Parasuraman Jaisankar

Tilorone, a 9-fluorenone scaffold-based molecule, is a known broad-spectrum antiviral with an IC₅₀ of 180 nM against SARS-CoV-2, but its mechanism is not known. In the present study, we found it to have weak activity against PLpro (IC₅₀ = 30.7 ± 7.5 μM) and was inactive against Mpro. Several sulfonamide derivatives of 9-fluorenone, having the same scaffold as tilorone, were synthesized based on our in-silico studies to enhance their protease activity. They were evaluated for their inhibitory potential for targeting SARS-CoV-2 Mpro (main protease) and PLpro (papain-like protease) using FRET-based high-throughput screening and gel-based assays. Among the derivatives, 3e exhibited dual inhibition against Mpro (IC₅₀ = 23 ± 3.4 μM) and PLpro (IC₅₀ = 6.33 ± 0.5 μM), while 3h selectively inhibited PLpro (IC₅₀= 5.94 ± 1.0 μM). Both 3e and 3h suppressed SARS-CoV-2 replication with IC₅₀ values of 13.4 ± 0.28 μM and 18.2 ± 3.2 μM, respectively. Molecular docking and dynamics studies revealed that the NO₂ group in 3h enhances the rigidity of the BL2 loop of PLpro, contributing to its higher PLpro activity. Both 3e and 3h showed antiviral activity comparable with standard alpha-ketoamide inhibitor (13b-K) in cell-based assays and were non-cytotoxic with acceptable selectivity indices (S.I. > 5.5). These findings suggest that 9-fluorenone-based sulfonamides, particularly 3e and 3h, may be promising candidates as dual or selective protease inhibitors against SARS-CoV-2. Graphical abstract 9-Fluorenone sulfonamides (3e, 3h) derived from tilorone inhibit SARS-CoV-2 proteases, suppress viral replication, and exhibit strong antiviral activity.

The amyloid-beta 42 (Aβ₄₂) peptide assembles into neurotoxic soluble oligomers and extracellular fibrillary aggregates during the progression of Alzheimer's disease (AD), which ultimately leads to amyloid plaque in the brain, causing major disruption of the neural circuit and leading to the severe loss of memory. Thus, perturbation or inhibition of this process through the development of advanced inhibitors is crucial for the treatment of AD. Here, we adopted an advanced strategy that showcases the design of a carbazole-based chemical inhibitor targeting the Aβ peptide. The new inhibitors are designed in such a way that they can bind selectively with the Aβ₄₂ peptide and inhibit the assembly process and disease progression. Initial assessments using the thioflavin-T assay and molecular docking experiments help screen the carbazole and theophylline-based CT-01 as effective lead molecules, which bind at the N-terminal hydrophobic region of the Aβ₄₂ peptide and inhibit the formation of soluble oligomers and extracellular fibrillary aggregates. Further, FT-IR spectroscopy, CD, TEM, dot blot, and ITC experiments suggest the inhibition potency of CT-01. Finally, the neuroprotection and apoptosis assay confirm that CT-01 reduces amyloid-mediated toxicity in neurons. The serum-stable CT-01 can also protect the NGF-deprived neurons and has the ability to cross the blood-brain barrier.

Small-molecule fluorescence probes capable of migrating between subcellular organelles under varying cellular conditions are essential tools for investigating live cell events. In this work, we present TNK-01, synthesized from pyridinium salt and indole derivatives known for their affinity to nucleic acids and ability to target mitochondria. TNK-01 exhibits migration from mitochondria to the nucleolus upon continuous light irradiation, driven by its differential binding affinities for the negatively charged mitochondrial membrane and RNA. The photo-triggered migration of TNK-01 is enhanced by its RNA binding affinity, resulting in an approximate 32-fold increase in fluorescent signal with selectivity for RNA over DNA. Furthermore, TNK-01 demonstrates stable emission across a pH range of 3 to 8, allowing for effective monitoring of translocation across various cell lines. Its large Stokes shift, high photostability, wash-free imaging, and low cytotoxicity make TNK-01 a promising tool for cellular imaging in live cells. This photo-triggered indole-based fluorescent probe enables new research in mitochondrial studies and organelle communication, which are increasingly important for understanding metabolism and disease progression.

