In silico study of the inhibition of SARS-COV-2 viral cell entry by neem tree extracts

The outbreak of COVID-19, caused by SARS-COV-2, is responsible for higher mortality and morbidity rates across the globe. Until now, there is no specific treatment of the disease and hospitalized patients are treated according to the symptoms they develop. Efforts to identify drugs and/or vaccines are ongoing processes. Natural products have shown great promise in the treatment of many viral related diseases. In this work, using in silico methods, bioactive compounds from the neem tree were investigated for their ability to block viral cell entry as spike RBD-ACE2 inhibitors. Azadirachtin H, quentin and margocin were identified as potential compounds that demonstrated viral cell entry inhibition properties. The structural re-orientation of azadirachtin H was observed as the mechanism for viral cell entry inhibition. These compounds possessed good pharmacodynamic properties. The proposed molecules can serve as a starting point towards developing effective anti-SARS-COV-2 drugs targeting the inhibition of viral cell entry upon further in vitro and in vivo validation.

The outbreak of COVID-19, caused by SARS-COV-2, is responsible for higher mortality and morbidity rates across the globe.     

Multicomponent synthesis of pyrano[2,3-c]coumarins

A base-catalyzed, pseudo-four-component reaction of 4-hydroxycoumarin, two molecules of acetone, and amine towards the synthesis of pyrano[2,3-c]coumarins is reported. The mechanism of this multicomponent reaction is proposed. The reaction is further extended to the preparation of coumarin-substituted pyrano[2,3-c]coumarins by a base-catalyzed, pseudo four-component reaction of two molecules of 4-hydroxycoumarin and two molecules of acetone.

A base-catalyzed, pseudo-four-component reaction of 4-hydroxycoumarin, two molecules of acetone, and amine towards the synthesis of pyrano[2,3-c]coumarins is reported.     

In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations

In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID: 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligand–enzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile.

The identification of AP-20 as a potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations.     

Furo[3,2-c]coumarins carrying carbon substituents at C-2 and/or C-3. Isolation,biological activity,synthesis and reaction mechanisms

The isolation, biological activity and synthesis of natural furo[3,2-c]coumarins are presented, covering mainly the developments in the last 35 years. The most relevant approaches toward the synthesis of 2-substituted, 3-substituted and 2,3-disubstituted heterocycles are also discussed, with emphasis on the efficiency of the processes and their mechanisms.

The isolation, synthesis and biological activity of naturally occurring furo[3,2-c] coumarins carrying carbon substituents at C-2 and/or C-3, is discussed. Synthetic approaches toward the properly functionalized heterocyclic motif are also presented.     

Recent updates on the biological efficacy of approved drugs and potent synthetic compounds against SARS-CoV-2

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, has triggered a global pandemic that has prompted severe public health concerns. Researchers worldwide are continuously trying to find options that could be effective against COVID-19. The main focus of research during the initial phase of the pandemic was to use the already approved drugs as supportive care, and efforts were made to find new therapeutic options. Nirmatrelvir (PF-07321332), a Pfizer chemical, recently received approval for usage in conjunction with ritonavir. This mini-review summarises the biological effectiveness of vital synthetic compounds and FDA-approved medications against SARS-CoV-2. Understanding how functional groups are included in the creation of synthetic compounds could help enhance the biological activity profile of those compounds to increase their efficacy against SARS-CoV-2. This opened the way for researchers to explore opportunities to develop better therapeutics by investigating synthetic analogs.

The role of functional group in discovery of Nirmatrelvir is valuable and interesting for development of various inhibitors against viral diseases.     

Potential repurposed SARS-CoV-2 (COVID-19) infection drugs

The global outbreak of COVID-19 viral infection is associated with the absence of specific drug(s) for fighting this viral infection. About 10 million people are already infected, about 500 000 deaths all over the world to date. Great efforts have been made to find solutions for this viral infection, either vaccines, monoclonal antibodies, or small molecule drugs; this can stop the spread of infection to avoid the expected human, economic and social catastrophe associated with this infection. In the literature and during clinical trials in hospitals, several FDA approved drugs for different diseases have the potential to treat or reduce the severity of COVID-19. Repurposing of these drugs as potential agents to treat COVID-19 reduces the time and cost to find effective COVID-19 agents. This review article summarizes the present situation of transmission, pathogenesis and statistics of COVID-19 in the world. Moreover, it includes chemistry, mechanism of action at the molecular level of the possible drug molecules which are liable for redirection as potential COVID-19 therapeutic agents. This includes polymerase inhibitors, protease inhibitors, malaria drugs, lipid lowering statins, rheumatoid arthritis drugs and some miscellaneous agents. We offer research data and knowledge about the chemistry and biology of potential COVID-19 drugs for the research community in this field.

The global outbreak of COVID-19 viral infection is associated with the absence of specific drug(s) for fighting this viral infection.     

