinolone resistance. Our findings emphasize the importance of adoption of infection control strategies to prevent dissemination of MDR isolates.

Evaluation of Conspiracy Beliefs, Vaccine Hesitancy, and Willingness to Pay towards COVID-19 Vaccines in Six Countries from Asian and African Regions: A Large Multinational Analysis.

Vaccination protects people from serious illness and associated complications. Conspiracy theories and misinformation on vaccines have been rampant during the COVID-19 pandemic and are considered significant drivers of vaccine hesitancy. Since vaccine hesitancy can undermine efforts to immunize the population against COVID-19 and interferes with the vaccination rate, this study aimed to ascertain the COVID-19-vaccine-related conspiracy beliefs, vaccine hesitancy, views regarding vaccine mandates, and willingness to pay for vaccines among the general population. A web-based, cross-sectional survey was conducted (April−August 2021) among the adult population in six countries (Pakistan, Saudi Arabia, India, Malaysia, Sudan, and Egypt). Participants were recruited using an exponential, non-discriminate snowball sampling method. A validated self-completed electronic questionnaire was used for the data collection. All the participants responded to questions on various domains of the study instrument, including conspiracy beliefs, vaccine hesitancy, and willingness to pay. The responses were scored according to predefined criteria and stratified into various groups. All data were entered and analyzed using SPSS version 22. A total of 2481 responses were included in the study (Pakistan 24.1%, Saudi Arabia 19.5%, India 11.6%, Malaysia 8.1%, Sudan 19.3%, and Egypt 17.3%). There was a preponderance of participants ≤40 years old (18−25 years: 55.8%, 26−40 years: 28.5%) and females (57.1%). The average score of the COVID-19 vaccine conspiracy belief scale (C19V-CBS) was 2.30 ± 2.12 (median 2; range 0−7). Our analysis showed that 30% of the respondents were found to achieve the ideal score of zero, indicating no conspiracy belief. The mean score of the COVID-19 vaccine hesitancy scale (C19V-HS) was 25.93 ± 8.11 (range: 10−50). The majority (45.7%) had C19V-HA scores of 21−30 and nearly 28% achieved a score greater than 30, indicating a higher degree of hesitancy. There was a significant positive correlation between conspiracy beliefs and vaccine hesitancy (Spearman's rho = 0.547, p < 0.001). Half of the study population were against the vaccine mandate. Respondents in favor of governmental enforcement of COVID-19 vaccines had significantly (p < 0.001) lower scores on the C19V-CBS and C19V-HS scale. Nearly 52% reported that they would only take vaccine if it were free, and only 24% were willing to pay for COVID-19 vaccines. A high prevalence of conspiracy beliefs and vaccine hesitancy was observed in the targeted countries. Our findings highlight the dire need for aggressive measures to counter the conspiracy beliefs and factors underlying this vaccine hesitancy.

Xanthone: A Promising Antimycobacterial Scaffold.

BACKGROUND: Tuberculosis (TB) is one of the infectious diseases associated with high rate of morbidity and mortality and still remains one of the top-ten leading causes of human death in the world. The development of new anti-TB drugs is mandatory due to the existence of latent infection as well as the expansion of the resistant Mycobacterium tuberculosis (MBT) strains. Xanthones encompass a wide range of structurally diverse bioactive compounds, obtained either naturally or through chemical synthesis. There is a growing body of literature that recognizes the antitubercular activity of xanthone derivatives. OBJECTIVE: The objective of this review is to highlight the main natural sources along with the critical design elements, structure-activity relationships (SARs), modes of action and pharmacokinetic profiles of xanthone-based anti-TB compounds. METHODS: In the present review, the anti-TB activity of xanthones reported in the literature from 1972 to date is presented and discussed. RESULTS: Exploration of xanthone scaffold led to the identification of several members of this class having superior activity against both sensitive and resistant MBT strains with distinctive mycobacterial membrane disrupting properties. However, studies regarding their modes of action, pharmacokinetic properties and safety are limited. CONCLUSION: Comprehendible data and information are afforded by this review and it would certainly provide scientists with new thoughts and means which will be conducive to design and develop new drugs with excellent anti-TB activity through exploration of xanthone scaffold.

Satisfaction with and adherence to warfarin treatment: A cross-sectional study among Sudanese patients.

BACKGROUND: Satisfaction with and adherence to oral anticoagulant treatment are important measures that decrease morbidity and mortality. Higher satisfaction and adherence to warfarin therapy was found to be associated among other factors with good International Normalized Ratio (INR) control. OBJECTIVES: To assess patient satisfaction with and adherence to oral anticoagulant therapy and to identify predictors of the two studied domains. METHODS: A cross-sectional study was conducted at the Cardiothoracic Clinic in Alshaab Teaching Hospital; Khartoum; Sudan during March-April 2015. A representative sample of patients on oral anticoagulant treatment was recruited. Data was collected through face-to-face interview method using oral Anti-Clot Treatment Scale (ATCS) to measure satisfaction and the 4-items Morisky Scale to measure adherence to therapy. Data was processed using SPSS. Logistic regression analysis was performed. P value <0.05 was considered statistically significant. RESULTS: A total of 93 patients was included, of them 46 were males. Overall, 47 (50.5%) were classified as satisfied with anti-clot treatment. Patients attained secondary and above educational level were approximately 8 times more satisfied with their anti-clot treatment, compared to those educated below this level, [OR 7.9 (2.9-21.7), P < 0.001]. Similarly, patients currently working were found to be approximately 3 times more satisfied with warfarin therapy, compared those who had no jobs, [OR 2.9 (1.1-7.6), P = 0.035]. Overall, 5.4% of the patients were found to be adherent to warfarin therapy. No definite background characteristic variable was found to be associated with adherence to treatment. No association was found between patient satisfaction and adherence to treatment, (P = 0.490). CONCLUSIONS: Ensuring health education on warfarin together with continuous patients motivation are needed, specifically among patients with low educational level. Efficient multidisciplinary effort from all healthcare providers is needed to make warfarin treatment more successful.