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1.
Adv Drug Deliv Rev ; 189: 114527, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2060293

ABSTRACT

Lactose is the most commonly used excipient in carrier-based dry powder inhalation (DPI) formulations. Numerous inhalation therapies have been developed using lactose as a carrier material. Several theories have described the role of carriers in DPI formulations. Although these theories are valuable, each DPI formulation is unique and are not described by any single theory. For each new formulation, a specific development trajectory is required, and the versatility of lactose can be exploited to optimize each formulation. In this review, recent developments in lactose-based DPI formulations are discussed. The effects of varying the material properties of lactose carrier particles, such as particle size, shape, and morphology are reviewed. Owing to the complex interactions between the particles in a formulation, processing adhesive mixtures of lactose with the active ingredient is crucial. Therefore, blending and filling processes for DPI formulations are also reviewed. While the role of ternary agents, such as magnesium stearate, has increased, lactose remains the excipient of choice in carrier-based DPI formulations. Therefore, new developments in lactose-based DPI formulations are crucial in the optimization of inhalable medicine performance.


Subject(s)
Excipients , Lactose , Administration, Inhalation , Aerosols , Chemistry, Pharmaceutical , Drug Carriers , Dry Powder Inhalers , Humans , Particle Size , Powders
2.
ChemMedChem ; 17(22): e202200440, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2047514

ABSTRACT

COVID-19, caused by SARS-CoV-2 infection, continues to be a major public health crisis around the globe. Development of vaccines and the first cluster of antiviral drugs has brought promise and hope for prevention and treatment of severe coronavirus disease. However, continued development of newer, safer, and more effective antiviral drugs are critically important to combat COVID-19 and counter the looming pathogenic variants. Studies of the coronavirus life cycle revealed several important biochemical targets for drug development. In the present review, we focus on recent drug design and medicinal chemistry efforts in small molecule drug discovery, including the development of nirmatrelvir that targets viral protein synthesis and remdesivir and molnupiravir that target viral RdRp. These are recent FDA approved drugs for the treatment of COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , SARS-CoV-2 , Chemistry, Pharmaceutical , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Drug Development
4.
AAPS PharmSciTech ; 23(6): 209, 2022 Jul 28.
Article in English | MEDLINE | ID: covidwho-1962929

ABSTRACT

The present study is focused on the use of solid dispersion technology to triumph over the solubility-related problems of bexarotene which is currently used for treating various types of cancer and has shown potential inhibitory action on COVID-19 main protease and human ACE2 receptors. It is based on comparison of green locust bean gum and synthetic poloxamer as polymers using extensive mechanistic methods to explore the mechanism behind solubility enhancement and to find suitable concentration of drug to polymer ratio to prepare porous 3rd generation solid dispersion. The prepared solid dispersions were characterized using different studies like X-ray diffraction (XRD), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), differential scanning calorimetry (DSC), and particle size analysis in order to determine the exact changes occurred in the product which are responsible for enhancing solubility profiles of an insoluble drug. The results showed different profiles for particle size, solubility, dissolution rate, porosity, BET, and Langmuir specific surface area of prepared solid dispersions by using different polymers. In addition to the comparison of polymers, the BET analysis deeply explored the changes occurred in all dispersions when the concentration of polymer was increased. The optimized solid dispersion prepared with MLBG using lyophilization technique showed reduced particle size of 745.7±4.4 nm, utmost solubility of 63.97%, pore size of 211.597 Å, BET and Langmuir specific surface area of 5.6413 m2/g and 8.2757 m2/g, respectively.


Subject(s)
COVID-19 , Chemistry, Pharmaceutical , Adsorption , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical/methods , Humans , Microscopy, Electron, Scanning , Polymers/chemistry , Solubility , Spectroscopy, Fourier Transform Infrared , X-Ray Diffraction
5.
Drug Deliv ; 28(1): 856-864, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1947906

