A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.

Hydroxychloroquine (HCQ) and its close relative chloroquine (CQ) were initially used as antimalarial agents but are now widely prescribed in rheumatology, dermatology and immunology for the management of autoimmune diseases. HCQ is considered to have a better long-term safety profile than CQ and is therefore more commonly used. HCQ has a key role in the treatment of connective tissue diseases including systemic lupus erythematosus (SLE), where it provides beneficial immunomodulation without clinically significant immunosuppression. HCQ can also assist in managing inflammatory arthritis, including rheumatoid arthritis (RA). Debate around toxicity of HCQ in COVID-19 has challenged those who regularly prescribe HCQ to discuss its potential toxicities. Accordingly, we have reviewed the adverse effect profile of HCQ to provide guidance about this therapeutic agent in clinical practice. This article is protected by copyright. All rights reserved.

Many antiviral drugs were developed to counteract coronavirus disease, 2019 (COVID-19) with severe acute respiratory syndrome. Therefore, the scientific community's efforts have focused on the detection and quantification of antiviral compounds currently being tested for COVID-19 treatment. Cuttlefish bone powder (CFBP) has been used for the first time as solid-phase extraction (SPE) sorbent for the extraction of SARS CoV-2 antiviral drugs (chloroquine, ritonavir and indomethacin) from water samples. An effective and sensitive method was developed by combining SPE and liquid chromatography- UV detection (LC-UV). An experimental design was applied for the optimization of extraction process. Experimental variables were optimized using Doehlert matrix. The developed method included 50 mg of CFBP sorbent, 20 mL of water sample at pH = 9 and 5 mL of ACN/KH2PO4 buffer solution (80:20, v/v) in the elution step. For validation of the method, selectivity, linearity precision, and sensitivity were evaluated. Extraction recovery percentage of all Sars cov-2 antivirals were above 98.2%. The detection and quantification limits were between 0.1 and 0.5 µg L-1 and 0.6 and 2 µg L-1, respectively. The current study suggested that CFBP has the application potential for the enhanced SPE of SARS CoV-2 antiviral drugs from water samples.

Remdesivir (RDV, Veklury®) is an FDA-approved prodrug for the treatment of hospitalized patients with COVID-19. Recent in vitro studies have indicated that human carboxylesterase 1 (CES1) is the major metabolic enzyme catalyzing RDV activation. COVID-19 treatment for hospitalized patients typically also involves a number of antibiotics and anti-inflammatory drugs. Further, individuals who are carriers of a CES1 variant (polymorphism in exon 4 codon 143 [G143E]) may experience impairment in their ability to metabolize therapeutic agents which are CES1 substrates. The present study assessed the potential influence of nine therapeutic agents (hydroxychloroquine, ivermectin, erythromycin, clarithromycin, roxithromycin, trimethoprim, ciprofloxacin, vancomycin, and dexamethasone) commonly used in treating COVID-19 and 5 known CES1 inhibitors on the metabolism of RDV. Additionally, we further analyzed the mechanism of inhibition of cannabidiol (CBD), as well as the impact of the G143E polymorphism on RDV metabolism. An in vitro S9 fraction incubation method and in vitro to in vivo pharmacokinetic scaling were utilized. None of the nine therapeutic agents evaluated produced significant inhibition of RDV hydrolysis; CBD was found to inhibit RDV hydrolysis by a mixed type of competitive and noncompetitive partial inhibition mechanism. In vitro to in vivo modeling suggested a possible reduction of RDV clearance and increase of AUC when coadministration with CBD. The same scaling method also suggested a potentially lower clearance and higher AUC in the presence of the G143E variant. In conclusion, a potential CES1-mediated DDI between RDV and the nine assessed medications appears unlikely. However, a potential CES1-mediated DDI between RDV and CBD may be possible with sufficient exposure to the cannabinoid. Patients carrying the CES1 G143E variant may exhibit a slower biotransformation and clearance of RDV. Further clinical studies would be required to evaluate and characterize the clinical significance of a CBD-RDV interaction.

