Toluene Dioxygenase-Catalyzed cis-Dihydroxylation of Quinolines: A Molecular Docking Study and Chemoenzymatic Synthesis of Quinoline Arene Oxides

Molecular docking studies of toluene dioxygenase led to the prediction that angular and lateral cis‐dihydroxylation of tricyclic arene and heteroarene substrates could occur. Biotransformations of biphenylene, dibenzofuran, carbazole and dibenzothiophene, using Pseudomonas putida UV4 whole cells, expressing toluene dioxygenase, confirmed that both angular and lateral cis‐dihydroxylation had occurred in the predicted regioselective and stereoselective manner. The toluene dioxygenase‐catalysed (Pseudomonas putida UV4) biotransformation of dibenzofuran was optimized, to produce 1,2‐dihydrodibenzofuran‐1,2‐diol as the major metabolite in excellent yield. 2‐Hydroxydibenzofuran, resulting from dehydration of 1,2‐dihydrodibenzofuran‐1,2‐diol, was also found to undergo cis‐ dihydroxylation to give a very minor cis‐dihydrodiol metabolite. The enantiopurity (>98% ee) and (1R,2S) absolute configuration of the major dibenzofuran cis ‐dihydrodiol was rigorously established by catalytic hydrogenation and formation of methoxy(trifluoromethyl)phenylacetate derivatives and by X‐ray crystallography of an epoxide derivative. Biotransformation of carbazole yielded anthranilic acid as the major metabolite and was consistent with angular cis‐dihydroxylation. Synthesis of a cis‐ diol epoxide derivative showed that the main cis‐dihydrodiol metabolite of dibenzofuran has potential in the chemoenzymatic synthesis of natural products.magnified image

Oxidative biotransformations of phenol substrates catalysed by toluene dioxygenase: A molecular docking study

Toluene- and naphthalene-dioxygenase-catalysed sulfoxidation of nine disubstituted methylphenyl sulfides, using whole cells of Pseudomonas putida, consistently gave the corresponding enantioenriched sulfoxides. Using the P. putida UV4 mutant strain, and these substrates, differing proportions of the corresponding cis-dihydrodiol sulfides were also isolated. Evidence was found for the concomitant dioxygenase-catalysed cis-dihydroxylation and sulfoxidation of methyl para-tolyl sulfide. A simultaneous stereoselective reductase-catalysed deoxygenation of (S)-methyl para-tolyl sulfoxide, led to an increase in the proportion of the corresponding cis-dihydrodiol sulfide. The enantiopurity values and absolute configurations of the corresponding cis-dihydrodiol metabolites from methyl ortho- and para-substituted phenyl sulfides were determined by different methods, including chemoenzymatic syntheses from the cis-dihydrodiol metabolites of para-substituted iodobenzenes. Further evidence was provided to support the validity of an empirical model to predict, (i) the stereochemistry of cis-dihydroxylation of para-substituted benzene substrates, and (ii) the regiochemistry of cis-dihydroxylation reactions of ortho-substituted benzenes, each using toluene dioxygenase as biocatalyst.

Background: The outbreak of the global pandemic COVID-19 has infected and killed more than millions of people in a short period of time. Given the condition, there is an urgent need for developing anti-viral therapy for eradicating the coronavirus. Plant metabolites remain to be valuable resources in treating various ailments, including viral diseases. Since Clausena anisata (CA) has been reported for its antiviral activity, exploration of anti coronavirus activity will lead to the development of anti coronavirus drug molecules. Protease enzymes play a crucial role in the process of converting the core proteins into structural and functional proteins,which is essential for the survival of coronavirus life cycle. Hence, proteases, such as main protease and papain like protease, were selected therapeutic targets to explore the anti-COVID activity of CA. Objectives: The present study aims to carry out insilico molecular docking, ADME-Tox prediction and molecular dynamic studies to unfold the possible protease inhibitory activities of phyto principles of CA against main protease (Mpro) and papain like protease (PLpro) of SARS-CoV-1& 2. Methods: All the insilico studies were carried out using Schrödinger software. Molecular docking studies were carried out targeting main protease (PDB ID: 2GTB, 6LU7) and papain-like protease (PDB ID: 4OW0, 7CMD), which were retrieved from the Protein Data Bank (PDB). Studies were also conducted on the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. Molecular dynamic simulation study was carried out to observe the behaviour of the Ligandtarget complex and to calculate the stability over time on the top-scored phytoprinciples of CA. Results and Discussion: Out of 139 phyto principles selected for the study, some phytoprinciples, such as Heptaphylline, Clausenamide, indicolactone, and xanthotaxol showed better docking scores. The phytoprinciples of CA interacted with Mpro and PLpro of both SARS-CoV-1& 2. These phyto compounds were found to have molecular interaction with the essential amino acid residues, such as TYR 268, ASP 164, GLN 269, Trp106, Asn109, Lys232, Pro247, His272, Asp286 and Thr301 of PLpro and HIS 41, Glu 166 and Cys 145 of Mpro. Molecular dynamics study demonstrated the stability of the phytochemicals-target complexes. ADME-Tox prediction results showed the drug likeness and non-toxic nature of the phytoprinciples selected for the study. Conclusion: The anti-coronavirus activity of CA was explored by in silico studies. The molecular docking studies against proteases of SARS-CoV-1& 2 indicate that CA has the anti-coronavirus activity through interacting with the main protease and papain protease. The combined PLpro and Mpro inhibitory activity of CA will have additional benefit in restricting the survival coronaviruses. This study will be a base for exploring the anti-coronavirus activity of CA in multiple directions to obtain a novel anti COVID lead molecules.