ABSTRACT

SARS-CoV-2 is a novel coronavirus that was isolated and identified for the first time in Wuhan, China in 2019. Nowadays, it is a worldwide danger and the WHO named it a pandemic. In this investigation, a functionalization post-synthesis method was used to assess the ability of an adapted SBA-15 surface as a sorbent to load the drug from an aqueous medium. Different characterization approaches were used to determine the characterization of the substance before and after functionalization such as X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), nitrogen adsorption-desorption porosimetry (Brunauer-Emmett-Teller) BET surface area analysis, and thermal gravimetric analysis (TGA). Batch adsorption testing was carried out in a single adsorption device to find the impact of multiple variables on the drug amoxicillin charge output. The following parameters were studied: 0-72 hr. contact time, 20-120 mg/l initial concentration, and 20-250 mg of NH2-SBA-15 dose. The outcomes from such experiments revealed the strong influence and behavior of the amino-functional group to increase the drug's load. Drug delivery outcomes studies found that amoxicillin loading was directly related to NH2-SBA-15 contact time and dose, but indirectly related to primary concentration. It was observed that 80% of amoxicillin was loaded while the best release test results were 1 hour and 51%.


Subject(s)
Amoxicillin/therapeutic use , COVID-19/drug therapy , Silicon Dioxide/chemistry , Amoxicillin/administration & dosage , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Delivery Systems , Humans , Microscopy, Electron, Scanning , Porosity , SARS-CoV-2 , Spectroscopy, Fourier Transform Infrared , Surface Properties , X-Ray Diffraction
6.
ChemMedChem ; 17(7): e202100641, 2022 04 05.
Article in English | MEDLINE | ID: covidwho-1705258

ABSTRACT

The pentafluorosulfanyl (-SF5 ) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5 -containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry.


Subject(s)
Chemistry, Pharmaceutical , Dihydroorotate Dehydrogenase , Amides , Dihydroorotate Dehydrogenase/antagonists & inhibitors , Humans
7.
Molecules ; 27(3)2022 Jan 20.
Article in English | MEDLINE | ID: covidwho-1648332

ABSTRACT

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Chemistry, Pharmaceutical , Humans , Inflammation/drug therapy , Inflammation/etiology , SARS-CoV-2/drug effects , SARS-CoV-2/ultrastructure
8.
Pharm Res ; 38(12): 2179-2184, 2021 12.
Article in English | MEDLINE | ID: covidwho-1611449
9.
Biomolecules ; 11(12)2021 12 18.
Article in English | MEDLINE | ID: covidwho-1581038

ABSTRACT

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.


Subject(s)
Drug Discovery , Gasotransmitters/pharmacology , Hydrogen Sulfide/pharmacology , Animals , Benzenesulfonates/administration & dosage , Benzenesulfonates/metabolism , Benzenesulfonates/pharmacology , Benzenesulfonates/therapeutic use , Chemistry, Pharmaceutical , Gasotransmitters/administration & dosage , Gasotransmitters/metabolism , Gasotransmitters/therapeutic use , Humans , Hydrogen Sulfide/administration & dosage , Hydrogen Sulfide/metabolism , Hydrogen Sulfide/therapeutic use , Morpholines/administration & dosage , Morpholines/metabolism , Morpholines/pharmacology , Morpholines/therapeutic use , Naproxen/administration & dosage , Naproxen/analogs & derivatives , Naproxen/metabolism , Naproxen/pharmacology , Naproxen/therapeutic use , Organothiophosphorus Compounds/administration & dosage , Organothiophosphorus Compounds/metabolism , Organothiophosphorus Compounds/pharmacology , Organothiophosphorus Compounds/therapeutic use
10.
Pharm Res ; 39(1): 115-141, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1588758

