Synthesis, characterization, molecular modeling studies, and biological evaluation of metal piroxicam complexes (M = Ni(II), Pt(IV), Pd(II), Ag(I)) as antibacterial and anticancer agents.

Four piroxicam metal complexes; NiL2 , PtL2 , PdL2 , and AgL were synthesized and characterized by different techniques with enhanced antibacterial and anticancer activity. Regarding in vitro antimicrobial activity, complex NiL2 displayed potent antibacterial effect against Escherichia coli and Pseudomonas aeruginosa that was 1.9-folds higher than piroxicam (minimum inhibitory concentration [MIC] = 31.85, 65.32 µM), respectively. In case of G+ve bacteria, complex PtL2 had potent activity on Staphylococcus aureus which was 2.1-folds higher than piroxicam (MIC = 43.12 µM), while activity of complex AgL against Enterococcus faecalis was threefolds higher than piroxicam (MIC = 74.57 µM. Complexes PtL2 and PdL2 exhibited higher inhibition of DNA gyrase than piroxicam (IC50 = 6.21 µM) in the range of 1.9-1.7-folds. The in vitro antiproliferative activity depicted that all investigated complexes showed better cytotoxic effect than piroxicam, specifically Pt and Pd complexes which had lower IC50 values than piroxicam on human liver cancer cell line HepG2 by 1.8 and 1.7-folds, respectively. While Pd and Ag complexes showed 2 and 1.6-folds better effect on human colon cancer cell line HT-29 compared with piroxicam. Molecular modeling studies including docking on Stranded DNA Duplex (1juu) and DNA gyrase enzyme (1kzn) that gave good insight about interaction of complexes with target molecules, calculation of electrostatic potential map and global reactivity descriptors were performed.

N4-Substituted Piperazinyl Norfloxacin Derivatives with Broad-Spectrum Activity and Multiple Mechanisms on Gyrase, Topoisomerase IV, and Bacterial Cell Wall Synthesis.

Fluoroquinolones are an important class of antibiotics with broad-spectrum antibacterial and antitubercular activity. Here, we describe the design and synthesis of a series of 38 N4-substituted piperazinyl norfloxacin derivatives. Their activity and mechanism of action were characterized using in silico, in vitro, and in vivo approaches. Several compounds displayed interesting activities against both Gram-negative and Gram-positive bacteria, and few displayed antimycobacterial activity, whereby some were as potent as norfloxacin and ciprofloxacin. Molecular docking experiments suggested that the new derivatives inhibit both DNA gyrase and DNA topoisomerase IV in a similar manner as norfloxacin. Selecting the most promising candidates for experimental mode of action analysis, we confirmed DNA gyrase and topoisomerase IV as targets of all tested compounds using enzymatic in vitro assays. Phenotypic analysis of both Escherichia coli and Bacillus subtilis confirmed a typical gyrase inhibition phenotype for all of the tested compounds. Assessment of possible additional targets revealed three compounds with unique effects on the B. subtilis cell wall synthesis machinery, suggesting that they may have an additional target in this pathway. Comparison with known cell wall synthesis inhibitors showed that the new compounds elicit a distinct and, so far, unique phenotype, suggesting that they act differently from known cell wall synthesis inhibitors. Interestingly, our phenotypic analysis revealed that both norfloxacin and ciprofloxacin displayed additional cellular effects as well, which may be indicative of the so far unknown additional mechanisms of fluoroquinolones.

Rational design, synthesis, molecular modeling, biological activity, and mechanism of action of polypharmacological norfloxacin hydroxamic acid derivatives.

