Dft and Td-Dft Study of Triazavirin Drug Derivatives as Antiviral to Coronavirus Covid-19

A global health pandemic that began in December 2019 was the newSARS-CoV-19 coronavirus. The bioactivities of the heterocyclic drug triazavirin selected have been assessed in this study using computer modelling strategies as inhibitors and nucleotide analogs for COVID-19. Triazavirin is an antiviral drug that is synthesized with triazavirin (2-methylsulfanyl-6-nitro[1,2,4]triazolo[5,1-C][1,2,4]triazine-7(4H)-one, TZV). For potential requirements against the 2019-nCoV Coronavirus, TZV is being investigated. We have conducted a computerized study for the screening of effective Triazavirin (C 5H4N6O3S) available medication which can be inhibitors for the Mpro of 2019-nCoVin order to find candidate drugs for the 2019-nCoV period. In the present work, (DFT/TD-DFT/B3LYP/6-31 G(d,p)) calculations have been carried out first of all for the purposes of estimating the thermal parameters, dipole momentum, polarization, and molecular power of the drug currently in the gas stage of the molecular structure of the title molecules. The studied compound has also calculated and shown its molecular HOMO-LUMO, its excitation energy, and its oscillator strengths. DFT and TD-DFT studies have been conducted to interact the TZV compound with the Coronavirus. Thus, TZV can be applied for possible application against Coronavirus 2019-nCoV applications.

N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

The presence of N-heterocyclic ring systems as promising features in the molecular skele-ton of FDA-approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with the COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and aromatic N-heterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling those FDA-approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles are highlighted. © 2023 Bentham Science Publishers.

SARS-CoV-2 proteases Mpro and PLpro: Design of inhibitors with predicted high potency and low mammalian toxicity using artificial neural networks, ligand-protein docking, molecular dynamics simulations, and ADMET calculations.

The main (Mpro) and papain-like (PLpro) proteases are highly conserved viral proteins essential for replication of the COVID-19 virus, SARS-COV-2. Therefore, a logical plan for producing new drugs against this pathogen is to discover inhibitors of these enzymes. Accordingly, the goal of the present work was to devise a computational approach to design, characterize, and select compounds predicted to be potent dual inhibitors - effective against both Mpro and PLpro. The first step employed LigDream, an artificial neural network, to create a virtual ligand library. Ligands with computed ADMET profiles indicating drug-like properties and low mammalian toxicity were selected for further study. Initial docking of these ligands into the active sites of Mpro and PLpro was done with GOLD, and the highest-scoring ligands were redocked with AutoDock Vina to determine binding free energies (ΔG). Compounds 89-00, 89-07, 89-32, and 89-38 exhibited favorable ΔG values for Mpro (-7.6 to -8.7 kcal/mol) and PLpro (-9.1 to -9.7 kcal/mol). Global docking of selected compounds with the Mpro dimer identified prospective allosteric inhibitors 89-00, 89-27, and 89-40 (ΔG -8.2 to -8.9 kcal/mol). Molecular dynamics simulations performed on Mpro and PLpro active site complexes with the four top-scoring ligands from Vina demonstrated that the most stable complexes were formed with compounds 89-32 and 89-38. Overall, the present computational strategy generated new compounds with predicted drug-like characteristics, low mammalian toxicity, and high inhibitory potencies against both target proteases to form stable complexes. Further preclinical studies will be required to validate the in silico findings before the lead compounds could be considered for clinical trials.

Medication Errors

Paxlovid drug interaction... Eprontia oral solution concentration conversion... Different concentrations of oral liquid Baclofen

Synthesis and Antiviral Properties of Camphor-Derived Iminothiazolidine-4-Ones and 2,3-Dihydrothiazoles.

