Search

Objective: To evaluate the effect of trigonelline on bleomycin-induced idiopathic pulmonary fibrosis (IPF) and to explore its underlying mechanisms using network pharmacology. Methods: IPF was induced in C57BL/6 mice by a single intratracheal instillation of bleomycin (5 mg/kg). Trigonelline was administered at doses of 25, 50, and 100 mg/kg/day orally from the 2nd day post-bleomycin induction up to the 14th day. In IPF-induced mice, lung coefficient, immune cell infiltration in bronchoalveolar lavage fluid, and oxidative stress were measured. Histological alterations in lung tissues were also assessed. Moreover, network pharmacology approach was conducted to reveal molecular interactions of bleomycin and trigonelline with targets of IPF. Results: Trigonelline treatment reduced bleomycin-induced oxidative stress and immune cell infiltration, and mitigated physiological changes in the lung tissues of mice. Moreover, trigonelline alleviated bleomycin-induced histological alterations in lung tissues. Network pharmacology analysis showed that bleomycin and trigonelline interacted with IPF targets, such as NFKB1, HDAC2, HIF1A, and TLR4. Conclusions: The interaction of trigonelline with key IPF targets and its ameliorative effects on lung damage and oxidative stress highlight its potential in treating IPF. It may be considered an antifibrotic agent for further clinical development.

The chlorpyrifos-mineralizing rice root endophyte Enterobacter sp. HSTU-ASh6 strain was identified, which enormously enhanced the growth of tomato plant under epiphytic conditions. The strain solubilizes phosphate and grew in nitrogen-free Jensen’s medium. It secreted indole acetic acid (IAA; 4.8 mg/mL) and ACC deaminase (0.0076 μg/mL/h) and hydrolyzed chlorpyrifos phosphodiester bonds into 3,5,6-trichloro-2-pyridinol and diethyl methyl-monophosphate, which was confirmed by Gas Chromatography – Tandem Mass Spectrometry (GC–MS/MS) analysis. In vitro and in silico (ANI, DDH, housekeeping genes and whole genome phylogenetic tree, and genome comparison) analyses confirmed that the strain belonged to a new species of Enterobacter. The annotated genome of strain HSTU-ASh6 revealed a sets of nitrogen-fixing, siderophore, acdS, and IAA producing, stress tolerance, phosphate metabolizing, and pesticide-degrading genes. The 3D structure of 28 potential model proteins that can degrade pesticides was validated, and virtual screening using 105 different pesticides revealed that the proteins exhibit strong catalytic interaction with organophosphorus pesticides. Selected docked complexes such as α/β hydrolase–crotoxyphos, carboxylesterase–coumaphos, α/β hydrolase–cypermethrin, α/β hydrolase–diazinon, and amidohydrolase–chlorpyrifos meet their catalytic triads in visualization, which showed stability in molecular dynamics simulation up to 100 ns. The foliar application of Enterobacter sp. strain HSTU-ASh6 on tomato plants significantly improved their growth and development at vegetative and reproductive stages in fields, resulting in fresh weight and dry weight was 1.8–2.0-fold and 1.3–1.6-fold higher in where urea application was cut by 70%, respectively. Therefore, the newly discovered chlorpyrifos-degrading species Enterobacter sp. HSTU-ASh6 could be used as a smart biofertilizer component for sustainable tomato cultivation.

Background: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. Material and Method: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17a to AR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. Result: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20 mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25 μg/mL for inhibition of bacteria by most of the compounds. Conclusion: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections. Keywords: Imidazothiazole, Fluoroquinolone, Anti-Inflammatory, Antibacterial, MIC

A major global health risk has been witnessed with the development of drug-resistant bacteria and multidrug-resistant pathogens linked to significant mortality. Coumarins are heterocyclic compounds belonging to the benzophenone class enriched in different plants. Coumarins and their derivatives have a wide range of biological activity, including antibacterial, anticoagulant, antioxidant, anti-inflammatory, antiviral, antitumour, and enzyme inhibitory effects. In the past few years, attempts have been reported towards the optimization, synthesis, and evaluation of novel coumarin analogues as antimicrobial agents. Several coumarin-based antibiotic hybrids have been developed, and the majority of them were reported to exhibit potential antibacterial effects. In the present work, studies reported from 2016 to 2020 about antimicrobial coumarin analogues are the focus. The diverse biological spectrum of coumarins can be attributed to their free radical scavenging abilities. In addition to various synthetic strategies developed, some of the structural features include a heterocyclic ring with electron-withdrawing/donating groups conjugated with the coumarin nucleus. The suggested structure−activity relationship (SAR) can provide insight into how coumarin hybrids can be rationally improved against multidrug-resistant bacteria. The present work demonstrates molecular insights for coumarin derivatives having antimicrobial properties from the recent past. The detailed SAR outcomes will benefit towards leading optimization during the discovery and development of novel antimicrobial therapeutics.

Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016–2020. The structure–activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.