ABSTRACT

MOTIVATION: With the coronavirus pandemic still raging, prophylactic-nasal and early-treatment throat-sprays could help prevent infection and reduce viral load. Niclosamide has the potential to treat a broad-range of viral infections if local bioavailability is optimized as mucin-penetrating solutions that can reach the underlying epithelial cells. EXPERIMENTAL: pH-dependence of supernatant concentrations and dissolution rates of niclosamide were measured in buffered solutions by UV/Vis-spectroscopy for niclosamide from different suppliers (AK Sci and Sigma), as precipitated material, and as cosolvates. Data was compared to predictions from Henderson-Hasselbalch and precipitation-pH models. Optical-microscopy was used to observe the morphologies of original, converted and precipitated niclosamide. RESULTS: Niclosamide from the two suppliers had different polymorphs resulting in different dissolution behavior. Supernatant concentrations of the "AKSci-polymorph" increased with increasing pH, from 2.53µM at pH 3.66 to 300µM at pH 9.2, reaching 703µM at pH 9.63. However, the "Sigma-polymorph" equilibrated to much lower final supernatant concentrations, reflective of more stable polymorphs at each pH. Similarly, when precipitated from supersaturated solution, or as cosolvates, niclosamide also equilibrated to lower final supernatant concentrations. Polymorph equilibration though was avoided by using a solvent-exchange technique to make the solutions. CONCLUSIONS: Given niclosamide's activity as a host cell modulator, optimized niclosamide solutions could represent universal prophylactic nasal and early treatment throat sprays against COVID19, its more contagious variants, and other respiratory viral infections. They are the simplest and potentially most effective formulations from both an efficacy standpoint as well as manufacturing and distribution, (no cold chain). They now just need testing.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , COVID-19/drug therapy , Mucins/drug effects , Niclosamide/administration & dosage , Niclosamide/chemistry , Virus Diseases/drug therapy , Administration, Intranasal , Aerosols , Biological Availability , Chemistry, Pharmaceutical , Drug Compounding , Humans , Hydrogen-Ion Concentration , Pharynx , Powders , Solubility , Viral Load
11.
Int J Pharm ; 605: 120818, 2021 Aug 10.
Article in English | MEDLINE | ID: covidwho-1457706

ABSTRACT

During pandemics and global crises, drug shortages become critical as a result of increased demand, shortages in personnel and lockdown restrictions that disrupt the supply chain. The pharmaceutical industry is therefore moving towards continuous manufacturing instead of conventional batch manufacturing involving numerous steps, that normally occur at different sites. In order to validate the use of large-scale industrial processes, feasibility studies need to be performed using small-scale laboratory equipment. To that end, the scale-up of a continuous process and its effect on the critical quality attributes (CQAs) of the end product were investigated in this work. Hydroxychloroquine Sulphate (HCQS) was used as the model drug, Soluplus® as a model polymeric carrier and both horizontal and vertical twin screw extruders used to undertake this hot melt extrusion (HME) study. Seven formulations were processed using a small-scale horizontal extruder and a pilot-scale vertical extruder at various drug loadings, temperature profiles and screw speeds. When utilising a horizontal extruder, formulations with the highest drug load and processed at the lowest screw speed and temperature had the highest crystallinity with higher drug release rates. Upon scale-up to a vertical extruder, the crystallinity of the HCQS was significantly reduced, with less variation in both crystallinity and release profile across the different extrudates. This study demonstrates improved robustness with the pilot-scale vertical extruder compared to lab-scale horizontal extruder. The reduced variation with the vertical extruder will allow for short increases in production rate, with minimum impact on the CQAs of the final product enabling high-performance continuous manufacturing with minimum waste of raw materials. Finally, this research provides valuable information for the pharmaceutical industry in accessing continuous technologies for the manufacture of pharmaceutical products, allowing for efficient utilisation of resources upon scale-up and mass production during global pandemics and drug shortages.


Subject(s)
Hot Melt Extrusion Technology , Pharmaceutical Preparations , Chemistry, Pharmaceutical , Drug Compounding , Hot Temperature , Hydroxychloroquine , Pandemics , Technology, Pharmaceutical
12.
J Virol ; 95(24): e0143721, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1434897

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 19 (COVID-19) pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of Spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design approach, we identified and validated five potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both compounds showed antiviral activity with IC50 values in the micromolar range (MU-UNMC-1: IC50 = 0.67 µM and MU-UNMC-2: IC50 = 1.72 µM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC50 = 9.27 and 3.00 µM) and Scotland variant B.1.222 (IC50 = 2.64 and 1.39 µM), respectively. Following these assays, we conducted "induced-fit (flexible) docking" to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir, the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2-specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 Spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir (RDV), suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19 patients.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/pharmacology , Chemistry, Pharmaceutical/methods , Chlorocebus aethiops , Computer Simulation , Drug Design , HEK293 Cells , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Dynamics Simulation , Mutation , Protein Binding , Protein Domains , Protein Interaction Domains and Motifs , Spike Glycoprotein, Coronavirus , Vero Cells
13.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1389404

ABSTRACT

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Adenine/administration & dosage , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/metabolism , COVID-19/drug therapy , Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Hematologic Neoplasms/drug therapy , Humans , Inflammation/drug therapy , Neoplasms/drug therapy , Piperidines/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , SARS-CoV-2/drug effects
14.
Nat Commun ; 12(1): 4396, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1387353

ABSTRACT

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases.