The COVID-19 pandemic has caused substantial losses worldwide in people's lives, health, and property. Currently, COVID-19 is still prominent worldwide without any specific drug treatment. The SARS-CoV-2 pathogen is the cause of various systemic diseases, mainly acute pneumonia. Within the pathological process, neutrophils are recruited to infected sites, especially in the lungs, for the first stage of removing invading SARS-CoV-2 through a range of mechanisms. Macroautophagy/autophagy, a conserved autodegradation process in neutrophils, plays a crucial role in the neutrophil phagocytosis of pathogens. NETosis refers to neutrophil cell death, while auto-inflammatory factors and antigens release NETs. This review summarizes the latest research progress and provides an in-depth explanation of the underlying mechanisms of autophagy and NETosis in COVID-19. Furthermore, after exploring the relationship between autophagy and NETosis, we discuss potential targets and treatment options. This review keeps up with the latest research on COVID-19 from neutrophil autophagy and NETosis with a new perspective, which can guide the urgent development of antiviral drugs and provide guidance for the clinical treatment of COVID-19.Abbreviations: AKT1: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; AP: autophagosome; ARDS: acute respiratory distress syndrome; ATG: autophagy related; BECN1: beclin 1; cfDNA: cell-free DNA; COVID-19: coronavirus disease 2019; CQ: chloroquine; DMVs: double-membrane vesicles; ELANE/NE: elastase, neutrophil expressed; F3: coagulation factor III, tissue factor; HCQ: hydroxychloroquine; MAP1LC3/LC3: microtubule associated protein 1 light chain of 3; MPO: myeloperoxidase; MTORC1: mechanistic target of rapamycin kinase complex 1; NETs: neutrophil traps; NSP: nonstructural protein; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SKP2: S-phase kinase associated protein 2; TCC: terminal complement complex; ULK1: unc-51 like.

Herein, we report two novel multidentate luminogen proligands bis(3,5-diiodosalicylidene) carbohydrazone (H4L1) and bis(3,5-diiodosalicylidene) thiocarbohydrazone (H4L2), which are suitable candidates for biomedical applications. Though the thiocarbohydrazone H4L2 shows aggregation caused quenching (ACQ), the carbohydrazone H4L1 exhibits stronger fluorescence due to aggregation induced emission enhancement (AIEE). Molecular docking studies of H4L1 and H4L2 along with four similar (thio)carbohydrazones with the active sites of SARS-CoV-2 main protease 3CLpro reveals that the thiocarbohydrazones, in general, are showing better propensity compared to their oxygen analogues. Both the thiocarbohydrazones and the carbohydrazones, however, exhibit better binding potential at the active sites than that of some of the repurposed drugs such as chloroquine, hydroxychloroquine, lopinavir, ritonavir, darunavir and remdesivir. Also, the carbohydrazone H4L1 can be a better bioprobe compared to H4L2 as the former is found to have better binding potential with SARS-CoV-2 spike glycoprotein along with AIEE feature.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing pandemic named COVID-19 which causes a serious emergency on public health hazards of international concern. In the face of a critical medical emergency, repositioning of drugs is one of the most authentic options to design an adequate treatment for infected patients immediately. In this strategy, Remdesivir (Veklury), Hydroxychloroquine appears to be the drug of choice and garnered unprecedented attention as potential therapeutic agents against the pandemic realized worldwide due to SARS-CoV-2 infection. These are the breathtaking instances of possible repositioning of drugs, whose pharmacokinetics and optimal dosage are familiar. In this review, we provide an overview of these medications, their synthesis, and the possible mechanism of action against SARS-CoV-2.

Two randomized controlled trials demonstrated no clinical benefit of hydroxychloroquine (HCQ) for either post-exposure prophylaxis (PEP) or early treatment of SARS-CoV-2 infection. Using data from these studies, we calculated time-weighted average change from baseline SARS-CoV-2 viral load and demonstrated that HCQ did not affect viral clearance. This article is protected by copyright. All rights reserved.

Background: COVID-19 patients with underlying medical conditions are vulnerable to drug-drug interactions (DDI) due to the use of multiple medications. We conducted a discovery-driven data analysis to identify potential DDIs and associated adverse events (AEs) in COVID-19 patients from the FDA Adverse Event Reporting System (FAERS), a source of post-market drug safety. Materials and Methods: We investigated 18,589 COVID-19 AEs reported in the FAERS database between 2020 and 2021. We applied multivariate logistic regression to account for potential confounding factors, including age, gender, and the number of unique drug exposures. The significance of the DDIs was determined using both additive and multiplicative measures of interaction. We compared our findings with the Liverpool database and conducted a Monte Carlo simulation to validate the identified DDIs. Results: Out of 11,337 COVID-19 drug-Co-medication-AE combinations investigated, our methods identified 424 signals statistically significant, covering 176 drug-drug pairs, composed of 13 COVID-19 drugs and 60 co-medications. Out of the 176 drug-drug pairs, 20 were found to exist in the Liverpool database. The empirical p-value obtained based on 1,000 Monte Carlo simulations was less than 0.001. Remdesivir was discovered to interact with the largest number of concomitant drugs (41). Hydroxychloroquine was detected to be associated with most AEs (39). Furthermore, we identified 323 gender- and 254 age-specific DDI signals. Conclusion: The results, particularly those not found in the Liverpool database, suggest a subsequent need for further pharmacoepidemiology and/or pharmacology studies.

