In Vivo and in Silico Based Evaluation of Antidiabetic Potential of an Isolated Flavonoid from Allium hookeri in Type 2 Diabetic Rat Model.

Allium hookeri (F: Liliaceae), an indigenous plant of Manipur, India, is traditionally used to treat various diseases and disorders like diabetes, hypertension, and stomach ache. In our previous study, the methanol extract of the plant showed significant antidiabetic potential in rats. In the present study, we evaluated the antidiabetic potential of a flavonoid compound named MEA isolated from the methanolic leaf extract of A. Hookeri in rats. Additionally, we assessed the compound's mode of action through the molecular docking study. The MEA reduced the blood glucose level from 317±12.8 to 99.4±6.67 mg/dl after 21 days of treatment. Besides, MEA also restored the body weights and other biochemical parameters including lipid profile significantly compared to the diabetic group (p<0.001). The histoarchitecture of the pancreatic tissues of the MEA treated group was also improved compared to the diabetic group. In the docking study, the compound showed good binding affinity in the active binding site of the two structures of pancreatic beta-cell SUR1 (Sulfonylurea Receptor 1) subunit with CDocker energy -31.556 kcal/mol and -39.703 kcal/mol, respectively. The compound MEA was found to be drug-like with non-carcinogenic, non-mutagenic and non-irritant properties. These findings indicate the antidiabetic potential of MEA, which might act by modulating the pancreatic beta-cell SUR1 subunit present in the KATP channel. Hence, the MEA would be a promising lead molecule to develop new antidiabetic drug candidates of the future.

In vitro and in silico guided identification of antimalarial phytoconstituent(s) in the root of Citrus maxima (Burm.) Merr.

As a part of our continuous effort to find new therapeutic agents from natural sources, the hydroalcoholic (1:1) extract of Citrus maxima (Burm.) Merr. root was selected for the identification of possible antimalarial phytoconstituents. From the extract, three flavonoids including luteolin were isolated and evaluated for in vitro antimalarial activity against the chloroquine-sensitive (Pf3D7) and resistant (PfRKL-9) strains of Plasmodium falciparum. Among these, luteolin (CM3) showed the highest antimalarial activity with IC50 values of 2.315 ± 0.489 and 2.691 ± 0.454 µg/ml against the Pf3D7 and PfRKL-9 strains respectively. To assess the safety of luteolin (CM3), a cytotoxicity study against a normal human embryonic kidney cell line (HEK-293) was performed and the compound was found to be safe with a CC50 value of 222.3 ± 1.443 µg/ml. The docking study against 26 target proteins of P. falciparum revealed that luteolin (CM3) has a better binding affinity with two proteins, viz. P. falciparum lactate dehydrogenase (PfLDG) and P. falciparum enoyl-ACP reductase (PfEAR) in comparison to the co-crystallized ligands. Furthermore, the molecular dynamics simulation study of the protein-ligand complexes also supported the binding affinity and interactions of luteolin (CM3) at the active sites. Finally, the binding free energy calculation revealed that the luteolin formed a thermodynamically more stable complex with PfLDG (-50.955 ± 17.184 kJ/mol) than PfEAR (-24.856 ± 13.739 kJ/mol). Overall, in this study, we identified an antimalarial marker in the hydroalcoholic extract of C. maxima root which may act by inhibiting PfLDG.Communicated by Ramaswamy H. Sarma.

Revelation of potential drug targets of luteolin in Plasmodium falciparum through multi-target molecular dynamics simulation studies.

In-silico techniques offer a fast, accurate, reliable, and economical approach to studying the molecular interactions between compounds and proteins. In this study, our main aim is to use in-silico techniques as a rational approach for the prediction of the molecular drug targets for luteolin against Plasmodium falciparum. Multi-target molecular docking, 100 nanoseconds (ns) molecular dynamics (MD) simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations were carried out for luteolin against dihydrofolate reductase thymidylate synthase (PfDHFR-TS), dihydroorotate dehydrogenase (PfDHODH), and falcipain-2. The native ligands of each protein were used as a reference to evaluate the performance of luteolin. Luteolin outperformed the native ligands of all proteins at molecular docking and MD simulations studies. However, in the MM-GBSA calculations, luteolin outperformed the native ligand of only PfDHFR-TS but not PfDHODH and falcipain-2. Among the studied proteins, the in-silico approach predicted PfDHFR-TS as the most favorable drug target for luteolin.Communicated by Ramaswamy H. Sarma.

