Synthesis, theoretical calculations, X-ray, HS and energy framework analysis, molecular docking of amino pyrazole containing azo dye and its inhibition activity of COVID-19 main protease

The synthesis and characterization of 5-Amino-4-Phenylazo-3-Methyl-1-(2-hydroxyethyl) Pyrazole (AD2a) were investigated in our study. The novel synthesized pyrazole-based disperse diazo dye has been elucidated by using UV–Vis, FT-IR, elemental analysis, LC/MS-MS, NMR and X-ray analysis. The AD2a molecule containing pyrazole and phenyl rings, hydroxy‑ethyl and azo group moieties crystallized in the orthorhombic space group Pbca. The crystal structures of AD2a are consolidated by N(3)-H(3A)⋯O(1) and O(1)-H(1)⋯N(5) intermolecular hydrogen bonds. The geometry of AD2a has been optimized with the DFT calculation B3LYP/6–31G(d,p) level and it has been observed that the obtained results give very good results with the X-ray diffraction data. The theoretical vibrational analysis, frontier orbital energies, electronic absorption spectrum, electronic properties, global reactivity descriptors and other theoretical parameters were obtained by using the same DFT method. Additionally, Hirshfeld surface analysis (HSA) with 2D fingerprint plots (FP) was performed to estimate contacts and the energy framework diagrams of AD2a (Eele, Edis and Etot) were determined. The inhibitor-receptor relationship established by the molecular docking study confirmed the inhibition activity of the AD2a construct against COVID-19. It showed that the AD2a molecule, shown as a drug candidate, binds strongly to SARS-CoV-2 (Mpro) (-6.5 kcal/mol) receptors.

COMPUTATIONAL MOLECULAR DOCKING AND IN SILICO ADMET PREDICTION STUDIES OF PYRAZOLE DERIVATIVES AS COVID-19 MAIN PROTEASE (MPRO) AND PAPAIN-LIKE PROTEASE (PLPRO) INHIBITORS

The inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) and papain-like protease (PLpro) prevents viral multiplications. Molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of pyrazole-indole molecules 6a, b, Schiff bases 8a, b, and pyrazolo[1,5-a]pyrimidines 10a, b were performed and done. Based on the molecular docking study verified that the presented structures (6a, 6b, 8a, 8b, 10a, and 10b) give promised attached bonds with the active site in the COVID-19 main protease (Mpro). The results of in silico ADMET prediction study revealed that these compounds may be considered candidates for the discovery or development of new series of COVID-19 drugs. © 2023 Chemical Society of Ethiopia and The Authors.

ZEOLITE A/ZnCl2 NANOPARTICLES AS A CATALYST FOR ECO-FRIENDLY SYNTHESIS OF PYRAZOLE-1-CARBOTHIOAMIDES WITH DOCKING VALIDATION AS COVID-19 MAIN PROTEASE (MPRO) INHIBITOR

The synthesized Zeolite A/ZnCl2 nanoparticles via the hydrothermal route were characterized using FTIR, XRD, and SEM/EDAX techniques. The characterized catalyst was used for the eco-friendly synthesis of 4,5-dihydro-pyrazole-1-carbothioamide derivatives. Under solvent-free conditions, a multi-component reaction between hydrazine, isothiocyanate, and chalcone was done with a prepared nano-catalyst as an inexpensive, recyclable, easy-to-get, and nontoxic catalyst. The molecular docking study explained that dihydro-1carbothioamide pyrazoles can be considered COVID-19 main protease (Mpro) inhibitors. In order to investigate the 3D conformation of the compounds that were synthesized, the density functional theory (DFT) was applied with a B3LYP hybrid functional and a 6-311++ G(d,p) basis set. This allowed us to investigate the compounds' electronic and charge transfer properties. In this series of compounds, the derivative 30d showed the lowest HOMO–LUMO energy gap. © 2023 Chemical Society of Ethiopia and The Authors.

Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

The Coronavirus pandemic, Covid-19 and SARS-Cov-2 put multidisciplinary research by chemists, biologists, pharmacists and theorists necessary and primordial task to find new active biomolecules which will be beneficial for all humanity. The azoles drugs are electronic rich, they should be used with caution, and an understanding of their pharmacokinetic profile, safety, absorption, distribution, excretion, metabolism, toxicity, and drug-drug interaction profiles is important to provide effective and cure therapy. In these objectives and goals, twenty aromatic nitrogen heterocycle compounds were chosen for in silico, docking and AMET studies against SARS-CoV-2. In this paper with respect to the protein S of SARS-CoV-2 properties, the GAUSSIAN 09w program used in the semi-empirical method at the AM1 level with the optimization of the geometry of the structures. Then Toxicity and physicochemical properties were evaluated by AMET. Molecular docking investigations conducted; the binding affinities as well as interactions of the sieve compounds with the SRAS-CoV-2 protein Spike using PyRx software. In general, the preliminary results are fructuous and needs further in vitro testes.

Synthesis, antimicrobial and ergosterol biosynthesis inhibition activity of clubbed 1,1'-biphenyl-pyrazole derivatives

Microbial infections remain a grave threat to global health security due to the increase in antibiotic resistance. The ongoing coronavirus pandemic has increased the risk of microbial and fungal infections. New therapeutic agents are needed to combat microbial infections. Two series of new clubbed 1,1'-biphenyl-pyrazole have been synthesized. The newly synthesized pyrazole derivatives were evaluated for in vitro antibacterial activity against E. coli (NCIM 2574), P. mirabilis (NCIM 2388), B. subtilis (NCIM 2063), S. albus (NCIM 2178), and in vitro antifungal activity against A. niger (ATCC 504) and C. albicans (NCIM 3100). Compound 10b has shown good activity against P. mirabilis with MIC of 15.62 µg mL-1. Against C. albicans, eleven pyrazole derivatives 5c, 5e, 5f, 5g, 6a, 6b, 6c, 6e, 10b, 10c, and 11a have shown good antifungal activity with MIC of 62.5-31.25 µg mL-1. Also, against A. niger, seven compounds 5f, 5g, 6e, 10a, 10b, 10c, and 11b, have exhibited good activity with MIC of 62.5-31.25 µg mL-1. Compounds 6e, 10c, and 11b were further evaluated and showed ergosterol biosynthesis inhibition activity. Thus, the significant antimicrobial activity of 1-(3-substituted-4'-alkoxy-3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-5-substituted-3-(trifluoromethyl)-1H-pyrazole, and 1-isobutyl-5-(4'-alkoxy-3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-3-(fluoromethyl)-1H-pyrazole derivatives indicate that these compounds could assist in the development of lead compounds to treat microbial infections. © 2023 The Royal Society of Chemistry.

Identification of Pyrazole Derivatives of Usnic Acid as Novel Inhibitor of SARS-CoV-2 Main Protease Through Virtual Screening Approaches.

The infection produced by the SARS-CoV-2 virus remains a significant health crisis worldwide. The lack of specific medications for COVID-19 necessitates a concerted effort to find the much-desired therapies for this condition. The main protease (Mpro) of SARS-CoV-2 is a promising target, vital for virus replication and transcription. In this study, fifty pyrazole derivatives were tested for their pharmacokinetics and drugability, resulting in eight hit compounds. Subsequent molecular docking simulations on SARS-CoV-2 main protease afforded two lead compounds with strong affinity at the active site. Additionally, the molecular dynamics (MD) simulations of lead compounds (17 and 39), along with binding free energy calculations, were accomplished to validate the stability of the docked complexes and the binding poses achieved in docking experiments. Based on these findings, compound 17 and 39, with their favorable projected pharmacokinetics and pharmacological characteristics, are the proposed potential antiviral candidates which require further investigation to be used as anti-SARS-CoV-2 medication.

Synthesis and In Silico Docking Study towards M-Pro of Novel Heterocyclic Compounds Derived from Pyrazolopyrimidinone as Putative SARS-CoV-2 Inhibitors.