A new synthetic strategy for the construction of C2‐quaternary indole for the formation of Indolin‐3‐ones has been explored via indium(III) trifluoromethansulphonate catalyst at room temperature with TBHP as a green oxidant in water. This approach for the oxidative dearomatization process allows for the production of the natural product Halichrome A and a broad range of C2‐arylated Indolin‐3‐ones under a milder condition in very good yields. The oxidative self‐dimerization and self‐trimerization of various indole derivatives have also been achieved under the same conditions.

Indomethacin, a known nonsteroidal anti-inflammatory drug (NSAID) induces gastric inflammation, causing degradation of the extracellular matrix by specific matrix metalloproteinases (MMPs). We investigated the antiulcer efficacy of 3-indolyl furanoids (3g and 3c, i.e., methoxy substitution at 4- and 5-positions of the indole ring, respectively), derived from indomethacin. Interestingly, 3g protected against indomethacin-induced gastropathy in vivo by inhibiting MMP-9. Our work established a chemical modification strategy for the development of safer NSAIDs. Moreover, in vitro and in silico studies confirmed that 3g inhibited MMP-9 activity with an IC₅₀ value of 50 μM by binding to the catalytic cleft of MMP-9, leading to ulcer prevention. Pharmacokinetics was presented as the mean concentration-time profile in the rat plasma, and the extraction efficiency was greater than 70%, showing a C_max of 104.48 μg/mL after 6.0 h (t_max) treatment with half-life and area under the curve being 7.0 h and 1273.8 h μg/mL, respectively, indicating the higher antiulcer potency of 3g.

Corrigendum: Standardised Sonneratia apetala Buch.-Ham. fruit extract inhibits human neutrophil elastase and attenuates elastase-induced lung injury in mice

Chronic obstructive pulmonary disease (COPD) along with asthma is a major and increasing global health problem. Smoking contributes to about 80%–90% of total COPD cases in the world. COPD leads to the narrowing of small airways and destruction of lung tissue leading to emphysema primarily caused by neutrophil elastase. Neutrophil elastase plays an important role in disease progression in COPD patients and has emerged as an important target for drug discovery. Sonneratia apetala Buch.-Ham. is a mangrove plant belonging to family Sonneratiaceae. It is widely found in the Sundarban regions of India. While the fruits of this plant have antibacterial, antifungal, antioxidant and astringent activities, fruit and leaf extracts have been shown to reduce the symptoms of asthma and cough. The aim of this study is to find whether hydro alcoholic fruit extracts of S. apetala inhibit neutrophil elastase and thus prevent the progression of neutrophil elastase-driven lung emphysema. The hydroalcoholic extract, ethanol: water (90:10), of the S. apetala Buch.-Ham. fresh fruits (SAM) were used for neutrophil elastase enzyme kinetic assay and IC₅₀ of the extract was determined. The novel HPLC method has been developed and the extract was standardized with gallic acid and ellagic acid as standards. The extract was further subjected to LC-MS² profiling to identify key phytochemicals. The standardized SAM extract contains 53 μg/mg of gallic acid and 95 μg/mg of ellagic acid, based on the HPLC calibration curve. SAM also reversed the elastase-induced morphological change of human epithelial cells and prevented the release of ICAM-1 in vitro and an MTT assay was conducted to assess the viability. Further, 10 mg/kg SAM had reduced alveolar collapse induced by neutrophil elastase in the mice model. Thus, in this study, we reported for the first time that S. apetala fruit extract has the potential to inhibit human neutrophil elastase in vitro and in vivo.

A green approach, catalyzed by the catecholase enzyme obtained from sweet potato, to generate bioactive wedelolactone and many of its analogs which are useful precursors for a variety of coumestan-based natural products.