Fluoroquinolones are broad-spectrum antibiotics that target gyrase and topoisomerase IV, involved in DNA compaction and segregation. We synthesized 28 novel norfloxacin hydroxamic acid derivatives with additional metal-chelating and hydrophobic pharmacophores, designed to enable interactions with additional drug targets. Several compounds showed equal or better activity than norfloxacin against Gram-positive, Gram-negative, and mycobacteria, with MICs as low as 0.18 µM. The most interesting derivatives were selected for in silico, in vitro, and in vivo mode of action studies. Molecular docking, enzyme inhibition, and bacterial cytological profiling confirmed inhibition of gyrase and topoisomerase IV for all except two tested derivatives (10f and 11f). Further phenotypic analysis revealed polypharmacological effects on peptidoglycan synthesis for four derivatives (16a, 17a, 17b, 20b). Interestingly, compounds 17a, 17b, and 20b, showed never seen before effects on cell wall synthetic enzymes, including MreB, MurG, and PonA, suggesting a novel mechanism of action, possibly impairing the lipid II cycle.

Design, Synthesis, Molecular Modeling, Biological Activity, and Mechanism of Action of Novel Amino Acid Derivatives of Norfloxacin.

Two series of N4-substituted piperazinyl amino acid derivatives of norfloxacin (24 new compounds) were designed and synthesized to attain structural surrogates with additional binding sites and enhanced antibacterial activity. Synthesized derivatives showed increased antibacterial and antimycobacterial activity compared to their lead structure, norfloxacin. Molecular modeling studies supported the notion that the derivatives can establish additional bonds with the target enzymes gyrase and topoisomerase IV. In vitro enzyme inhibition assays confirmed that the tested compounds were significant inhibitors of these enzymes. Inhibition of gyrase and topoisomerase IV was then confirmed in living bacterial cells using bacterial cytological profiling of both Gram-negative Escherichia coli and Gram-positive Bacillus subtilis, revealing a typical topoisomerase inhibition phenotype characterized by severe nucleoid packing defects. Several derivatives exhibited additional effects on the Gram-positive cell wall synthesis machinery and/or the cytoplasmic membrane, which likely contributed to their increased antibacterial activity. While we could not identify specific cell wall or membrane targets, membrane depolarization was not observed. Our experiments further suggest that cell wall synthesis inhibition most likely occurs outside the membrane-bound lipid II cycle.

Longevity of Immunoglobulin-G Antibody Response Against Nucleocapsid Protein Against SARS-CoV-2 Among Healthcare Workers.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the latest pandemic and the most significant challenge in public health worldwide. Studying the longevity of naturally developed antibodies is highly important clinically and epidemiologically. This paper assesses the longevity of antibodies developed against nucleocapsid protein amongst our health-care workers. Methods: This longitudinal cohort study was conducted at a tertiary hospital, Saudi Arabia. Anti-SARSsCoV-2 antibodies were tested among health-care workers at three-point intervals (baseline, eight weeks, and 16 weeks). Results: Of the 648 participants, 112 (17.2%) tested positive for Coronavirus (COVID-19) by PCR before the study. Of all participants, 87 (13.4%) tested positive for anti-SARS-CoV-2 antibodies, including 17 (2.6%) participants who never tested positive for COVID-19 using rt-PCR. Out of the 87 positive IgG participants at baseline, only 12 (13.7%) had remained positive for anti-SARS-CoV-2 antibodies by the end of the study. The IgG titer showed a significant reduction in values over time, where the median time for the confirmed positive rt-PCR subgroup from infection to the last positive antibody test was 70 (95% CI: 33.4-106.5) days. Conclusion: Health-care workers are at high risk of exposure to the SARS-CoV-2 virus, and contracting an asymptomatic infection is not unlikely. Developing and sustaining natural immunity differs from one person to another, while the rate of positive IgG anti-SARS-CoV-2 wanes over time. Clinicaltrialsgov Identifier: NCT04469647, July 14, 2020.

Assessment of binding interaction to salmon sperm DNA of two antiviral agents and ecofriendly nanoparticles: comprehensive spectroscopic study.