Multi-target molecular dynamic simulations reveal glutathione-S-transferase as the most favorable drug target of knipholone in Plasmodium falciparum.

Knipholone is an antiplasmodial phytocompound obtained from the roots of Kniphofia foliosa. Despite several available studies, the molecular drug targets of knipholone in P. falciparum remained unknown. Nowadays, in silico techniques are widely used to study the molecular interactions between compounds and proteins as they provide results quickly with high precision and accuracy. In this study, we aim to identify the potential molecular drug targets of knipholone in P. falciparum. We selected 10 proteins of P. falciparum with unique metabolic functions and we found that knipholone showed better binding affinity than the native ligands of 6 proteins. Out of the 6 proteins, knipholone showed better enzyme inhibitory potential than the native ligands of 4 proteins. We carried out a 100 ns MD simulations for knipholone and the native ligands of four proteins and this was followed by binding free energy calculations. In each step, the performance of knipholone was compared to the native ligands of the proteins. Knipholone outperformed the native ligand of Glutathione-S-Transferase (1OKT) at crucial computational studies as evidence from the lower protein-ligand root mean square deviation value, protein root mean square fluctuation value, and protein-ligand binding free energies. The ligand properties of knipholone provide additional evidence for its stability and it maintains adequate protein-ligand contacts during the entire simulation. The density functional theory study also supported the stability of knipholone at the active binding site of 1OKT. From the studied proteins, we conclude that Glutathione-S-Transferase is the most favorable drug target for knipholone in P. falciparum.Communicated by Ramaswamy H. Sarma.

Integrated computational approach towards repurposing of antimalarial drug against SARS-CoV-2 main protease.

Huge vaccination drives are underway around the world for the ongoing COVID-19 pandemic. However, the search for antiviral drugs is equally crucial. As new drug discovery is a time-consuming process, repurposing of existing drugs or developing drug candidates against SARS-CoV-2 will make the process faster. Considering this, 63 approved and developing antimalarial compounds were selected to screen against main protease (Mpro) and papain-like protease (PLpro) of SARS-CoV-2 using in silico methods to find out possible new drug candidate(s). Out of 63 compounds, epoxomicin showed the best binding affinity against the Mpro with CDocker energy of - 57.511 kcal/mol without any toxic effect. This compound was further taken for molecular dynamic simulation study, where the Mpro-epoxomicin complex was found to be stable with binding free energy - 79.315 kcal/mol. The possible inhibitory potential of the selected compound was determined by 3D-QSAR analysis and found to be 0.4447 µM against SARS-CoV-2 Mpro. Finally, the structure activity relationship of the compound was analyzed and two fragments responsible for overall good binding affinity of the compound at the active site of Mpro were identified. This study suggests a safe antimalarial drug, namely epoxomicin, as a probable inhibitor of SARS-CoV-2 Mpro which needs further validation by in vitro/in vivo studies before clinical use. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01916-0.

Antiviral phytocompounds "ellagic acid" and "(+)-sesamin" of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor "3WL" of 6M2N. BR6 and BR13 were found to have a high LD50 value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein-ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein-ligand contacts, ligand torsions, and ligand properties. BR6 (-22.3064 kcal/mol) and BR13 (-19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01959-3.

Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations.

Severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic is the present worldwide health emergency. The global scientific community faces a significant challenge in developing targeted therapies to combat the SARS-CoV-2 infection. Computational approaches have been critical for identifying potential SARS-CoV-2 inhibitors in the face of limited resources and in this time of crisis. Main protease (Mpro) is an intriguing drug target because it processes the polyproteins required for SARS-CoV-2 replication. The application of Ayurvedic knowledge from traditional Indian systems of medicine may be a promising strategy to develop potential inhibitor for different target proteins of SARS-CoV-2. With this endeavor, we docked bioactive molecules from Triphala, an Ayurvedic formulation, against Mpro followed by molecular dynamics (MD) simulation (100 ns) to investigate their inhibitory potential against SARS-CoV-2. The top four best docked molecules (terflavin A, chebulagic acid, chebulinic acid, and corilagin) were selected for MD simulation study and the results obtained were compared to native ligand X77. From docking and MD simulation studies, the selected molecules showed promising binding affinity with the formation of stable complexes at the active binding pocket of Mpro and exhibited negative binding energy during MM-PBSA calculations, indication their strong binding affinity with the target protein. The identified bioactive molecules were further analyzed for drug-likeness by Lipinski's filter, ADMET and toxicity studies. Computational (in silico) investigations identified terflavin A, chebulagic acid, chebulinic acid, and corilagin from Triphala formulation as promising inhibitors of SARS-CoV-2 Mpro, suggesting experimental (in vitro/in vivo) studies to further explore their inhibitory mechanisms.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies.