Subject(s)
Chemistry Techniques, Synthetic/instrumentation , Chemistry, Pharmaceutical/instrumentation , High-Throughput Screening Assays/instrumentation , Morpholinos/chemical synthesis , Oligonucleotides, Antisense/chemical synthesis , Animals , COVID-19/drug therapy , COVID-19/virology , Chlorocebus aethiops , Communicable Diseases, Emerging/drug therapy , Communicable Diseases, Emerging/microbiology , Disease Models, Animal , High-Throughput Screening Assays/methods , Humans , Morpholinos/pharmacology , Morpholinos/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/genetics , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Precision Medicine/methods , RNA, Messenger/antagonists & inhibitors , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/genetics , Time Factors , Vero Cells
15.
Molecules ; 26(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1320599

ABSTRACT

Deferoxamine B is an outstanding molecule which has been widely studied in the past decade for its ability to bind iron and many other metal ions. The versatility of this metal chelator makes it suitable for a number of medicinal and analytical applications, from the well-known iron chelation therapy to the most recent use in sensor devices. The three bidentate hydroxamic functional groups of deferoxamine B are the centerpiece of its metal binding ability, which allows the formation of stable complexes with many transition, lanthanoid and actinoid metal ions. In addition to the ferric ion, in fact, more than 20 different metal complexes of deferoxamine b have been characterized in terms of their chemical speciation in solution. In addition, the availability of a terminal amino group, most often not involved in complexation, opens the way to deferoxamine B modification and functionalization. This review aims to collect and summarize the available data concerning the complex-formation equilibria in solutions of deferoxamine B with different metal ions. A general overview of the progress of its applications over the past decade is also discussed, including the treatment of iron overload-associated diseases, its clinical use against cancer and neurodegenerative disorders and its role as a diagnostic tool.


Subject(s)
Chelating Agents/chemistry , Deferoxamine/chemistry , Animals , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Chelating Agents/pharmacology , Chemistry, Pharmaceutical/methods , Electrochemistry/methods , Electrolytes , Humans , Hydrogen-Ion Concentration , Ions , Iron/metabolism , Iron Chelating Agents/chemistry , Iron Overload/drug therapy , Kinetics , Ligands , Metals/chemistry , Neoplasms/drug therapy , Potentiometry , SARS-CoV-2 , Temperature , Zirconium/chemistry
16.
Crit Rev Ther Drug Carrier Syst ; 38(2): 75-102, 2021.
Article in English | MEDLINE | ID: covidwho-1251764

ABSTRACT

Viral infections such as AIDS, hepatitis, herpes keratitis, and herpes labialis became resistant to drugs and it is difficult to design vaccine. In current era drug-resistant viruses are now treated by nanoparticles (NPs) and this field is known as nanobiotechnology that relates nanoscience with the biological system. NPs due to their antiviral activity are used in the treatment of viral diseases. The advantages of using the NP is its specific target action and increase the efficiency of treatment with minimum side effects. Liposomes, quantum dots, polymeric NPs, solid lipid NPs, silver NPs, gold NPs, and magnetic NPs are used to treat viral infections. NP-based therapeutics have completely replaced the usage of drugs and vaccines for viral diseases treatment. Nano vaccines have been investigated for the delivery of drugs; biomaterials-based NPs are in development to be formulated into nano vaccines. But there are limitations in the manufacturing and stabilization of NPs in the body. This review focuses on the antiviral activity of several NPs, its uptake by different viruses for viral disease treatment, nano vaccines, and the limitation of the NPs as nanotherapeutics.


Subject(s)
Antiviral Agents/therapeutic use , Drug Compounding/methods , Nanoparticles/therapeutic use , Virus Diseases/drug therapy , Viruses/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Chemistry, Pharmaceutical , Drug Resistance, Viral , Humans , Nanoparticles/chemistry , Treatment Outcome , Virus Diseases/virology , Viruses/isolation & purification
17.
Molecules ; 26(11)2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1259549

ABSTRACT

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.