The direct binding of antiviral agents; Daclatasvir and valacyclovir and green synthesized nanoparticles to salmon sperm DNA have been assessed in a comparative study. The nanoparticles were synthesized by the hydrothermal autoclave method and have been fully characterized. The interactive behavior and competitive binding of the analytes to DNA in addition to the thermodynamic properties were deeply investigated by the UV-visible spectroscopy. The binding constants were monitored in the physiological pH conditions to be 1.65 × 106, 4.92 × 105 and 3.12 × 105 for daclatasvir,valacyclovir and quantum dots, respectively. The significant changes in the spectral features of all analytes have proven intercalative binding. The competitive study has confirmed that, daclatasvir, valacyclovir, and the quantum dots have exhibited groove binding. All analytes have shown good entropy and enthalpy values indicating stable interactions. The electrostatic and non-electrostatic kinetic parameters have been determined through studying the binding interactions at different concentrations of KCl solutions. A molecular modelling study has been applied to demonstrate the binding interactions and their mechanisms. The obtained results were complementary and afforded new eras for the therapeutic applications.

A Cohort Study of Seroprevalence of Antibodies Against SARS-CoV-2 Infection Among Healthcare Workers at a Tertiary Hospital in Saudi Arabia.

Background: The nature of the healthcare workers' jobs standing at the frontline against the coronavirus disease 2019 (COVID-19) puts them at a higher risk of unknowingly contracting the disease and potentially contributing to the spread. This study aims to assess the overall positive seroconversion prevalence of SARS-CoV-2. Methods: This is a longitudinal cohort study of healthcare workers at Johns Hopkins Aramco Healthcare (JHAH). JHAH is a tertiary hospital located in Dhahran serving patients in several districts in the Eastern Province of Saudi Arabia. Participants were recruited between June and December 2020. Each participant had a serology blood test and completed the World Health Organization's risk factor assessment questionnaire. Results: This study included 682 participants working in JHAH, representing 15.7% of our population. Out of the 682 participants, 15.2% had a positive SARS-CoV-2 rt-PCR before taking part in the study. However, only 87 tested positive for SARS-CoV-2 antibodies, a prevalence of 12.7% of all participants. Out of the 87 positives for SARS-CoV-2 antibodies, 17 participants never tested positive for COVID-19 rt-PCR, a prevalence of 2.9%. Moreover, not properly using alcohol-based hand rub or soap and water after the risk of body fluid exposure and wearing personal protective equipment when indicated were found to be statistically significant to having a positive SARS-CoV-2 IgG assay. Conclusion: Positive seroconversion rate was considerably low during the first wave of COVID-19 amongst JHAH's healthcare workers and similar to other healthcare organizations in Saudi Arabia. Seropositivity correlated significantly with following infection prevention and control recommendations. Clinicaltrialsgov Identifier: NCT04469647.

Comparing the use of Arabic decision aid to usual care. A multicenter randomized controlled trial for Arabic speaking metastatic colorectal cancer patients in Saudi Arabia.

OBJECTIVES: To evaluate the effect of decision aids (DAs) for metastatic colorectal cancer (mCRC) patients in the Arabic language. METHODS: A multi-centered randomized control trial was used to evaluate the effect of Arabic DA use with usual care for mCRC patients compared to usual care alone. Patients were recruited from 4 main oncology centers in Saudi Arabia: King Fahad Medical City, Riyadh; King Khalid University Hospital, Riyadh; King Saud Medical City, Riyadh; and King Fahd Specialist Hospital, Dammam, Saudi Arabia, between March 2016 and  October 2018. The final follow up was in April 2019. The study measured patient understanding of prognosis, treatment options, and the level of the patient's anxiety. RESULTS: Ninety-two patients were included in the analysis; 51 in the intervention group. A small proportion of both (DA with usual care and usual care) understood that mCRC was incurable (8% and 5%) of the 2 groups, respectively. There was no significant difference between groups in anxiety level; however, a time effect both initially and after one month was significantly higher than at 6 month. CONCLUSION: The study shows that a higher level of patient's baseline understanding lowered anxiety levels over time.  Decision aids group presented low levels of anxiety over time than those provided the usual care. We recommend  using Arabic DA in the oncology centers dealing with mCRC patients, aiming to empower patients in decision making.