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Computational guided identification of potential leads from Acacia pennata (L.) Willd. as inhibitors for cellular entry and viral replication of SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in 2019 and is still an on-going pandemic. SARS-CoV-2 uses a human protease called furin to aid in cellular entry and its main protease (Mpro) to achieve viral replication. By targeting these proteins, scientists are trying to identify phytoconstituents of medicinal plants as potential therapeutics for COVID-19. Therefore, our study was aimed to identify promising leads as potential inhibitors of SARS-CoV-2 Mpro and furin using the phytocompounds reported to be isolated from Acacia pennata (L.) Willd. RESULTS: A total of 29 phytocompounds were reported to be isolated from A. pennata. Molecular docking simulation studies revealed 9 phytocompounds as having the top 5 binding affinities towards SARS-CoV-2 Mpro and furin. Among these phytocompounds, quercetin-3-O-α-L-rhamnopyranoside (C_18), kaempferol 3-O-α-L-rhamnopyranosyl-(1 → 4)-ß-D-glucopyranoside (C_4), and isovitexin (C_5) have the highest drug score. However, C_18 and C_4 were not selected for further studies due to bioavailability issues and low synthetic accessibility. Based on binding affinity, molecular properties, drug-likeness, toxicity parameters, ligand interactions, bioavailability, synthetic accessibility, structure-activity relationship, and comparative analysis of our experimental findings with other studies, C_5 was identified as the most promising phytocompound. C_5 interacted with the active site residues of SARS-CoV-2 Mpro (GLU166, ARG188, GLN189) and furin (ASN295, ARG298, HIS364, THR365). Many phytocompounds that interacted with these amino acid residues were reported by other studies as potential inhibitors of SARS-CoV-2 Mpro and furin. The oxygen atom at position 18, the -OH group at position 19, and the 6-C-glucoside were identified as the pharmacophores in isovitexin (also known as apigenin-6-C-glucoside). Other in-silico studies reported apigenin as a potential inhibitor of SARS-CoV-2 Mpro and apigenin-o-7-glucuronide was reported to show stable conformation during MD simulations with SARS-CoV-2 Mpro. CONCLUSION: The present study found isovitexin as the most promising phytocompound to potentially inhibit the cellular entry and viral replication of SARS-CoV-2. We also conclude that compounds having oxygen atom at position 18 (C-ring), -OH group at position 19 (A-ring), and 6-C-glucoside attached to the A-ring at position 3 on a C6-C3-C6 flavonoid scaffold could offer the best alternative to develop new leads against SARS-CoV-2.

Identification of potential plant-based inhibitor against viral proteases of SARS-CoV-2 through molecular docking, MM-PBSA binding energy calculations and molecular dynamics simulation.

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, SARS-CoV-2, has recently emerged as a pandemic. Here, an attempt has been made through in-silico high throughput screening to explore the antiviral compounds from traditionally used plants for antiviral treatments in India namely, Tea, Neem and Turmeric, as potential inhibitors of two widely studied viral proteases, main protease (Mpro) and papain-like protease (PLpro) of the SARS-CoV-2. Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (-)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the selected receptors, with the lowest CDocker energy - 46.22 kcal mol-1 for SARS-CoV-2 Mpro and CDocker energy - 44.72 kcal mol-1 for SARS-CoV-2 PLpro, respectively. The SARS-CoV-2 Mpro complexed with (-)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 Mpro-Co-crystal ligand (N3) and SARS-CoV-2 Mpro- (-)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (-)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC50 of 0.3281 nM against SARS-CoV-2 Mpro. Overall, (-)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment.

Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: an in silico based approach.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which was first reported in Wuhan province of China, has become a deadly pandemic causing alarmingly high morbidity and mortality. In the absence of new targeted drugs and vaccines against SARS-CoV-2 at present, the choices for effective treatments are limited. Therefore, considering the exigency of the situation, we focused on identifying the available approved drugs as potential inhibitor against the promising Coronavirus drug target, the Main Protease, using computer-aided methods. We created a library of U. S. Food and Drug Administration approved anti-microbial drugs and virtually screened it against the available crystal structures of Main Protease of the virus. The study revealed that Viomycin showed the highest -CDocker energy after docking at the active site of SARS-CoV-2 Main Protease. It is noteworthy that Viomycin showed higher -CDocker energy as compared to the drugs currently under clinical trial for SARS-CoV-2 treatment viz. Ritonavir and Lopinavir. Additionally, Viomycin formed higher number of H-bonds with SARS-CoV-2 Main Protease than its co-crystallised inhibitor compound N3. Molecular dynamics simulation further showed that Viomycin embedded deeply inside the binding pocket and formed robust binding with SARS-CoV-2 Main Protease. Therefore, we propose that Viomycin may act as a potential inhibitor of the Main Protease of SARS-CoV-2. Further optimisations with the drug may support the much-needed rapid response to mitigate the pandemic.Communicated by Ramaswamy H. Sarma.

Multiple-targets Directed Screening of Flavonoid Compounds from Citrus Species to find out Antimalarial Lead with Predicted Mode of Action: An In Silico and Whole Cell-based In vitro Approach.

BACKGROUND: Development of resistance by the malaria parasite Plasmodium falciparum has created challenges in the eradication of this deadly infectious disease. Hence newer strategies are adopted to combat this disease and simultaneously, new lead/hit identification is going on worldwide to develop new chemotherapeutic agents against malaria. OBJECTIVE: In this study, 44 flavonoids found mainly in the fruit juice of Citrus species having traditional use in malaria-associated fever were selected for in silico multiple-target directed screening against three vital targets of the parasite namely dihydroorotate dehydrogenase (PfDHODH), dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation translocating ATPase (PfATP4) to find out new lead molecule(s). METHODS: The in silico screening was carried out using different protocols of the Biovia Discovery Studio 2018 software and Network analyzer plugin of Cytoscape 3.6.0 followed by in vitro screening of the best lead. RESULTS: After screening, CF8 or luteolin was found to have good binding affinity against PfDHODH and PfATP4 with -CDocker energy 42.2719 and 33.1447 with respect to their cocrystal ligands. These findings were also supported by structure-based pharmacophore, DFT (Density Functional Theory) study and finally by in vitro screening of the lead with IC50 values of 8.23 µm and 12.41 µm against 3D7 (chloroquine-sensitive) and RKL-9 (chloroquine-resistant) strain of P. falciparum, respectively. CONCLUSION: Our study found a moderately active lead molecule with the predicted mode of action which can be utilized to design some new derivatives with more safety and efficacy by targeting the two enzymes.

Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors.

Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method. The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4-trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.

Computational guided identification of a citrus flavonoid as potential inhibitor of SARS-CoV-2 main protease.

Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (Mpro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of Mpro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to Mpro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with Mpro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of Mpro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.

A Simple Work-Up-free, Solvent-free Approach to Novel Amino Acid Linked 1,4-Disubstituted 1,2,3-Triazoles as Potent Antituberculosis Agents.

An efficient, green strategy for synthesis of 1,4-disubstituted-1,2,3-triazole has been developed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) acetate ionic liquid (200 µL) under a solvent- and external base-free condition. This protocol is further applied for the synthesis of novel amino acid containing 1,2,3-triazole molecules, which were then evaluated for potential antitubercular and antibacterial activities. Cytotoxicity assay of the compounds was also performed. In silico analysis of the promising compounds selected through experimental analysis was thereafter performed for visualizing molecular interactions and predicting binding affinities between our synthesized molecules, which exhibited good activity in experimental studies and the DprE1 target protein of Mycobacterium tuberculosis. Durg-likeness studies also show potential of the synthesized molecules as drug candidates.

In Vivo Validation of Folkloric Use of Costus pictus D. Don as Antidiabetic Plant in Assam, Using Streptozotocin Induced Wister Rat Model.