A set of heterocyclic products was synthesized from natural (+)-camphor and semi-synthetic (-)-camphor. Then, 2-Imino-4-thiazolidinones and 2,3-dihydrothiazoles were obtained using a three-step procedure. For the synthesized compounds, their antiviral activity against the vaccinia virus and Marburg virus was studied. New promising agents active against both viruses were found among the tested compounds.

Pyridine Compounds with Antimicrobial and Antiviral Activities.

In the context of the new life-threatening COVID-19 pandemic caused by the SARS-CoV-2 virus, finding new antiviral and antimicrobial compounds is a priority in current research. Pyridine is a privileged nucleus among heterocycles; its compounds have been noted for their therapeutic properties, such as antimicrobial, antiviral, antitumor, analgesic, anticonvulsant, anti-inflammatory, antioxidant, anti-Alzheimer's, anti-ulcer or antidiabetic. It is known that a pyridine compound, which also contains a heterocycle, has improved therapeutic properties. The singular presence of the pyridine nucleus, or its one together with one or more heterocycles, as well as a simple hydrocarbon linker, or grafted with organic groups, gives the key molecule a certain geometry, which determines an interaction with a specific protein, and defines the antimicrobial and antiviral selectivity for the target molecule. Moreover, an important role of pyridine in medicinal chemistry is to improve water solubility due to its poor basicity. In this article, we aim to review the methods of synthesis of pyridine compounds, their antimicrobial and antiviral activities, the correlation of pharmaceutical properties with various groups present in molecules as well as the binding mode from Molecular Docking Studies.

Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients. Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations. Consequently, a therapeutic target concentration that may be useful for one patient may not be appropriate for another. Regular doses do not take into account the important PK variations in the critically ill, and the need to select an effective dose while minimising toxicity advocates for the use of therapeutic drug monitoring (TDM). This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.

Heterocyclic compounds derived from cyclohexane-1,4-dione: synthesis of tetrahydro-4H-chromene and tetrahydrobenzo[d]thiazole derivatives as target SARS-CoV-2 main protease (Mpro) and potential anti-Covid-19

Tetrahydro-4H-chromene-3-carbonitrile derivatives 4a-c where prepared from the reaction of 1,4-cyclohexane dione (1), malononitrile (2) and either of benzaldehyde (3a), 2-chlorobenzaldehyde (3b) or 4-methoxybenzaldehyde (3c) in ethanol containing triethylamine. Compound 4b was used to prepare pyrazole, pyrimidine and thiazole derivatives. Moreover, tetrahydrobenzo[d]thiazole derivative 18 was prepared from the reaction of 1,4-cyclohexane dione (1) with elemental sulfur followed by phenyl isothiocyanate (12) in absolute ethanol containing triethylamine. The latter compound reacted with ethyl orthoformate and either malononitrile or ethyl cyanoacetate in 1,4-dioxane in the presence of triethylamine to produce the 9-ethoxy-2H-chromeno[6,5-d]thiazole derivatives 20a,b. In addition, fused thiophene and pyran derivatives were synthesized starting from compound 18. The screened compounds were designed as mimics of the transition state of RNA2’-O-methylation were screened against several viral RNA 2’-OMTases from SARS-CoV (nsp10/nsp16 complex), Zika, West Nile, dengue, vaccinia (VP39) viruses. At the same time, the compounds were tested against human RNA N7-MTase (hRNMT) and selected viral N7-MTases such as SARS-CoV nsp14 and vaccinia D1-D12 complex to evaluate their specificity. Compounds 4a, 4b, 6b, 6c, 6e, 9a, 9b, 15, 16, 21b, and 23b showed high % inhibitions against SARs-Cov nsp 14 with values 93.42, 87.49, 98.23, 88.15, 89.24, 96.31, 93.28, 89.25, 89.20, 87.24, and 94.49, respectively.

An insight into the recent developments in anti-infective potential of indole and associated hybrids.