Pharmacophore modeling studies were undertaken for a series of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors. A five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), and two aromatic rings (R) as pharmacophore features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r2 = 0.8621 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of q2 = 0.6943 and for a test set of compounds. Furthermore, the structure–activity relationships of quinoline derivatives as VEGFR-2 tyrosine kinase inhibitors were elucidated and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds were docked into the active site of the VEGFR-2 crystal structure to analyze drug-receptor interactions. Further we analyzed all the compounds for Lipinski’s rule of five to evaluate drug likeness and established in silico ADME parameters using QikProp. The results provide insights that will aid the optimization of these classes of VEGFR-2 inhibitors for better activity, and may prove helpful for further lead optimization and virtual screening.

In the present study, a series of imidazo[2,1-b][1,3,4]thiadiazole derivatives 5(a–j) were synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectral technique. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by using Alamar Blue susceptibility test as part of the TAACF TB screening program under direction of the US National Institutes of Health, the NIAID division. Among the tested compounds, 2-(1-methyl-1H-imidazol-2-yl)-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazole (5f) has shown the highest (98%) inhibitory activity with MIC of 3.14 μg/ml as compared to other tested compounds. Further, some potent compounds were also assessed for their cytotoxic activity against a mammalian Vero cell line using MTT assay. The results reveal that these compounds exhibit anti-tubercular activity at non-cytotoxic concentrations.

A series of 1,3,4-thiadiazole derivatives of 2-(4-formyl-2-methoxyphenoxy) acetic acid (6a–s) were synthesized by cyclization of carboxylic acid group of 2-(2-methoxy-4-(3-oxo-3-substituted phenylprop-1-enyl)phenoxy) acetic acid (4a–s) with thiosemicarbazide in the presence of POCl3 or PPA. The structures of the compounds were confirmed by IR, 1H NMR and mass analysis. All the compounds have been evaluated in vitro for their antimicrobial activities against several strains of microbes and show significant activity.

With the aim of producing new biologically active compounds, a series of New Pyridine Imidazo [2,1b]-1,3,4-thiadiazole derivatives 4(a–k) were synthesized. All the compounds were characterized via IR, 1H-NMR and Mass spectral studies. The antimicrobial activity of newly synthesized compounds against various bacteria; Bacillus pumillus, Staphylococcus aureus, Vibrio cholera, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, and fungi; Candida albicans were evaluated. Among the compounds tested, 4(a), 4(b), 4(f), 4(h) and 4(k) exhibited good antimicrobial activity while others responded moderately with reference to standard drugs ampicillin and amphotericin B.

A new stability-indicating reversed-phase high-performance thin-layer chromatographic (RP-HPTLC) method for densitometric analysis of thiocolchicoside was developed and validated. The chromatograms were developed using aluminum plates pre-coated with silica gel 60 RP-18 F254S as a stationary phase and methanol : water (70 : 30 ) as a mobile phase. The compact band for thiocolchicoside was observed at value of at an absorption wavelength of 377 nm. The linear regression data for the calibration plots () was found with respect to peak area in the concentration range of 100–600 ng per band. The limit of detection (LOD) and limit of quantification (LOQ) were 9.77 ng and 29.63 ng, respectively. The drug was exposed to acidic and alkaline hydrolysis, oxidation, photo degradation, and dry heat conditions. The peaks of degradation products were well-resolved from the peak of the standard drug with significantly different values. Statistical analysis proved that the established RP-HPTLC method is reproducible, selective, and accurate for the determination of thiocolchicoside in its formulations. The method can effectively separate the drug from its degradation products, and it can be considered as stability-indicating assay.

Pentacyclic Triterpenoids (PTs) and their analogues as well as derivatives are emerging as important drug leads for various diseases. They act through a variety of mechanisms and a majority of them inhibit the nuclear factor kappa-beta (NF-κB) signaling pathway. In this study, we examined the effects of the naturally occurring PTs on IκB kinase-β (IKKβ), which has great scientific relevance in the NF-κB signaling pathway. On virtual screening, 109 PTs were screened through the PASS (prediction of activity spectra of substances) software for prediction of NF-κB inhibitory activity followed by docking on the NEMO/IKKβ association complex (PDB: 3BRV) and testing for compliance with the softened Lipinski's Rule of Five using Schrodinger (LLC, New York, USA). Out of the projected 45 druggable PTs, Corosolic Acid (CA), Asiatic Acid (AA) and Ursolic Acid (UA) were assayed for IKKβ kinase activity in the cell free medium. The UA exhibited a potent IKKβ inhibitory effect on the hotspot kinase assay with IC50 of 69 μM. Whereas, CA at 50 μM concentration markedly reduced the NF-κB luciferase activity and phospho-IKKβ protein expressions. The PTs tested, attenuated the expression of the NF-κB cascade proteins in the LPS-stimulated RAW 264.7 cells, prevented the phosphorylation of the IKKα/β and blocked the activation of the Interferon-gamma (IFN-γ). The results suggest that the IKKβ inhibition is the major mechanism of the PTs-induced NF-κB inhibition. PASS predictions along with in-silico docking against the NEMO/IKKβ can be successfully applied in the selection of the prospective NF-κB inhibitory downregulators of IKKβ phosphorylation.