Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.

A series of potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors (hnNOS), based on a difluorobenzene ring linked to a 2-aminopyridine scaffold with different functionalities at the 4-position, is reported. In our efforts to develop novel nNOS inhibitors for the treatment of neurodegenerative diseases, we discovered 17, which showed excellent potency toward both rat (Ki 15 nM) and human nNOS (Ki 19 nM), with 1075-fold selectivity over human eNOS and 115-fold selectivity over human iNOS. 17 also showed excellent permeability (Pe = 13.7 × 10-6 cm s-1), a low efflux ratio (ER 0.48), along with good metabolic stability in mouse and human liver microsomes, with half-lives of 29 and >60 min, respectively. X-ray cocrystal structures of inhibitors bound with three NOS enzymes, namely, rat nNOS, human nNOS, and human eNOS, revealed detailed structure-activity relationships for the observed potency, selectivity, and permeability properties of the inhibitors.

Noscapine-Amino Acid Conjugates Suppress the Progression of Cancer Cells.

Lung cancer is the leading cause of cancer deaths globally; 1 in 16 people are diagnosed with lung cancer in their lifetime. Microtubules, a critical cytoskeletal assembly, have an essential role in cell division. Interference with the microtubule assembly leads to genetic instability during mitosis and cancer cell death. Currently, available antimitotic drugs such as vincas and taxanes are limited due to side effects such as alopecia, myelosuppression, and drug resistance. Noscapine, an opium alkaloid, is a tubulin-binding agent and can alter the microtubule assembly, causing cancer cell death. Amino acids are fundamental building blocks for protein synthesis, making them essential for the biosynthesis of cancer cells. However, the ability of amino acids in drug transportation has yet to be exploited in developing noscapine analogues as a potential drug candidate for cancer. Hence, in the present study, we have explored the ninth position of noscapine by introducing a hydroxymethylene group using the Blanc reaction and further coupled it with a series of amino acids to construct five target conjugates in good yields. The synthesized amino acid conjugate molecules were biologically evaluated against the A549 lung cancer cell line, among which the noscapine-tryptophan conjugate showed IC50 = 32 µM, as compared to noscapine alone (IC50 = 73 µM). Morphological changes in cancer cells, cell cycle arrest in the G1 phase, and ethidium bromide/acridine orange staining indicated promising anticancer properties. Molecular docking confirmed strong binding to tubulin, with a score of -41.47 kJ/mol with all 3D coordinates and significant involvement of molecular forces, including the hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations demonstrated a stable binding of noscapine-tryptophan conjugate for a prolonged time (100 ns) with the involvement of free energy through the reaction coordinates analyses, solving the bioavailability of parent noscapine to the body.

Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis.

Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.

A comprehensive review on potential therapeutics interventions for COVID-19.

COVID-19 is an infectious respiratory disease caused by SARS-CoV-2, a new beta coronavirus that emerged in Wuhan, China. Being primarily a respiratory disease, it is highly transmissible through both direct and indirect contacts. It displays a range of symptoms in different individuals and thus has been grouped into mild, moderate, and severe diseases. The virus utilizes spike proteins present on its surface to recognize ACE-2 receptors present on the host cells to enter the cell cytoplasm and replicate. The viral invasion of cells induces damage response, pyroptosis, infiltration of immune cells, expression of pro-inflammatory cytokines (cytokine storm), and activation of the adaptive immune system. Depending on viral load and host factors like age and underlying medical conditions, the immune responses mounted against SARS-CoV-2 may cause acute respiratory distress syndrome (ARDS), multiple organ failure, and death. In this review, we specify and justify both viral and host therapeutic targets that can be modulated to relieve the symptoms and treat the disease. Furthermore, we discuss vaccine development in the time of pandemic and the most promising vaccine candidates by far, according to WHO database. Finally, we discuss the conventional re-purposed drugs and potential alternative treatments as adjuvants.