Emergency Use Authorization (EUA) allows the U.S. Food and Drug Administration (FDA) to expedite the availability of therapeutics in the context of a public health emergency. To date, an evidentiary standard for clinical efficacy to support an EUA has not yet been established. This review examines the clinical data submitted in support of EUA for anti-viral and anti-inflammatory therapeutics for COVID-19 through December of 2021 and the resilience of the authorization as new clinical data arose subsequent to the authorization. In the vast majority of cases, EUA was supported by at least one well powered randomized controlled trial (RCT) where statistically significant efficacy was demonstrated. This included branded medications already approved for use outside of the context of COVID-19. When employed, the standard of a single RCT seemed to provide adequate evidence of clinical efficacy such that subsequent clinical studies generally supported or expanded the EUA of the therapeutic in question. The lone generic agent that was granted EUA (Chloroquine/Hydroxychloroquine) was not supported by a well-controlled RCT, and the EUA was withdrawn within three months time. This highlighted not only the ambiguity of the EUA standard, but also the need to provide avenues through which high quality clinical evidence for the efficacy of a generic medication could be obtained. Therefore, maintaining the clinical trial networks assembled during the COVID-19 pandemic could be a critical component of our preparation for future pandemics. Consideration could also be given to establishing a single successful RCT as regulatory guidance for obtaining an EUA.

During the COVID-19 pandemic, wastewater surveillance was leveraged as a powerful tool for monitoring community-scale health. Further, the well-known persistence of some pharmaceuticals through wastewater treatment plants spurred concerns that increased usage of pharmaceuticals during the pandemic would increase the concentrations in wastewater treatment plant effluent. We collected weekly influent and effluent samples from May 2020 through May 2021 from two wastewater treatment plants in central Pennsylvania, the Penn State Water Reclamation Facility and the University Area Joint Authority, that provide effluent for beneficial reuse, including for irrigation. Samples were analyzed for SARS-CoV-2 (influent only), two over-the-counter medicines (acetaminophen and naproxen), five antibiotics (ampicillin, doxycycline, ofloxacin, sulfamethoxazole, and trimethoprim), two therapeutic agents (remdesivir and dexamethasone), and hydroxychloroquine. While there were no correlations between pharmaceutical and virus concentration, remdesivir detection occurred when the number of hospitalized COVID-19 patients increased and dexamethasone detection co-occurred with the presence of COVID-19 patients on ventilators. Additionally, Penn State decision-making regarding instruction modes explained the temporal variation of influent pharmaceutical concentrations, with detection occurring primarily when students were on campus. Risk quotients calculated for pharmaceuticals with known EC50 or LC50 values for fish, daphnia, and algae were generally low in the effluent; however, some acute risks from sulfamethoxazole and dexamethasone were high when students returned to campus. Remdesivir and dexamethasone persisted through the wastewater treatment plants, thereby introducing novel pharmaceuticals directly to soils and surface water. These results highlight connections between human health and water quality during and further demonstrate broad utility of wastewater surveillance. This article is protected by copyright. All rights reserved.

A novel series of fused pyrazolo[5',1':2,3]imidazo[1,5-c]quinazolin-6(5H)-ones were synthesized and their affinity against the COVID-19 main protease was investigated using molecular docking study and compared to that of some used standard clinical drugs. These compounds were obtained in good to excellent yields from 63 to 91% in the presence of 30 mol% catalyst in ethanol at reflux for 2 h through an efficient one-pot three-component reaction including an intramolecular rearrangement and a cyclization through intramolecular nucleophilic reaction. The results of in silico studies showed that electronegativity, resonance effects, hydrophobic interaction, halogen and hydrogen bonding had significant effects on the performance of these compounds as an inhibitor ligand. Also, these results indicated the proper affinity of these compounds against the COVID-19 main protease with excellent binding energies (especially 4r = -8.77, 4q = -8.73 and 4m = -8.63) in comparison to remdesivir, chloroquine, hydroxychloroquine, molnupiravir and nirmatrelvir drugs.

