PTSA-induced synthesis, in silico and nano study of novel ethylquinolin-thiazolo-triazole in cervical cancer.

Aim: p-Toluenesulfonic acid-(PTSA) and grinding-induced novel synthesis of ethylquinolin-thiazolo-triazole derivatives was performed using green chemistry. Materials & methods: Development of a nanoconjugate drug-delivery system of ethylquinolin-thiazolo-triazole was carried out with D-α-tocopheryl polyethylene glycol succinate (TPGS) and the formulation was further characterized by transmission electron microscopy, atomic force microscopy, dynamic light scattering and in vitro drug release assay. The effect of 3a nanoparticles was assessed against a cervical cancer cell line (HeLa) through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect on apoptosis was determined. Results & discussion: The 3a nanoparticles triggered the apoptotic mode of cell death after increasing the intracellular reactive oxygen level by enhancing cellular uptake of micelles. Furthermore, in silico studies revealed higher absorption, distribution, metabolism, elimination and toxicity properties and bioavailability of the enzyme tyrosine protein kinase. Conclusion: The 3a nanoparticles enhanced the therapeutic potential and have higher potential for targeted drug delivery against cervical cancer.

Design, synthesis, and molecular modeling of heterodimer and inhibitors of α-amylase as hypoglycemic agents.

A series of rosiglitazone-based heterodimers were designed and synthesized, and their α-amylase and antioxidant activity was evaluated. The binding mode of the compounds at the active site of PPARγ and α-amylase enzyme was explored using MolDock docking method. In molecular docking studies against crystal structure of PPARγ (PDB code: 1FM6), compounds 10 and 13 showed interaction with amino acids Arg379, Asp379, Asn385, Ala387, Glu388, Val389, Glu390, and Lys438. Docking results of α-amylase enzyme (PDB code: 5EOF) with compounds 10 and 13 showed excellent interaction with amino acids Ala169, Lys172, Asp173, Tyr174, Val175, Arg176, and Lys178. Depending on the docking score, the designed compounds were selectively prioritized for synthesis. All synthesized compounds were subjected to in vitro α-amylase activity and antioxidant activity. Compounds 10 and 13 were to possess higher potency than acarbose, and most of the compounds showed antioxidant activity. Additionally, the most active compound 10 was evaluated for in vivo anti-diabetic activity.

Ligand-based designing of DPP-4 inhibitors via hybridization; synthesis, docking, and biological evaluation of pyridazine-acetohydrazides.

A series of novel pyridazine-acetohydrazide hybrids were designed, synthesized, and evaluated for their in vitro and in vivo antihyperglycemic activity. In this context, pyridazine-acetohydrazides (6a-6p) were synthesized by coupling substituted aldehyde with 2-(5-cyano-6-oxo-3,4-diphenylpyridazine-1-6H-yl) acetohydrazide, which was prepared via the reaction of pyridazine ester with hydrazine hydrate. The molecular docking study was carried out to examine the binding affinities and interaction of designed compounds against the DPP-4 enzyme. Compounds 6e, 6f, 6l, and 6n exhibited interaction with active residue. In silico ADMET properties, and toxicity studies corroborated that compounds were found to have good bioavailability and less toxic. The synthesized compounds were further estimated for in vitro DPP-4 activity. Compounds 6e and 6l were found as the most effective DPP-4 inhibitor in this series with IC50 values (6.48, 8.22 nM) when compared with sitagliptin (13.02 nM). According to the toxicity assay compound, 6l showed very less toxicity at a higher concentration so further selected for the in vivo antihyperglycemic activity.

Lead modification via computational studies: Synthesis of pyrazole-containing ß-amino carbonyls for the treatment of type 2 diabetes.

This article describes studies on the design, synthesis, and biological evaluation of pyrazole-containing ß-amino carbonyl compounds (5a-5q) as DPP-4 inhibitors and anti-diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO3 )3 ) catalyst in the presence of ethanol and produced pyrazole-containing ß-amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP-4 enzyme (PDB: 2OLE), compounds 5d, 5h, 5j, and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme-based in vitro DPP-4 inhibitory activity, and 5d, 5h, 5i, 5j, and 5k exhibited IC50 toward DPP-4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5 nM, respectively. The most potent compound, 5j, was further selected for in vivo anti-diabetic activity using an STZ-induced diabetic mice model, and 5j showed a significant diabetic control effect.

Novel pyrimido-pyridazine derivatives: design, synthesis, anticancer evaluation and in silico studies.