Awareness, understanding, attitude and barriers toward prescribing modern cancer immunotherapies in the Arabian Gulf countries.

INTRODUCTION: The use of modern immunotherapy has been evolving over the past few years, and various new agents have been developed for new indications at multiple primary sites in oncology. It is important for physicians who are involved in cancer care to be aware and updated about new therapeutic agents and their indications, potential benefits, and side effects. PATIENTS AND METHODS: From October to November 2017, we conducted a survey on the awareness, understanding, attitude, and barriers associated with prescribing modern cancer immunotherapies among physicians in the Arabian Gulf countries. The study included practicing physicians who delivered chemotherapy; trainees were not eligible. A total of 460 physicians were contacted and invited to complete an online survey, of which approximately 74.8% did not respond, and 4 (3.4%) were excluded because they had not recently treated patients with cancer. 112 (24.3%) physicians completed the survey (completion rate = 25.2%). An online electronic survey questionnaire was developed via Planet Surveys. The survey was designed with multidisciplinary inputs of the study investigators practicing in the Arabian Gulf countries, piloted, and subsequently revised on the basis of feedback from 10 additional oncologists. The final survey included 23 questions and took 8-10 minutes for completion. RESULTS: All respondents were aware of modern immunotherapies, but 62.5% reported having limited experience in implementing them, whereas 31.3% reported good experience. The overall physicians' attitudes toward modern immunotherapy were favorable, with a mean score of 7.4 (scale of 1-10, with 10 being extremely favorable). Efficacy, clear indications, and good safety profile were perceived as key potential benefits. Cost, lack of experience, and lack of access to specific testing were the major barriers. DISCUSSION AND CONCLUSION: There was a high level of awareness and an overall positive attitude toward modern cancer immunotherapy among oncologists in the Arabian Gulf countries, but there was a limited experience in prescribing cancer immunotherapeutic agents. Efficacy, clear indications, and good safety profile were perceived as key potential benefits, whereas cost, lack of experience, and lack of access to specific testing prior to prescription were the major barriers. Patients were likely to be receptive to modern immunotherapy as a therapeutic option for cancer treatment. Long-term efficacy data, financial support programs, and educational activities for prescribers may increase the access to modern immunotherapy.

Detailed disclosure to Saudi Arabian patients on risks related to an invasive procedure.

OBJECTIVE: To measure the effect of providing a detailed description of coronary angiography risks on obtaining informed consent from Saudi Arabian patients. METHODS: This randomized controlled trial was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia from August 2006 to June 2007. Patients were randomized to either an information sheet containing brief information on procedure-related risks (brief sheet), or full disclosure of risks (detailed sheet). Both groups completed a brief questionnaire following exposure to either sheet. Primary endpoint was refusal to consent to coronary angiography. Secondary endpoints were anxiety following exposure to the detailed sheet and appropriateness of the amount of risk disclosure contained in both information sheets. RESULTS: One hundred and six Saudi patients were enrolled, 6 patients were later excluded. Mean age was 58 years; 45 patients (45%) were illiterate. Fifty-three patients were randomized to the brief sheet, and 47 to the detailed sheet. Only one patient (1.8%) given the brief sheet refused consent, compared to 5 patients (10.6%) given the detailed sheet (p=0.06, 95% confidence interval 1.2 to 2.8). Ninety-four patients responding to the questionnaire felt that the information given was enough, including all of the patients randomized to the brief sheet. Twenty-two patients randomized to the detailed sheet indicated increased anxiety after hearing procedure-related risks. CONCLUSION: We found no significant difference in consent status between the detailed and brief disclosure of procedure-related risk groups. Most patients did not require detailed risk disclosure.