Recent advancements in synthetic methodologies of 3-substituted phthalides and their application in the total synthesis of biologically active natural products.

We have provided a critical review that focuses on key developments in the area of 3-substituted phthalides and their role in the development of important biologically active natural products. 3-Substituted phthalides are vital molecules owing to their fascinating biological activity. The scope, isolation, and characterization of various naturally occurring racemic and chiral 3-substituted phthalides have been covered. We have put significant emphasis on recently developed research methodologies for the synthesis of racemic and chiral 3-substituted phthalides. These newer approaches are essential for the development of newer and elegant strategies for the synthesis of phthalide-based or similar molecular architecture with broader substrate scope and higher stereoselectivities. Also, we have discussed the application of 3-substituted phthalides as a precursor for the synthesis of natural products and their analogs.

MoS4 2- intercalated NiFeTi LDH as an efficient and selective adsorbent for elimination of heavy metals.

The enormous increase of heavy metal pollution has led to a rise in demand for synthesizing efficient and stable adsorbents for its treatment. Therefore, we have designed a novel adsorbent by introducing (MoS4)2- moieties within the layers of NiFeTi LDH-NO3, via an ion exchange mechanism, as a stable and efficient adsorbent to deal with the increasing water pollution due to heavy metals. Characterization techniques such as XRD, FTIR, TGA, SEM, TEM, and Raman spectroscopy were used to confirm the formation of (MoS4)2- intercalated NiFeTi LDH and structural changes after the adsorption process. The efficiency of the material was tested with six heavy metal ions, among which it was found to be effective for toxic Pb2+ and Ag+ ions. When selectivity was studied with all six of the metal ions copresent in one solution, the material showed greater selectivity for Pb2+ and Ag+ ions with the selectivity order of Ni2+ < Cu2+ < Zn2+ < Fe3+ < Pb2+ < Ag+, with great adsorption capacities of 653 mg g-1 for Pb2+ and 856 mg g-1 for Ag+ metal ions. Further, the kinetics adsorption study for both the metal ions had a great correlation with the pseudo-second-order model and supported the chemisorption process via the formation of M-S bonding. The adsorption process obeyed the Langmuir model. Therefore, the MoS4-LDH material could be a promising adsorbent for the removal of heavy metals.

Calcined Layered Double Hydroxides: Catalysts for Xanthene, 1,4-Dihydropyridine, and Polyhydroquinoline Derivative Synthesis.

This work is generally focused on the synthesis of NiFeTi-layered double hydroxides (LDHs) using a hydrothermal route, which were calcined at various temperatures (varying from 200 to 600 °C). The synthesized materials were physicochemically characterized. X-ray diffraction results revealed the loss of the layered structure on calcination resulting in the formation of layered double oxides (LDOs) or mixed metal oxides, which was also supported by Fourier transform infrared studies. Scanning electron microscopy results also show loss of the layered structure and the creation of LDOs on increasing the temperature. These LDOs were tested as the catalysts for the synthesis of biologically significant xanthene, 1,4-dihydropyridine, and polyhydroquinoline derivatives. Among all, NiFeTi LDH calcined at 600 °C proved to be the best catalyst for the synthesis of these derivative compounds under optimized conditions. The advantages obtained were excellent yields in a lesser reaction time. Stability and reusability were also assessed; the catalyst was stable even after five cycles. Furthermore, the memory effect of the obtained NiFeTi CLDH calcined at 600 °C confirms that the material so formed is a calcined state of LDH itself. High catalytic efficiency, easy fabrication, and recycling ability of NiFeTi CLDH calcined at 600 °C make it a potential catalyst for the synthesis of xanthene, 1,4-dihydropyridine, and polyhydroquinoline derivatives.

Fabrication of a Gold-Supported NiAlTi-Layered Double Hydroxide Nanocatalyst for Organic Transformations.