Aim: A novel pyrimido-pyridazine derivative for developing anticancer agents was synthesized via Ullmann arylation using an efficient Cu(OAc)2 catalyst. Materials & methods: Compounds were investigated for their anticancer potential, against human breast adenocarcinoma cells, viz. MCF-7, MDA-MB-231 and normal cell line HEK-293. Further, an in vivo study was conducted on lymphoma-bearing mice while in silico analysis was carried out for molecular interactions. Results: Compound 2b displayed significant antitumor activity towards MDA-MB-231 cells through induction of apoptosis and arresting cells in S-phase in vitro, while it significantly increased the lifespan and reduced tumor growth in vivo. An in silico study revealed potent tyrosine-protein kinase inhibitors. Conclusion: Taken together the molecule has the potential to become an effective therapeutic treatment for breast cancer.

Changes in growth pattern and rhizospheric soil biochemical properties of a leguminous tree species Leucaena leucocephala under long-term exposure to elevated ozone.

Increasing concentrations of ground-level ozone (O3) exert significant impacts on the plants, but there is limited data for belowground processes. We studied the effects of long-term exposure of elevated O3 (EO3) on plant growth parameters (plant height and biomass) and biochemical parameters (nutrients, microbial biomass and enzymatic activities) of rhizospheric soil of leguminous tree species Leucaena leucocephala. L. leucocephala seedlings were grown under ambient O3 (AO3) and EO3 (+20 ppb above ambient) under Free Air Ozone Concentration Enrichment (O3-FACE) facility and changes in plant growth and their rhizospheric soil properties were studied during 6, 12, 18 and 24 months of EO3 exposure. L. leucocephala showed significant reductions in shoot length, root biomass, shoot biomass, leaf biomass and total biomass during 12, 18 and 24 months of exposure to EO3. Total nutrients in rhizospheric soil like carbon and phosphorus were significantly reduced after 24 months of EO3 exposure. Most of the available nutrients showed significant reduction after 6, 12 and 24 months of EO3 exposure. A significant decrease was apparent in microbial biomass carbon, nitrogen and phosphorus after 6, 12, 18 and 24 months of EO3 treatment. Significant reductions were observed in extracellular enzymatic activities (dehydrogenase, alkaline phosphatase, ß-glycosidase, fluorescein diacetate, arylsulfatase, cellulase and protease) of soil after 6, 12 and 24 months of EO3 exposure. These results suggest that increasing O3 concentrations will directly impact L. leucocephala growth as well as have indirect impact on the nutrient contents (C, N, and P), microbial biomass and extracellular enzymatic activities of rhizospheric soil of L. leucocephala. Our results suggest that continuous increase in O3 concentrations will have serious implications for aboveground plant growth and belowground soil fertility in this region considered as O3 hotspot. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03215-1.

Click inspired novel pyrazole-triazole-persulfonimide & pyrazole-triazole-aryl derivatives; Design, synthesis, DPP-4 inhibitor with potential anti-diabetic agents.

This work presented the first report on designing, synthesizing of novel pyrazole-triazole-persulfonimide (7a-i) and pyrazole-triazole-aryl derivatives (8a-j) via click reaction using CuI catalyst and evaluated for their anti-diabetic activity and DPP-4 inhibitory effect. Click reactions went smoothly with CuI catalyst in the presence of tridentate chelating ligands and produced copper-free target pyrazole-triazole-persulfonimide analogues in excellent yield at RT. The designed compounds were docked against DPP-4 enzyme and showed excellent interaction with active amino acids residue. Further, all novel pyrazole-triazole-persulfonimide and pyrazole-triazole derivatives were subjected to enzyme-based in vitro DPP-4 inhibitory activity. Based on the SAR study DPP-4 inhibitory capacity compounds 7f (9.52 nM) and 8h (4.54 nM) possessed the significant inhibition of DPP-4. Finally compounds 7f and 8h were evaluated for their in vivo anti-diabetic activity using STZ induced diabetic mice model, and 8h showed a significant diabetic control effect compared to the sitagliptin drug. These studies demonstrated that the novel pyrazole-triazole-persulfonimide and pyrazole-triazole-aryl derivatives might be used as the leading compounds to develop novel DPP-4 inhibitors as potential anti-diabetic agents.

Sodium sulphide promoted synthesis of fused quinoline at room temperature.

A novel, simple and eco-friendly strategy for the synthesis of thiopyrano[4,3-b]quinolin-1-ones and pyrrolo[3,4-b]quinolin-1-ones from 2-alkynylquinoline-3-carbonitriles and sodium sulphide (Na2S·9H2O) under catalyst-free conditions at room temperature has been described. In this reaction, a readily available inorganic salt (Na2S·9H2O) serves as the sulphur source and leads to the generation of diverse functionalized thiopyrano[4,3-b]quinolin-1-ones and pyrrolo[3,4-b]quinolin-1-ones in moderate to excellent yields through sulfuration, annulation, and aerial oxidation.