In addition to vaccines, antiviral drugs are essential in order to suppress COVID-19. Although some inhibitor candidates have been determined to target the SARS-CoV-2 protein, there is still an urgent need to continue researching novel inhibitors of the SARS-CoV-2 main protease 'Omicron P132H', a protein that has recently been discovered. In the present study, in the search for therapeutic alternatives to treat COVID-19 and its recent variants, we conducted a structure-based virtual screening using docking studies for a new series of pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives 5-13, which were synthesized from the condensation reaction of pyrazolopyrimidinone-hydrazide (4) with a series of electrophiles. Some significant ADMET predictions-in addition to the docking results-were obtained based on the types of interactions formed and the binding energy values were compared to the reference anti- SARS-CoV-2 redocked drug nirmatrelvir.

Crystallographic study, biological assessment and POM/Docking studies of pyrazoles-sulfonamide hybrids (PSH): Identification of a combined Antibacterial/Antiviral pharmacophore sites leading to in-silico screening the anti-Covid-19 activity.

The discovery and development of new potent antimicrobial and antioxidant agents is an essential lever to protect living beings against pathogenic microorganisms and free radicals. In this regard, new functionalized pyrazoles have been synthesized using a simple and accessible approach. The synthesized aminobenzoylpyrazoles 3a-h and pyrazole-sulfonamides 4a-g were obtained in good yields and were evaluated in vitro for their antimicrobial and antioxidant activities. The structures of the synthesized compounds were determined using IR, NMR, and mass spectrometry. The structure of the compound 4b was further confirmed by single crystal X-ray diffraction. The results of the in vitro screening show that the synthesized pyrazoles 3 and 4 exhibit a promising antimicrobial and antioxidant activities. Among the tested compounds, pyrazoles 3a, 3f, 4e, 4f, and 4g have exhibited remarkable antimicrobial activity against some microorganisms. In addition, compounds 3a, 3c, 3e, 4a, 4d, 4f, and 4g have shown a significant antioxidant activity in comparison with the standard butylhydroxytoluene (BHT). Hence, compounds 3a, 4f, and 4g represent interesting dual acting antimicrobial and antioxidant agents. In fact, pyrazole derivatives bearing sulfonamide moiety (4a-g) have displayed an important antimicrobial activity compared to pyrazoles 3a-h, this finding could be attributed to the synergistic effect of the pyrazole and sulfonamide pharmacophores. Furthermore, Molecular docking results revealed a good interaction of the synthesized compounds with the target proteins and provided important information about their interaction modes with the target enzyme. The results of the POM bioinformatics investigations (Petra, Osiris, Molinspiration) show that the studied heterocycles present a very good non toxicity profile, an excellent bioavailability, and pharmacokinetics. Finally, an antiviral pharmacophore (O δ-, O δ-) was evaluated in the POM investigations and deserves all our attention to be tested against Covid-19 and its Omicron and Delta mutants.

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.

Discovery of ( ±)-3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine derivatives with promising in vitro anticoronavirus and antitumoral activity.

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.

Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-ĸB for possible benefit against SARS-CoV-2.

Due to unavailability of a specific drug/vaccine to attenuate severe acute respiratory syndrome coronavirus 2, the current strategy to combat the infection has been largely dependent upon the use of anti-inflammatory drugs to control cytokines storm responsible for respiratory depression. Thus, in this study, we discovered novel pyrazole analogs as a potent nuclear factor kappa B (NF-ĸB) inhibitor. The compounds were assessed for NF-ĸB transcriptional inhibitory activity in RAW264.7 cells after stimulation with lipopolysaccharides (LPS), revealing Compound 6c as the most potent analog among the tested series. The effect of Compound 6c was further investigated on the levels of interleukin-1ß, tumor necrosis factor-α, and interleukin-6 in LPS-stimulated RAW267.4 cells by enzyme immunoassay, where it causes a significant reduction in the level of these cytokines. In Western blot analysis, Compound 6c also causes the inhibition of inhibitor kappa B-α and NF-κB. It was found to be snugly fitted into the inner grove of the active site of NF-ĸB by forming H-bonds and a nonbonded interaction with Asn28 in a docking analysis.