Enzymatic oxidation of para-substituted arenes: access to new non-racemic chiral metabolites for synthesis

COVID-19 (Coronavirus disease 2019) is a transmissible disease initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) since 31st December 2019 in Wuhan city of China and the infection has outspread globally influencing millions of people. Here, an attempt was made to recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular docking and molecular dynamics (MD) simulation study. Molecular docking study showed six probable inhibitors against SARS-CoV-2 Mpro (Main protease), two from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]), one from Tinospora cordifolia (Giloy) (Tinocordiside [8.10 kcal/mol]) and three from Ocimum sanctum (Tulsi) (Vicenin [8.97 kcal/mol], Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte [8.55 kcal/mol] and Ursolic acid [8.52 kcal/mol]). ADMET profile prediction showed that the best docked phytochemicals from present work were safe and possesses drug-like properties. Further MD simulation study was performed to assess the constancy of docked complexes and found stable. Hence from present study it could be suggested that active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. Highlights Holistic approach of Ayurvedic medicinal plants to avenge against COVID-19 pandemic. Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2. Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine, Tinocordiside, Vicenin, Ursolic acid and Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte were anticipated to impede the activity of SARS-CoV-2 Mpro. Drug-likeness and ADMET profile prediction of best docked compounds from present study were predicted to be safe, drug-like compounds with no toxicity. Communicated by Ramaswamy H. Sarma

Background: Heterocyclic compounds containing heteroatoms (O, N and S) as part of five or six-membered cyclic moieties exhibited various potential applications, such as pharmaceutical drugs, agrochemical products and organic materials. Among many known heterocyclic moieties, quinoline and its derivatives are one of the privileged scaffolds found in many natural products. In general, quinoline derivatives could be prepared by utilizing ortho-substituted anilines and carbonyl compounds containing a reactive α-methylene group of well-known reaction routes like Friedlander synthesis, Niemantowski synthesis and Pfitzinger synthesis. Moreover, polysubstituted quinolones and their derivatives also had shown considerable interest in the fields of organic and pharmaceutical chemistry in recent years. Objective: The main objective of our research work is towards the design and synthesis of divergent biological-oriented, proactive analogues with potential pharmacological value inspired by the anti-tubercular activity of 2-phenylquinoline analogues. In this study, we have been interested in the design and synthesis of bioactive, 2, 4-diphenyl, 8-arylated quinoline analogues. Methods: 6-phenyl-6h-chromeno [4, 3-b] quinoline derivatives were synthesized from 4-chloro-2- phenyl-2H-chromene-3-carbaldehyde and various substituted aromatic anilines as starting materials using sodium bisulfate embedded SiO2 re-usable catalyst. All these fifteen new compound structures confirmed by spectral data 1H & 13C NMR, Mass, CHN analysis etc. Furthermore, all these new compounds antibacterial activity strains recorded using the paper disc method. The compound molecular structures were designed using molecular docking study by utilizing the crystallographic parameters of S. Areus Murb protein. Results: A series of fifteen new quinoline derivatives synthesized in moderate to good yields using sodium bisulfate embedded SiO2 re-usable catalyst. The molecular structures of these newly synthesized compounds elucidated by the combination of spectral data along with the elemental analysis. These compounds antibacterial activity study have shown moderate to good activity against, Escherichia coli (Gram-negative) and Staphylococcus aureus (gram-positive) organisms. These antibacterial activity results were also a very good correlation with molecular docking studies. Conclusion: In this study, fifteen new quinoline derivatives synthesized and structures confirmed by spectral data. In fact, all the compounds have shown moderate to good antibacterial activity. In general, the compounds containing the electron donor group at R1 position (R1 = OMe) and the acceptor group at R2 positions (R2 = F or Cl) had shown good antibacterial activity. These antibacterial activity results were also a very good correlation with molecular docking studies showing strong binding energies with the highest value being, -12.45 Kcal mol-1 with S. aureus MurB receptor.