Impact of chronic elevated ozone exposure on photosynthetic traits and anti-oxidative defense responses of Leucaena leucocephala (Lam.) de wit tree under field conditions.

In this study, the impact of long term exposure of elevated ozone (+20 ppb above ambient) on photosynthetic traits and anti-oxidative defense system of Leucaena leucocephala, a tree of great economic importance, was studied in a Free Air Ozone Concentration Enrichment (O3-FACE) facility at different time intervals (6, 12, 18, and 24 months). Results showed that net photosynthesis, photosynthetic pigments and lipid peroxidation were significantly reduced after 6, 12 and 24 months of exposure to elevated ozone (eO3) whereas stomatal conductance and transpiration rate were significantly decreased after 12 months of exposure to eO3. Antioxidant enzymatic activities (catalase, ascorbate peroxidase and glutathione reductase) were significantly increased after 12 months of exposure to eO3. Ascorbate was increased significantly after 6 and 12 months of exposure to eO3 while reduced glutathione content declined significantly after 6 and 24 months of exposure to eO3. The study showed that there were several negative long lasting physiological and biochemical responses in Leucaena. The results provide evidence that Leucaena exhibited greater sensitivity to O3 during initial exposure (up to 12 months) but showed moderate tolerance by the end of the 2nd year.

Synthesis, biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents.

A novel series of pyrazole derivatives were synthesized and evaluated in vivo for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Among all compounds, 5a, and 5b showed comparable anti-inflammatory activity to Nimesulide, the standard drug taken for the studies. In silico (docking) studies were carried out to investigate the theoretical binding mode of the compounds to target the cyclooxygenase (COX-2) using Autodock 4.2.

Design, synthesis, docking and anti-inflammatory evaluation of novel series of benzofuran based prodrugs.

Several new benzofuran derivatives were synthesized, via appropriate synthetic route as anti-inflammatory agents. The anti-inflammatory activity of the prepared compounds was evaluated using carrageenan rat model. Among the synthesized compounds, some compounds showed comparable anti-inflammatory activity to nimesulide, the standard drug taken for anti-inflammatory studies. Docking study of the prepared compounds was performed for the study of interaction of molecules with the active site of COX-2. Preliminary biological studies and docking gave an interesting insight, into the validity of employing benzofuran analogues as good anti-inflammatory agent.

Molecular docking study of conformational polymorph: building block of crystal chemistry.

Two conformational polymorphs of novel 2-[2-(3-cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-ethoxy]-4,6-dimethyl nicotinonitrile have been developed. The crystal structure of both polymorphs (1a and 1b) seems to be stabilized by weak interactions. A difference was observed in the packing of both polymorphs. Polymorph 1b has a better binding affinity with the cyclooxygenase (COX-2) receptor than the standard (Nimesulide).

BIRS - Bioterrorism Information Retrieval System.

UNLABELLED: Bioterrorism is the intended use of pathogenic strains of microbes to widen terror in a population. There is a definite need to promote research for development of vaccines, therapeutics and diagnostic methods as a part of preparedness to any bioterror attack in the future. BIRS is an open-access database of collective information on the organisms related to bioterrorism. The architecture of database utilizes the current open-source technology viz PHP ver 5.3.19, MySQL and IIS server under windows platform for database designing. Database stores information on literature, generic- information and unique pathways of about 10 microorganisms involved in bioterrorism. This may serve as a collective repository to accelerate the drug discovery and vaccines designing process against such bioterrorist agents (microbes). The available data has been validated from various online resources and literature mining in order to provide the user with a comprehensive information system. AVAILABILITY: The database is freely available at http://www.bioterrorism.biowaves.org.

Comparative Molecular docking analysis of DNA Gyrase subunit A in Pseudomonas aeruginosaPAO1.