Background As the global death toll from new coronavirus illness (COVID-19) rises, the scientific community and healthcare systems are under massive pressure to manage the outbreak and develop effective medical remedies. Meanwhile, desperation has pushed practitioners, scientists, and authorities to recommend and attempt medicines with little or no proof. Despite the lack of clear and unequivocal facts supporting its efficacy and safety, hydroxychloroquine-sulfate (HCQS) has recently received substantial public and political interest in treating and prophylaxis new infectious diseases COVID-19. Aim To analyze the impact of HCQS in COVID-19-positive patients admitted at tertiary level government-owned Jawaharlal Nehru Medical College and Hospital (JLNMCH, Bhagalpur) Bihar. Methods Two hundred two RT-PCR-positive COVID-19 patients were included in this research. The study participants were randomly distributed into the intervention category and control category, each consisting of 101 study subjects. Study participants in the intervention category were administered hydroxychloroquine in 200 mg tablets. The control category was given placebo tablets that looked similar to tablets of hydroxychloroquine and were given in the same pattern. Chest X-ray PA view, 12 lead ECG, baseline hemogram including a concentration of CD4 cells, ratio between the concentration of CD8 cells and CD4 cells and concentration of CD8 cells, the concentration of C-reactive protein, RT PCR test of samples obtained from the oropharyngeal region and nasopharyngeal region nasopharyngeal for verification COVID-19 were done. These measurements were carried out in both the control and intervention categories at baseline and at the moment of obtaining a negative RT-PCR report. Results The confirmed cases of COVID-19 was 52.9% in the intervention category and 53.4% in the control category at the end of the administration of drugs. Symptoms related to COVID-19 were observed in 11.6% of subjects in the intervention category and 13.5% in the control category. Other new symptoms were observed in 16.8% of subjects in the intervention category and 14.5% of study subjects in the control category. One death was reported in the control category. Emergency hospitalization was required for one subject in the intervention category, while two subjects in the control category required emergency hospitalization. 12.4 days was the mean duration of recovery in the intervention category, while 13.6 days were the mean duration of recovery in the control category. The recovery duration and COVID-related symptoms were lesser in the intervention category than in the control category; however, the variation between the two categories was statistically non-significant (p˃0.01). Conclusion According to this research, no statistically significant difference was noticed in COVID-19 incidence between the control category and intervention category, showing that hydroxychloroquine sulfate cannot be utilized as the main curative agent in the treatment of COVID-19. However, there was a reduction in recovery days and symptoms related to COVID-19 in study subjects administered with HCQS.

COVID-19, a dreaded and highly contagious pandemic, is flagrantly known for its rapid prevalence across the world. Till date, none of the treatments are distinctly accessible for this life-threatening disease. Under the prevailing conditions of medical emergency, one creative strategy for the identification of novel and potential antiviral agents gaining momentum in research institutions and progressively being leveraged by pharmaceutical companies is target-based drug repositioning/repurposing. A continuous monitoring and recording of results offer an anticipation that this strategy may help to reveal new medications for viral infections. This review recapitulates the neoteric illation of COVID-19, its genomic dispensation, molecular evolution via phylogenetic assessment, drug targets, the most frequently worldwide used repurposed drugs and their therapeutic applications, and a recent update on vaccine management strategies. The available data from solidarity trials exposed that the treatment with several known drugs, viz. lopinavir-ritonavir, chloroquine, hydroxychloroquine, etc had displayed various antagonistic effects along with no impactful result in diminution of mortality rate. The drugs like remdesivir, favipiravir, and ribavirin proved to be quite safer therapeutic options for treatment against COVID-19. Similarly, dexamethasone, convalescent plasma therapy and oral administration of 2DG are expected to reduce the mortality rate of COVID-19 patients.

This study evaluates the use of the Global Pharma Health Fund (GPHF) Minilab for medicine quality screening by 16 faith-based drug supply organizations located in 13 low- and middle-income countries. The study period included the year before the COVID-19 pandemic (2019) and the first year of the pandemic (2020). In total 1,919 medicine samples were screened using the GPHF Minilab, and samples showing serious quality deficiencies were subjected to compendial analysis in fully equipped laboratories. Thirty-four (1.8%) of the samples were found not to contain the declared active pharmaceutical ingredient (API), or less than 50% of the declared API, or undeclared APIs, and probably represented falsified products. Fifty-four (2.8%) of the samples were reported as substandard, although the true number of substandard medicines may have been higher due to the limited sensitivity of the GPHF Minilab. The number of probably falsified products increased during the COVID-19 pandemic, especially due to falsified preparations of chloroquine; chloroquine had been incorrectly advocated as treatment for COVID-19. The reports from this project resulted in four international WHO Medical Product Alerts and several national alerts. Within this project, the costs for GPHF Minilab analysis resulted as 25.85 € per sample. Medicine quality screening with the GPHF Minilab is a cost-effective way to contribute to the global surveillance for substandard and falsified medical products.