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system that controls voluntary muscles; characterised by a slowly progressive weakness and stiffness of leg upper motor neuron syndrome. Many effective drugs act by modulating multiple targets, Drug repositioning/Drug repurposing can be used as an alternative methodology for drug discovery, and this ‘poly-pharmacology’ can be a therapeutic requirement for complex diseases. This study focuses on repurposing of FDA approved drugs against Transactive response DNA binding protein of 43 kDa (TDP43) protein of PLS disease by molecular docking and dynamic studies. The ligands were chosen from the FDA-approved chemical list and the target receptor was retrived from protein data bank (PDB ID: 7Q8V). The molecular docking study was carried out using the AutoDock Vina program and the results were visualised through Discovery studio tool. The ADMET features of top 10 drugs were predicted using pkCSM online software. Molecular dynamic study was carried out by Desmond. Several drugs showed extremely high binding free energies for chosen target of TDP43 Protein. The results have led to the discovery of Indinavir, Adapalene, Alclometasone, Amsacrine and other FDA-approved drugs as potential candidates for the treatment of PLS. Molecular dynamic studies were carried out for the best two complexes, complex was found to be stable during molecular dynamic simulation. This study led to the identify of Indinavir and Amsacrine as potential candidates for the treatment of PLS. Hence these drugs can be evaluated further in animal model to establish drug for treating PLS.

COVID-19 is caused by the SARS-CoV-2 virus. In this study, around 300 herbal compounds were screened virtually to find the best anti-COVID-19 structures. An extensive search in electronic databases was done. Around 300 herbal compounds, which were previously proven to be antiviral structures, were extracted from articles and considered our primary database. Then, molecular docking studies were performed to find the best inhibitors of the main SARS-COV-2 proteins, including spike protein (PDB 7BWJ), RNA-dependent RNA polymerase (PDB 6M71) and main protease (PDB 5R7Z). The molecular docking and dynamics studies revealed that fangchinoline as an alkaloid could bind to the main protease of the virus more potent than lopinavir (-42.26 vs. -30.9 kJ/mol). Fangchinoline can be orally active based on drug-like properties. According to the molecular dynamic study, the complex between the fangchinoline and SARS-CoV-2 main protease is stable. chebulagic acid is a benzopyrene tannin that could inhibit RNA-dependent RNA polymerase (RdRp) better than remdesivir (-43.9 vs. -28.8 kJ/mol). The molecular dynamic study showed that chebulagic acid-RdRp interaction is stable and strong. Furthermore, suramin could neutralize different variants of COVID-19 spike proteins (wild type, and alpha and beta variants). However, suramin is not orally active but it is a potential inhibitor for different coronavirus spike proteins. According to the promising in silico results of this study, fangchinoline, chebulagic acid and suramin could be introduced as potential lead compounds for COVID-19 treatment. We are hopeful to find a reliable remedy shortly through natural compounds.

cis-Dihydrodiol and arene oxide metabolites of carbocyclic and heterocyclic arenes yield the corresponding phenols via an ‘NIH Shift’ mechanism.

For Abstract see ChemInform Abstract in Full Text.

Determination of the interactions of a schiff base with different targets via molecular docking and cytotoxic activity studies