Pseudomonas aeruginosa is an opportunistic bacterium known for causing chronic infections in cystic fibrosis and chronic obstructive pulmonary disease (COPD) patients. Recently, several drug targets in Pseudomonas aeruginosa PAO1 have been reported using network biology approaches on the basis of essentiality and topology and further ranked on network measures viz. degree and centrality. Till date no drug/ligand molecule has been reported against this targets.In our work we have identified the ligand /drug molecules, through Orthologous gene mapping against Bacillus subtilis subsp. subtilis str. 168 and performed modelling and docking analysis. From the predicted drug targets in PA PAO1, we selected those drug targets which show statistically significant orthology with a model organism and whose orthologs are present in all the selected drug targets of PA PAO1.Modeling of their structure has been done using I-Tasser web server. Orthologous gene mapping has been performed using Cluster of Orthologs (COGs) and based on orthology; drugs available for Bacillus sp. have been docked with PA PAO1 protein drug targets using MoleGro virtual docker version 4.0.2.Orthologous gene for PA3168 gyrA is BS gyrAfound in Bacillus subtilis subsp. subtilis str. 168. The drugs cited for Bacillus sp. have been docked with PA genes and energy analyses have been made. Based on Orthologous gene mapping andin-silico studies, Nalidixic acid is reported as an effective drug against PA3168 gyrA for the treatment of CF and COPD.

Importance of weak interactions in developing 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs.

The structure of 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs has been characterized by X-ray diffraction, FT-IR, 1H and 13C NMR spectroscopies. The influence of intra and intermolecular weak interactions is thoroughly studied in solid state using single crystal X-ray diffraction and FT-IR. These polymorphs belong to monoclinic space group 'P2(1/n)' and 'P2(1/c)'. These polymorphs have C-H⋯n (lone pair), hydrogen bonds, C-N⋯π, C-H⋯π and π⋯π intermolecular non-covalent interactions. These polymorphs are the result of weak interactions and solvent used in crystallization. The FT-IR spectra have been recorded in the solid phase and NMR has been recorded in solvent. The optimized geometry has been calculated by B3LYP methods using different basis sets. The FT-IR and NMR spectra of 1st polymorphs has been calculated at B3LYP/6-31G (d) level. The scaled theoretical wave number showed good agreement with the experimental values. These two polymorphs as well as other stereomers are studied by DFT calculations.

Seed maturity indices in Aisandra butyracea--a multipurpose tree species of lower Himalaya.

Fruits of Aisandra butyracea (Roxb.) Lamb. were collected from two sites located at different altitudes in Kumaun Himalaya for analyzing the seed maturity in relation to various fruit and seed characters. The mean seed size (length x width) across the collection dates varied between 186.44 +/- 0.05 and 238.17 +/- 0.5 mm2 across both the elevations. The fruit colour changed from dark green in the beginning to pale yellow on the maturity. The range of seed moisture content (62.83 +/- 1.33 to 63.46 +/- 0.89%) coincided with maximum germination. The colour change and seed moisture content appear to be the major indicators of seed maturation in A. butyracea.

Novel anti-inflammatory agents based on pyrazole based dimeric compounds; design, synthesis, docking and in vivo activity.

Series of pyrazole ester prodrugs analogues have been synthesized and found to contain highly potent inhibitors of the cyclooxygenase-2 (COX-2) enzyme. The paper describes synthesis of the target pyrazole analogues. The structure of the synthesized mutual ester prodrugs (6-8c) were confirmed by (1)H-, (13)C-NMR mass spectroscopy (MS) and their purity were ascertained by TLC and elemental analyses. The biological in vivo evaluation of these compounds in experimental models (carrageenan-induced oedema) proved the presence of anti-inflammatory activity. Docking studies into the catalytic site of COX-2 were used to identify potential anti-inflammatory lead compounds. One lead derivative was chosen endowed with good binding energies.

Pyrazolo[3,4-d]pyrimidinophanes: convenient synthesis of a new class of cyclophane and X-ray structure of the first representative.

A convenient synthesis of a new class of novel pyrazolo[3,4-d]pyrimidinophanes (four products, 41%), a new class of cyclophane, and X-ray structure of the first dissymmetrical [3.4]pyrazolo[3,4-d]pyrimidinophane (22%) are reported for the first time. The conformation of major syn product 6b is stabilized by weak pi-pi and O...Ar interactions.

Emerging trends in molecular recognition: utility of weak aromatic interactions.

Aromatic interactions play a vital role in chemistry and biology. As about 20% are aromatic in nature, so the role of aromatic interactions become prominent in drug receptor interactions. Not only in drug receptor interactions but also in crystal engineering, protein folding, stacking interactions in DNA/RNA the role of the interactions is of utmost importance. With the emergence of supramolecular chemistry dendrimers, tweezers, rotaxanes, catenanes, and several supramolecular aggregates are associated with aromatic interactions. The mechanism of such interactions is still unknown by the replacement of a small substituent from the aromatic molecule may lead or destroy the interactions. In the present review several models are being discussed with arene interactions under selected heads.