Prevention, accurate diagnosis, and effective treatment of infections are the main challenges in the overall management of infectious diseases. The best example is the ongoing SARs-COV-2(COVID-19) pandemic; the entire world is extremely worried about at present. Interestingly, heterocyclic moieties provide an ideal scaffold on which suitable pharmacophores can be designed to construct novel drugs. Indoles are amongst the most essential class of heteroaromatics in medicinal chemistry, which are ubiquitous across natural sources. The aforesaid derivatives have become invaluable scaffolds because of their wide spectrum therapeutic applications. Therefore, many researchers are focused on the design and synthesis of indole and associated hybrids of biological relevance. Hence, in the present review, we concisely discuss the indole containing natural sources, marketed drugs, clinical candidates, and their biological activities like antibacterial, antifungal, anti-TB, antiviral, antimalarial, and anti-leishmanial activities. The structure-activity relationships study of indole derivatives is also presented for a better understanding of the identified structures. The literature data presented for the anti-infective agents herein covers largely for the last twelve years.

Computational details of molecular structure, spectroscopic properties, topological studies and SARS-Cov-2 enzyme molecular docking simulation of substituted triazolo pyrimidine thione heterocycles.

Investigation the molecular structure of the system requires a detailed experience in dealing with theoretical computational guides to highlight its important role. Molecular structure of three heterocyclic compounds 8,10-diphenylpyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (HL), 8-phenyl-10-(p-tolyl)pyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (CH3L) and10-(4-nitrophenyl)-8-phenylpyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (NO2L) was studied at DFT/B3LYP/6-31G (d,p) level in ethanol solvent. Spectroscopic properties such Infrared (IR, 1H NMR and 13C NMR) and ultraviolet-visible (UV-VIS) analyses were computed. Some quantum and reactivity parameters (HOMO energy, LUMO energy, energy gap, ionization potential, electron affinity, chemical potential, global softness, lipophelicity) were studied, also molecular electrostatic potential (MEP) was performed to indicate the reactive nucleophilic and electrophilic sites. The effects of H-, CH3- and NO2- substituents on heterocyclic ligands were studied and it was found that the electron donation sites concerned with hydrogen and methyl substituents over nitro substituent. Topological analysis using reduced density gradient (RDG) was discussed in details. To predict the relevant antiviral activity of the reported heterocyclic compounds, molecular docking simulation was applied to the crystal structure of SARS-Cov-2 viral Mpro enzyme with 6WTT code and PLpro with 7JRN code. The enzymatic viral protein gives an image about the binding affinity between the target protein receptor and the heterocyclic ligands entitled. The hydrogen bonding interactions were evaluated from molecular docking with different strength for each ligand compound to discuss the efficiency of heterocyclic ligands toward viral inhibition.

A comprehensive review on the biological interest of quinoline and its derivatives.

Amongst heterocyclic compounds, quinoline is an advantaged scaffold that appears as a significant assembly motif for the development of new drug entities. Quinoline and its derivatives tested with diverse biological activity constitute an important class of compounds for new drug development. Therefore, many scientific communities have developed these compounds as intent structure and evaluated their biological activities. The present, review provides brief natural sources of quinoline and including a new extent of quinoline-based marketed drugs. This review also confers information about the biological activities of quinoline derivatives such as antibacterial, antifungal, antimycobacterial, antiviral, anti-protozoal, antimalarial, anticancer, cardiovascular, CNS effects, antioxidant, anticonvulsant, analgesic, anti-inflammatory, anthelmintic and miscellaneous activities.

Recent Developments of Quinoline Derivatives and their Potential Biological Activities.

Heterocyclic compounds containing the quinoline ring play a significant role in organic synthesis and therapeutic chemistry. Polyfunctionalized quinolines have attracted the attention of many research groups, especially those who work on drug discovery and development. These derivatives have been widely explored by the research biochemists and are reported to possess wide biological activities. This review focuses on the recent progress in the synthesis of heterocyclic compounds based-quinoline and their potential biological activities.