Background: The COVID-19 pandemic emerged at the end of 2019 in China and spread rapidly all over the world. Scientists strive to find virus-specific antivirals against COVID-19 dis-ease. This study aimed to assess bioactive coumarinolignans (Aquillochin, Grewin) as potential SARS-CoV-2 main protease (SARS-CoV-2 Mpro) inhibitors using a molecular docking study. Methods: The detailed interactions between coumarinolignans and SARS-CoV-2 Mpro were de-termined as hydrophobic bonds, hydrogen bonds, electronic bonds, inhibition activity, ligand effi-ciency, bonding type, and distance using Autodock 4.2 software. SARS-CoV-2 Mpro was docked with Aquillochin and Grewin, and the docking results were analyzed by Autodock 4.2 and Biovia Discovery Studio 4.5. Nelfinavir and Lopinavir were used as standards for comparison. Results: The binding energies of the SARS-CoV-2 Mpro-coumarinolignan’s complexes were iden-tified from the molecular docking of SARS-CoV-2 Mpro. Aquillochin and Grewin were found to be -7.5 and -8.4 kcal/mol, respectively. The binding sites of the coumarinolignans to SARS-CoV-2 Mpro were identified with the main interactions being π-alkyl, alkyl, π-cation, π-π T-Shaped, and hydrogen bonding. Furthermore, SwissADME web tools were used to evaluate ADMET properties and pharmacokinetic parameters of Aquillochin and Grewin. The results of ADMET and pharma-cokinetic results of the Aquillochin and Grewin showed that these coumarinolignans were conso-nant with the many accepted rules and the criteria of drug-likeness. Conclusion: Aquillochin and Grewin obey Lipinski’s rule of five. According to the results obtained from molecular docking studies and ADMET predictions, Aquillochin and Grewin have shown weak efficacy as drug candidates against COVID-19 disease.

BackgroundLeishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a population of about 12 million people annually. This theoretical study was therefore conducted in support of the search for more effective drug candidates for the treatment of leishmaniasis. This study focuses on the in silico activity prediction of twenty-eight (28) maleimides, structure-based design, molecular docking study and pharmacokinetics analysis of the newly designed maleimides. All the studied compounds were drawn using ChemDraw Ultra and optimized by the density functional theory (DFT) approach using B3LYP with 6-31G⁄ basis set.ResultsThe built QSAR model was found to satisfy the requirement of both internal and external validation tests for an acceptable QSAR model with R2 = 0.801, R2adj = 0.748, Q2cv = 0.710, R2test = 0.892 and cRp2 = 0.664 and has shown excellent prediction of the studied compounds. Among the five (5) protein receptors utilized for the virtual docking screening, pyridoxal kinase (PdxK) receptor (Pdb id = 6k91) showed the strongest binding interactions with compounds 14, 21 and 24 with the highest binding affinities of − 7.7, − 7.7 and − 7.8 kcal/mol, respectively. The selected templates (14, 21 and 24) were used to design twelve (12) new compounds (N1–N12) with higher docking scores than the templates. N7 (affinity = − 8.9 kcal/mol) and N12 (− 8.5 kcal/mol) showed higher binding scores than the reference drug pentamidine (− 8.10 kcal/mol), while N3 and N7–N12 showed higher predicted pIC50 than the templates. Also, the pharmacokinetics properties prediction revealed that the newly designed compounds, obeyed the Lipinski’s rule for oral bio-availability, showed high human intestinal absorption (HIA), low synthetic accessibility score, CNS and BBB permeability and were pharmacologically active.ConclusionsThe activities of the various maleimides were predicted excellently by the built QSAR model. Based on the pharmacokinetics and molecular docking studies therefore, the newly designed compounds are suggested for further practical evaluation and/or validation as potential drug candidates for the treatment of leishmaniasis.

Background: α-Glucosidase inhibitors hinder the carbohydrate digestion and play an important role in the treatment of diabetes mellitus. α-glucosidase inhibitors available on the market are acarbose, miglitol, and voglibose. However, the use of acarbose is diminishing due to related side effects like diarrhea, bloating and abdominal distension. Objectives: This study aimed to synthesize 2,4,6-triaryl pyrimidines derivatives, screen their α- glucosidase inhibitory activity, perform kinetic and molecular docking studies. Methods: A series of 2,4,6-triaryl pyrimidine derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Pyrimidine derivatives 4a-m were synthesized via a twostep reaction with a yield between 49 and 93%. The structure of the synthesized compounds was confirmed by different spectroscopic techniques (IR, NMR and MS). The in vitro α-glucosidase inhibition activities of the synthesized compounds 4a-m was also evaluated against Saccharomyces cerevisiae α-glucosidase. Results and Discussion: The majority of synthesized compounds had α-glucosidase inhibitory activity. Particularly compounds 4b and 4g were the most active compounds with an IC50 value of 125.2± 7.2 and 139.8 ± 8.1 μM respectively. The kinetic study performed for the most active compound 4b revealed that the compound was a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The molecular docking study also revealed that the two compounds have important binding interactions with the enzyme active site. Conclusion: 2,4,6-triarylpyrimidine derivative 4a-m were synthesized and screened for α- glucosidase inhibitory activity. Most of the synthesized compounds possess α-glucosidase inhibitory activity, and compound 4b demonstrated the most significant inhibitory action as compared to acarbose.