Costus pictus D. Don belonging to the family Costaceae is one of the most commonly used plant among traditional healers in the upper Assam region in India, specifically used in the treatment of diabetes. Aerial parts of the plant are said to have potent anti diabetic property. The present study was aimed to evaluate the traditionally claimed antidiabetic activity of aerial parts of C. pictus in animal models. Healthy male Wister rats (120 ± 30 gm) were used in the study and diabetes was induced by Streptozotocin (STZ) i.p. prepared by dissolving in citrate buffer (pH 4.5), along with nicotinamide (120 mg/kg/b wt). Diabetic rats were treated for 14 days with daily doses of methanolic extract of C. pictus (MECP) in three different scheduled amounts (50, 100 and 200 mg/kg/b wt; p.o.). Control rats were treated with 0.3% CMC (Carboxy Methyl Cellulose) suspension (10 ml/kg/b wt; p.o.). Blood glucose level and plasma lipid profile was examined on 1st, 7th, 14th and 21st day 1 h after treatment. On the last day, 1 h after the treatment, animals were sacrificed followed by isolation of pancreas and liver for histopathological examination. The results were compared with that of the standard group treated with Glibenclamide (10 mg/kg/day; p.o). Comparison of the experimental data of different cohorts demonstrated the potential antidiabetic activity of C. pictus however the highest dose of 200 mg/kg/b wt; p.o. of MECP significantly (P < 0.05) reversed the STZ induced diabetic parameters (increased blood glucose level, altered plasma profile and histoarchitecture of the pancreatic and hepatic cells) that is comparable with that of the standard. The observed results suggest anti diabetic efficacy of C. pictus thereby uphelding the folkloric usage.

Design, Synthesis, Antimalarial Activity and Docking Study of 7-Chloro-4- (2-(substituted benzylidene)hydrazineyl)quinolines.

BACKGROUND: Malaria is a growing infectious disease burden due to the increasing emergence of resistant strains of Plasmodium falciparum. Because of the limited therapeutic efficacy of available antimalarial drugs, the development of potent antimalarial drug agents is therefore an urgent requirement to fight against resistant malaria. OBJECTIVE: The objective of this work was to develop novel quinoline-baed antimalarial agents that would be active against resistant P. falciparum malaria. METHODS: Some 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines were synthesized for the evaluation of their potential as possible antimalarial agents, particularly against resistant malaria. The antimalarial activity of synthesized compounds was evaluated in vitro against bloodstage parasites of P. falciparum. Further, molecular docking and drug-likeness including ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) studies were also carried out using in silico tools. RESULTS: Results reveal the in vitro antimalarial activity of synthesized 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines against P. falciparum. The docking study investigates the antimalarial effectiveness of synthesized quinolines as novel plasmepsin 2 inhibitors. Drug-likeness prediction exhibits acceptable drug-likeness and ADMET properties. CONCLUSION: Based upon our findings, it is concluded that the molecular scaffold of 7-chloro-4-(2- (substituted benzylidene)hydrazineyl)quinolines may be used as a lead structure for further modifications in the search of more potent antimalarial drug molecules.

Ruthenium(II)-Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction.

The first decarbonylative insertion of an alkyne through C-H/C-C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh3 to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.

Novel series of 1,2,4-trioxane derivatives as antimalarial agents.

Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski's rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

Design, in silico and in vitro evaluation of curcumin analogues against Plasmodium falciparum.

The polyphenolic compound curcumin has been reported for its antimalarial properties in various scientific studies. Plasmodium falciparum ATP6, the parasite orthologue of mammalian sarcoplasmic Ca2+ ATPase (SERCA) has been identified as a key molecular target of both artemisinin and curcumin. The work was thereby undertaken to study the anti-malarial properties of two different series of curcumin analogues based on their docking interactions with PfATP6 and correlating the results with their anti-malarial activity. The compounds were designed retaining similar functional groups as that of the parent curcumin nucleus while incorporating changes in the carbon chain length, unsaturated groups and the number of ketone groups. The compounds (1E, 4E)-1,5-bis(4-methylphenyl)penta-1,4-dien-3-one (CD-9), (1E, 4E)-1,5-bis(4-methoxyphenyl)penta-1,4-dien-3-one (CD-8) and (E)-1,3-bis(4-hydroxylphenyl)prop-2-en-1-one (CD-1) showed IC50 values of 1.642 µM, 1.764 µM and 2.59 µM in 3D7 strain and 3.039 µM, 7.40 µM and 11.3 µM in RKL-2 strain respectively. Detailed structure-activity relationship studies of the compounds showed that CD-9 and CD-8 had a common hydrophobic interaction with the residue Leu268 of the PfATP6 protein and has been postulated through our study to be the reason for their antimalarial activity as seen after corroborating the results with the in vitro study. The study provided valuable insight about the ligand-protein interaction of the various functional groups of curcumin and its analogues against the PfATP6 protein and their importance in imparting antimalarial action.