Discovery of novel inhibitors of RNA silencing suppressor P19 based on virtual screening

To control plant viruses, viral RNA silencing suppressors are important drug targets due to their key roles in interfering antiviral RNA silencing. Here we have presented a strategy, combining virtual and experimental screening, to discover the inhibitors of viral suppressor. By docking 157 026 compounds from a natural product library into P19 model, eighteen candidate compounds were selected. Candidates VS2, VS12, VS14 and VS15 displayed strong binding ability to P19 in the surface plasmon resonance imaging assay with K_D values of 136.2, 111.6, 81.2 and 124.5 nM, respectively. Then the inhibition activities of these inhibitors on the association between P19 and siRNA were also affirmed by electrophoretic mobility shift assay. Moreover, the antiviral effects on plants showed that compounds VS14 and VS15 both exhibited antiviral activities against Tomato bushy stunt virus (TBSV) in vivo with inhibition rates of 32.35% and 16.61% in 11 dpi, respectively. This strategy would be a powerful tool for the discovery of novel antiviral agents and provide new insights into the control of plant viruses.

The combined virtual and experimental screening method is a efficient strategy to discover inhibitors of RNA silencing suppressor.     

One-pot two-step synthesis of 3-iodo-4-aryloxy coumarins and their Pd/C-catalyzed annulation to coumestans

An efficient protocol for the synthesis of various coumestans from the intramolecular annulation of 3-iodo-4-aryloxy coumarins through C–H activation has been developed. When 3-iodo-4-aryloxy coumarins were treated with 10% Pd/C (0.3 mol% Pd) in the presence of sodium acetate, the corresponding coumestans were produced in good to excellent yield. Reusability of the palladium catalyst was investigated in up to three consecutive cycles and it was found that the yield of the reaction was almost unaltered. Sequential iodination and O-arylation of 4-hydroxy coumarins leading to the 3-iodo-4-aryloxy coumarins were also achieved in a one-pot two-step process starting from aryl iodides in high yield. Pivalic acid was revealed to be the most effective additive for the later method to produce 3-iodo-4-phenoxy coumarins. Different functional groups bearing electron-donating as well as withdrawing groups are also tolerant to the reaction conditions.

An efficient protocol for the synthesis of various coumestans from the intramolecular annulation of 3-iodo-4-aryloxy coumarins through C–H activation has been developed.     

Green synthesis of coumarin derivatives using Brønsted acidic pyridinium based ionic liquid [MBSPy][HSO4] to control an opportunistic human and a devastating plant pathogenic fungus Macrophomina phaseolina

An eco-friendly simple protocol has been devised for the preparation of coumarin derivatives using doubly Brønsted acidic task specific ionic liquid (TSIL) as a catalyst. Solvent-free conditions were employed for the reaction of different substituted phenols with β-ketoester in TSIL to produce corresponding substituted coumarin derivatives in good to excellent yields at ambient conditions; at room temperature and with reduced reaction times. The ionic liquid catalyst can be recycled and reused up to five times. All the synthesized coumarins were evaluated for their antifungal activities against Macrophomina phaseolina, a plant as well as an opportunistic human pathogenic fungus affecting more than 500 plant species worldwide and with no registered commercial fungicide available against it, to date. Amongst all the coumarins tested, compounds 3f and 3i showed excellent antifungal activity comparable to reference fungicide mancozeb. The current methodology provides an easy and expedient way to access the coumarin core in search of potential fungicides for sustainable agriculture.

An eco-friendly simple protocol has been devised for the preparation of coumarin derivatives using doubly Brønsted acidic task specific ionic liquid (TSIL) as a catalyst.     

Cross-dehydrogenative coupling of coumarins with Csp3–H bonds using an iron–organic framework as a productive heterogeneous catalyst

The iron–organic framework VNU-20 was utilized as an active heterogeneous catalyst for the cross-dehydrogenative coupling of coumarins with Csp³–H bonds in alkylbenzenes, cyclohexanes, ethers, and formamides. The combination of DTBP as the oxidant and DABCO as the additive led to high yields of coumarin derivatives. The VNU-20 was more active towards this reaction than numerous other homogeneous and heterogeneous catalysts. Heterogeneous catalysis was confirmed for the cross-dehydrogenative coupling transformation utilizing the VNU-20 catalyst, and the contribution of active iron species in the liquid phase was insignificant. The iron-based framework was reutilized many times for the functionalization of coumarins without a remarkable decline in catalytic efficiency. To the best of our knowledge, these reactions of coumarins have not previously been conducted using heterogeneous catalysts.

The iron–organic framework VNU-20 was utilized as an active heterogeneous catalyst for the cross-dehydrogenative coupling of coumarins with Csp³–H bonds in alkylbenzenes, cyclohexanes, ethers, and formamides.     

Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempt to computationally screen for possible medications for COVID-19 via rapidly estimating the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twenty-seven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.

Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV-2 Mpro can be promising inhibitors.     

Arylnaphthalene lactone analogues: synthesis and development as excellent biological candidates for future drug discovery

Arylnaphthalene lactones are natural products extracted from a wide range of different parts of plants. The progressing interest in the synthesis of these compounds is due to their significant biological activities, which have made them potential candidates in drug discovery and development. This review mainly covers recent developments in the synthesis and biological applications of arylnaphthalene lactone analogs.

A review of recent developments in the synthesis and biological applications of arylnaphthalene lactones analogs.     