Subject(s)
Antiviral Agents/chemical synthesis , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Nucleosides/analogs & derivatives , Nucleosides/chemical synthesis , SARS-CoV-2/enzymology , Chemistry, Pharmaceutical/methods , In Vitro Techniques , SARS-CoV-2/drug effects
18.
ChemMedChem ; 16(1): 4-10, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1226184

ABSTRACT

Pop the Champagne! ChemMedChem turns fifteen in 2021! Editor David Peralta reflects on the journal's transformation in the past fifteen years, looks back at 2020, and presents some exciting changes within the journal and Chemistry Europe.


Subject(s)
Publishing , Chemistry, Pharmaceutical , History, 21st Century , Publishing/history , Societies, Scientific
19.
Biochem Mol Biol Educ ; 49(3): 320-322, 2021 05.
Article in English | MEDLINE | ID: covidwho-1173781

ABSTRACT

The COVID-19 pandemic led to an abrupt suspension of face-to-face teaching activities in higher education institutions across the globe. The instructors and faculty at most institutions have had to adapt, invent, and implement adjustments quickly to adopt an online learning environment. This has been an extraordinarily challenging time for both students and instructors, particularly as many were not aware of the affordances and weaknesses of the online learning environment before it was uptaken. Particularly for chemistry and related disciplines, this change in delivery mode is even more disruptive in courses that have laboratory components due to loss of access to laboratories. As a teaching community, it was our responsibility to respond quickly and effectively to students' learning needs during this unprecedented global crisis. In our course, we provided succinct pre-recorded lecture-videos by topic rather than live-streaming of lectures. The recordings were made available to students a minimum of 24 h before the scheduled lecture time. Students were then provided opportunities to attend live tutorial sessions (held on Zoom and live Q&A feature on Piazza) if they had any questions that they wanted to ask the lecturer directly. We believe that the asynchronous sessions were more equitable than synchronous ones. This meant that students with difficult and challenging home/learning environments (i.e., disruptions at home, work/family schedules, poor internet, limited access to devices, etc.) were minimally disadvantaged. The approach worked well in general for teaching chemistry to pharmacy students and we believe that it can be adopted for other subjects.


Subject(s)
COVID-19 , Chemistry/education , Education, Distance , COVID-19/epidemiology , Chemistry, Pharmaceutical/education , Curriculum , Education, Pharmacy/methods , Humans , New Zealand/epidemiology , Pandemics , SARS-CoV-2 , Universities
20.
Mol Pharm ; 18(5): 1970-1984, 2021 05 03.
Article in English | MEDLINE | ID: covidwho-1164785

ABSTRACT

Physicochemical properties, in particular solubility and the associated bioavailability, are key factors in determining efficacy of poorly water-soluble drugs, which constitute 40% of new drugs in the market, and improving them is an important challenge for modern pharmacy. A recent strategy to achieve this goal is formation of stable co-amorphous solid dispersions with co-formers of low molecular weight. Here, the amorphization strategy was applied for low-soluble anti-hypertensive valsartan (VAL), an angiotensin II receptor blocker, and nicotinamide, which exhibits lung- and cardio-protective effects. Through interactions with the renin-angiotensin-aldosteron system, VAL may be used to treat both hypertension and the current pandemic coronavirus SARS-CoV-2 infection. Using mechanochemical and liquid- and solid-state approaches, solvated co-amorphous solid dispersions of VAL with nicotinamide were obtained. They were characterized by spectroscopic, thermal, and X-ray analyses. The density functional theory, quantum theory of atoms in molecules, and non-covalent interaction index calculations revealed the presence of two types of hydrogen bonds between VAL and NIC (i.e., N-H···O and O-H···O). One of them had a partially covalent character, which caused conformational changes in the flexible VAL molecule, restricting contribution of the tetrazolyl N-H donor and thus limiting the possibility of co-crystal formation. The recognized VAL/NIC1- and VAL/NIC2-type heterodimeric interactions were responsible for the excellent durability of the solid compositions and up to 24-fold better solubility than VAL alone. The synthesized dispersions constitute a new class of dually acting drugs, containing an active pharmaceutical ingredient (VAL) and supporting nutraceutical (nicotinamide).


Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Antihypertensive Agents/chemistry , COVID-19/drug therapy , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistry , Niacinamide/chemistry , Valsartan/chemistry , Antihypertensive Agents/chemical synthesis , Biological Availability , Calorimetry, Differential Scanning , Drug Compounding , Humans , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Microscopy, Electron, Scanning , Quantum Theory , Solubility , Spectroscopy, Fourier Transform Infrared , X-Ray Diffraction
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