This work is mainly focused on the synthesis of an efficient and reusable heterogeneous Au/NiAlTi layered double hydroxide (LDH) nanocatalyst and its applications in the preparation of biologically important xanthene, 1,4-dihydropyridine, polyhydroquinoline, and 4H-pyran derivatives. NiAlTi LDH was designed hydrothermally and then gold was supported over the surface of LDH by using ion-exchange and NaBH4 reduction methods. The synthesized nanocatalyst was physicochemically characterized by X-ray diffractrometry, Fourier-transform infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy, and transmission electron microscopy (TEM). The TEM images confirmed the support of gold nanoparticles over the surface of LDH with a size distribution of 7-9 nm. The well-characterized nanocatalyst was tested for the synthesis of biologically important xanthene, 1,4-dihydropyridine, polyhydroquinoline, and 4H-pyran derivatives. The advantages obtained were excellent yields in a lesser reaction time. Stability and reusability were also accessed; the catalyst was stable even after five cycles. High catalytic efficiency, easy fabrication, and recycling ability of Au/NiAlTi LDH make it a potential catalyst for the synthesis of xanthene, 1,4-dihydropyridine, polyhydroquinoline, and 4H-pyran derivatives.

A new biocompatible ternary Layered Double Hydroxide Adsorbent for ultrafast removal of anionic organic dyes.

It would be of great significance to introduce a new biocompatible Layered Double Hydroxide (LDH) for the efficient remediation of wastewater. Herein, we designed a facile, biocompatible and environmental friendly layered double hydroxide (LDH) of NiFeTi for the very first time by the hydrothermal route. The materialization of NiFeTi LDH was confirmed by FTIR, XRD and Raman studies. BET results revealed the high surface area (106 m2/g) and the morphological studies (FESEM and TEM) portrayed the sheets-like structure of NiFeTi nanoparticles. The material so obtained was employed as an efficient adsorbent for the removal of organic dyes from synthetic waste water. The dye removal study showed >96% efficiency for the removal of methyl orange, congo red, methyl blue and orange G, which revealed the superiority of material for decontamination of waste water. The maximum removal (90%) of dyes was attained within 2 min of initiation of the adsorption process which supported the ultrafast removal efficiency. This ultrafast removal efficiency was attributed to high surface area and large concentration of -OH and CO32- groups present in NiFeTi LDH. In addition, the reusability was also performed up to three cycles with 96, 90 and 88% efficiency for methyl orange. Furthermore, the biocompatibility test on MHS cell lines were also carried which revealed the non-toxic nature of NiFeTi LDH at lower concentration (100% cell viability at 15.6 µg/ml). Overall, we offer a facile surfactant free method for the synthesis of NiFeTi LDH which is efficient for decontamination of anionic dyes from water and also non-toxic.

Designing of a Novel Indoline Scaffold Based Antibacterial Compound and Pharmacological Evaluation Using Chemoinformatics Approach.

Antibiotic resistance is not only a global public health threat but also a huge economic burden to our society that urgently needs to be addressed by improved antibiotics and continuing development of novel molecules to treat resistant bacterial infections. Nowadays combination therapies offer a competent approach to counteract antibiotic resistance in bacteria. Better knowledge of mechanisms of antibiotic resistance has lead to the finding of new alternatives to antibiotic therapy. Hence, in this article, we report a novel series of indoline derivatives and their computational study as potent antimicrobials. The present study investigates the indoline based derived library interaction with DNA gyrase B enzyme to be used as a potential antimicrobial drug. Computational approaches were employed to carry out the molecular interactions and pharmacological studies. In this study, we have compared indoline with its derivatives and have found that compound 13 (1m) resulted in the strong binding with the highest score (-9.02 kcal/mol) in the designed library where indoline showed (-6.43 kcal/mol). Furthermore, molecular dynamics simulation run also confirmed the strongest interaction of a compound and target protein with less RMSD and RMSF deviation of the complex. Notably, the compound was also found to possess the good pharmacological properties and pharmacokinetic properties.