Remdesivir analog as SARS-CoV-2 polymerase inhibitor: virtual screening of a database generated by scaffold replacement

By the end of 2019, a novel strain of the corona viral family named SARS-CoV-2 emerged in Wuhan, China and started to spread worldwide causing one of the most dangerous lethal pandemics. Researchers utilized various reported inhibitors and drug databases for virtual screening analysis against this novel strain. Later on, they succeeded to fish and repurpose remdesivir, an antiviral nucleotide analogue that inhibits RNA polymerase of the Ebola virus, as a promising candidate against SARS-CoV-2. In this study, we used the interactions of the co-crystallized metabolite of remdesivir with SARS-CoV-2 RdRp isozyme (PDB 7BV2) to design an analog with potential extra activity. This design was based on a scaffold replacement of a pyrrolotriazine moiety. This design was guided by a generated structure-based pharmacophore. The database generated from scaffold replacement was subjected to molecular docking and molecular dynamics simulations within the active site of SARS-CoV-2 RdRp (PDB 7BV2) to suggest HA-130383 and HA-130384 as potential lead compounds.

By the end of 2019, a novel strain of the corona viral family named SARS-CoV-2 emerged in Wuhan, China and started to spread worldwide causing one of the most dangerous lethal pandemics.     

An efficient,mild and metal free l-proline catalyzed construction of fused pyrimidines under microwave conditions in water

One-pot condensation of 4-hydroxy coumarins, aldehydes and urea/thiourea to build C–C and C–N bonds is described. Fused pyrimidines have been synthesized under mild reaction conditions using l-proline. The protocol has been performed rapidly and efficiently in water under metal free conditions. Heterocyclic derivatives have been synthesized using the present methodology and avoid the use of hazardous solvents over conventional organic solvents. A proposed mechanism could be established for three component reactions. The present study reveals the first case in which l-proline has been explored as a homogeneous catalyst in the synthesis of fused pyrimidines in water under microwave irradiation. This synthesis involves simple workup and acceptable efficiency. The most notable feature of this protocol is the ability of the catalyst to influence asymmetric induction in the reaction.

One-pot condensation of 4-hydroxy coumarins, aldehydes and urea/thiourea to build C–C and C–N bonds is described.     

Activator free diastereoselective 1,3-dipolar cycloaddition: a quick access to coumarin based spiro multi heterocyclic adducts

A formal diastereoselective 1,3-dipolar cycloaddition of azomethine ylide and coumarin derivatives to construct coumarin based spiro multi heterocyclics has been described. The in situ generation of azo-ylide was achieved for various heterocyclic carbonyls (indenoquinoxaline and isatin). This transformation is also suitable for maleimide dipolarophiles for the synthesis of hydro-maleimide derivatives. These decarboxylative annulations neither required any catalyst nor any activator. Further the pure products were isolated by filtration from the reaction mixture after the reaction under ambient conditions.

A formal diastereoselective decarboxylative 1,3-dipolar cycloaddition of azomethine ylide and coumarins is achieved for the synthesis of spiro multi heterocyclic adducts without engaging any catalyst or activator in good yields.     

Microwave-assisted simple synthesis of 2-anilinopyrimidines by the reaction of 2-chloro-4,6-dimethylpyrimidine with aniline derivatives

A series of 2-anilinopyrimidines including novel derivatives has been obtained from 2-chloro-4,6-dimethylpyrimidine by aromatic nucleophilic substitution with differently substituted anilines under microwave conditions. The substituents had a significant impact on the course and efficiency of the reaction. The results reported herein demonstrate the efficacy of microwaves in the synthesis of the title heterocyclic compounds as compared to the results obtained with conventional heating. The 2-anilinopyrimidines described are of potential bioactivity.

A rapid, one pot, green approach by microwave heating in ethanol provides a new method to obtain active and new potentially active compounds in high yields.     

Discovery of 4-(2-(dimethylamino)ethoxy)benzohydrazide derivatives as prospective microtubule affinity regulating kinase 4 inhibitors

Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC₅₀ value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.

Inhibition studies of MARK4 with selected hydrazone derivatives.     

Solvent-free synthesis of propargylamines: an overview

Propargylamines are a class of compounds with many pharmaceutical and biological properties. A green approach to synthesize such compounds is very relevant. This review aims to describe the solvent-free synthetic approaches towards propargylamines via A³ and KA² coupling reactions covering the literature up to 2021.

This review focuses on solvent-free methodologies for the synthesis of propargylamines, a versatile class of compounds with numerous applications.     

Consecutive reactions to construct tricarbonyl compounds and synthetic applications thereof

Lithium anions derived from O-carbonate-protected cyanohydrins undergo conjugate addition to cycloalkenones with the concomitant transfer of the alkoxycarbonyl group to produce tricarbonyl compounds. These products offer numerous possibilities for further elaboration. The synthetic potential of the cascade products was demonstrated by forming bicyclic and tricyclic systems through intramolecular condensation reactions.

A cascade process to construct synthetically valuable β-keto-β′-acylcycloalkanecarboxylic acid esters and their transformation into bicyclic and tricyclic systems through intramolecular condensation reactions.