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1.
Int J Mol Sci ; 22(24)2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1594431

ABSTRACT

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-ß-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Carbolines/chemistry , Carbolines/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Carbolines/chemical synthesis , Cell Line , Drug Design , Humans , Malaria, Falciparum/drug therapy , Molecular Docking Simulation , Plasmodium falciparum/enzymology , Plasmodium falciparum/metabolism
2.
Eur J Pharmacol ; 915: 174670, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1549763

ABSTRACT

Hydroxychloroquine (HCQ) is a derivative of the antimalaria drug chloroquine primarily prescribed for autoimmune diseases. Recent attempts to repurpose HCQ in the treatment of corona virus disease 2019 has raised concerns because of its propensity to prolong the QT-segment on the electrocardiogram, an effect associated with increased pro-arrhythmic risk. Since chirality can affect drug pharmacological properties, we have evaluated the functional effects of the R(-) and S(+) enantiomers of HCQ on six ion channels contributing to the cardiac action potential and on electrophysiological parameters of isolated Purkinje fibers. We found that R(-)HCQ and S(+)HCQ block human Kir2.1 and hERG potassium channels in the 1 µM-100 µM range with a 2-4 fold enantiomeric separation. NaV1.5 sodium currents and CaV1.2 calcium currents, as well as KV4.3 and KV7.1 potassium currents remained unaffected at up to 90 µM. In rabbit Purkinje fibers, R(-)HCQ prominently depolarized the membrane resting potential, inducing autogenic activity at 10 µM and 30 µM, while S(+)HCQ primarily increased the action potential duration, inducing occasional early afterdepolarization at these concentrations. These data suggest that both enantiomers of HCQ can alter cardiac tissue electrophysiology at concentrations above their plasmatic levels at therapeutic doses, and that chirality does not substantially influence their arrhythmogenic potential in vitro.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Heart/drug effects , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Ion Channels/drug effects , Action Potentials/drug effects , Animals , Arrhythmias, Cardiac/chemically induced , Electrocardiography , Electrophysiologic Techniques, Cardiac , Ether-A-Go-Go Potassium Channels , Humans , Membrane Potentials/drug effects , Patch-Clamp Techniques , Purkinje Fibers/drug effects , Rabbits , Stereoisomerism
3.
Molecules ; 26(18)2021 Sep 12.
Article in English | MEDLINE | ID: covidwho-1410349

ABSTRACT

Chemical and biological investigation of the Madagascar endemic plant Saldinia proboscidea led to the isolation of an isomer of artemisinin, (-)-6-epi-artemisinin (2). Its structure was elucidated using a combination of NMR and mass spectrometry. The absolute configuration was established by chemical syntheses of compound 2 as well as a new stereoisomer (3). The comparable bioactivities of artemisinin (1) and its isomer (-)-6-epi-artemisinin (2) revealed that this change in configuration was not critical to their biological properties. Bioactivity was assessed using an apoptosis induction assay, a SARS-CoV-2 inhibitor assay, and a haematin polymerization inhibitory activity (HPIA) assay. This is the first report of an artemisinin-related compound from a genus not belonging to Artemisia and it is the first isolation of an artemisinin-related natural product that is the opposite enantiomeric series relative to artemisinin from Artemisia annua.


Subject(s)
Antimalarials/chemistry , Artemisinins/chemistry , Plant Extracts/chemistry , Rubiaceae/chemistry , Madagascar , Stereoisomerism
4.
Molecules ; 25(22)2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917015

ABSTRACT

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.


Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cardiovascular System/drug effects , Flavonoids/economics , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Nervous System/drug effects , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants/chemistry , Polyphenols/chemistry , Polyphenols/pharmacology , Quercetin/chemistry , Quercetin/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stroke/drug therapy , Stroke/prevention & control
5.
Appl Microbiol Biotechnol ; 105(4): 1333-1343, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1052959

ABSTRACT

The anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been suggested as promising agents against the new coronavirus SARS-CoV-2 that induces COVID-19 and as a possible therapy for shortening the duration of the viral disease. The antiviral effects of CQ and HCQ have been demonstrated in vitro due to their ability to block viruses like coronavirus SARS in cell culture. CQ and HCQ have been proposed to reduce immune reactions to infectious agents, inhibit pneumonia exacerbation, and improve lung imaging investigations. CQ analogs have also revealed the anti-inflammatory and immunomodulatory effects in treating viral infections and related ailments. There was, moreover, convincing evidence from early trials in China about the efficacy of CQ and HCQ in the anti-COVID-19 procedure. Since then, research and studies have been massive to ascertain these drugs' efficacy and safety in treating the viral disease. In the present review, we construct a synopsis of the main properties and current data concerning the metabolism of CQ/HCQ, which were the basis of assessing their potential therapeutic roles against the new coronavirus infection. The effective role of QC and HCQ in the prophylaxis and therapy of COVID-19 infection is discussed in light of the latest international medical-scientific research results. KEY POINTS: • Data concerning metabolism and properties of CQ/HCQ are discussed. • The efficacy of CQ/HCQ against COVID-19 has been the subject of contradictory results. • CQ/HCQ has little or no effect in reducing mortality in SARS-CoV-2-affected patients.


Subject(s)
Antimalarials/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Chloroquine/therapeutic use , Hydroxychloroquine/therapeutic use , SARS-CoV-2 , Antimalarials/chemistry , Antiviral Agents/chemistry , Chloroquine/chemistry , Humans , Hydroxychloroquine/chemistry
6.
Pharm Dev Technol ; 26(3): 328-334, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1020096

ABSTRACT

Hydroxychloroquine is an antimalarial drug indicated in the treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and more recently proposed in COVID-19 therapy. Hydroxychloroquine is only available in tablets which are not easy to administer for pediatric and geriatric patients, and patients unable to swallow such as patients found in intensive care units. The aim of this work was to develop and optimize a ready to use liquid hydroxychloroquine formulation and to carry out the corresponding chemical and microbiological stability studies. The formulation was evaluated for ease of preparation, physical properties, and palatability. Its stability was performed at ambient temperature and under refrigeration. After 6 months of stability testing, the results showed no pH change, no drug loss, no microbial development, and no visual change. The formulation, employing excipients in a range that EMA has recommended, showed chemical and microbiological stability for at least 6 months even in the worst storage conditions.


Subject(s)
Antimalarials/chemistry , COVID-19/drug therapy , Hydroxychloroquine/chemistry , Chromatography, High Pressure Liquid , Drug Compounding , Drug Contamination/prevention & control , Drug Stability , Humans , Quality Control , Suspensions , Taste
7.
Molecules ; 26(1)2020 Dec 31.
Article in English | MEDLINE | ID: covidwho-1011589

ABSTRACT

The chloroquine family of antimalarials has a long history of use, spanning many decades. Despite this extensive clinical experience, novel applications, including use in autoimmune disorders, infectious disease, and cancer, have only recently been identified. While short term use of chloroquine or hydroxychloroquine is safe at traditional therapeutic doses in patients without predisposing conditions, administration of higher doses and for longer durations are associated with toxicity, including retinotoxicity. Additional liabilities of these medications include pharmacokinetic profiles that require extended dosing to achieve therapeutic tissue concentrations. To improve chloroquine therapy, researchers have turned toward nanomedicine reformulation of chloroquine and hydroxychloroquine to increase exposure of target tissues relative to off-target tissues, thereby improving the therapeutic index. This review highlights these reformulation efforts to date, identifying issues in experimental designs leading to ambiguity regarding the nanoformulation improvements and lack of thorough pharmacokinetics and safety evaluation. Gaps in our current understanding of these formulations, as well as recommendations for future formulation efforts, are presented.


Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/chemistry , Communicable Diseases/drug therapy , Drug Compounding/methods , Hydroxychloroquine/chemistry , Nanomedicine , Animals , Humans
8.
J Mol Graph Model ; 102: 107769, 2021 01.
Article in English | MEDLINE | ID: covidwho-856885

ABSTRACT

Coronavirus outbreak in December 2019 (COVID-19) is an emerging viral disease that poses major menace to Humans and it's a crucial need to find the possible treatment strategies. Spike protein (S2), a envelop glycoprotein aids viral entry into the host cells that corresponds to immunogenic ACE2 receptor binding and represents a potential antiviral drug target. Several drugs such as antimalarial, antibiotic, anti-inflammatory and HIV-protease inhibitors are currently undergoing treatment as clinical studies to test the efficacy and safety of COVID-19. Some promising results have been observed with the patients and also with high mortality rate. Hence, there is a need to screen the best CoV inhibitors using insilico analysis. The Molecular methodologies applied in the present study are, Molecular docking, virtual screening, drug-like and ADMET prediction helps to target CoV inhibitors. The results were screened based on docking score, H-bonds, and amino acid interactions. The results shows HIV-protease inhibitors such as cobicistat (-8.3kcal/mol), Darunavir (-7.4kcal/mol), Lopinavir (-9.1kcal/mol) and Ritonavir (-8.0 kcal/mol), anti-inflammatory drugs such as Baricitinib (-5.8kcal/mol), Ruxolitinib (-6.5kcal/mol), Thalidomide (-6.5kcal/mol), antibiotic drugs such as Erythromycin(-9.0kcal/mol) and Spiramycin (-8.5kcal/mol) molecules have good affinity towards spike protein compared to antimalarial drugs Chloroquine (-6.2kcal/mol), Hydroxychloroquine (-5.2kcal/mol) and Artemisinin (-6.8kcal/mol) have poor affinity to spike protein. The insilico pharmacological evaluation shows that these molecules exhibit good affinity of drug-like and ADMET properties. Hence, we propose that HIVprotease, anti-inflammatory and antibiotic inhibitors are the potential lead drug molecules for spike protein and preclinical studies needed to confirm the promising therapeutic ability against COVID-19.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Computer Simulation , Drug Discovery , Drug Evaluation, Preclinical , Drug Repositioning , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , User-Computer Interface
9.
OMICS ; 24(10): 568-580, 2020 10.
Article in English | MEDLINE | ID: covidwho-696599

ABSTRACT

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (MPro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.


Subject(s)
Antimalarials/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antimalarials/chemistry , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Binding Sites , COVID-19 , Computer Simulation , Coronavirus 3C Proteases , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/drug effects , Doxycycline/chemistry , Doxycycline/pharmacology , Drug Evaluation, Preclinical , Humans , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/drug effects , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/drug effects
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