Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer.

Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.

Peptides and peptidomimetics as a therapeutic candidate for the treatment of COVID-19: A brief review.

Novel SARS-CoV-2 (COVID-19) is affecting worldwide as declared pandemic by the WHO. Various repositioning and novel therapeutic agents are being evaluated under different clinical setups; however, there is no promising therapeutic agent reported to date. Small molecules like peptides have their popularity as their specificity, delivery, and synthesizability as promising therapeutic agents. In this study, we have reviewed the published literature describing peptide designing, in silico binding mode, antiviral activity, preventive measures, and in vivo assessments. Here, we reported all the results which are promising against SARS-CoV-2 as therapeutic and preventive (vaccine candidates), and their status in the drug development process.

Efficacy and safety of inhaled nitric oxide in the treatment of severe/critical COVID-19 patients: A systematic review.

OBJECTIVE: Present systematic review aimed to analyze the effect of inhaled nitric oxide (iNO) in the treatment of severe COVID-19 and to compare it to standard of care (SOC), antiviral medications, and other medicines. MATERIALS AND METHODS: Medline (PubMed), Scopus, Embase, Ovid, Web of Science, Science Direct, Wiley Online Library, BioRxiv and MedRxiv, and Cochrane (up to April 20, 2021) were the search databases. Two reviewers (SK and CK) independently selected the electronic published literature that studied the effect of nitric oxide with SOC or control. The clinical and physiological outcomes such as prevention of progressive systemic de-oxygenation/clinical improvement, mortality, duration of mechanical ventilation, improvement in pulmonary arterial pressure, and adverse events were assessed. RESULTS: The 14 retrospective/protective studies randomly assigning 423 patients met the inclusion criteria. Cumulative study of the selected articles showed that iNO has a mild impact on ventilation time or ventilator-free days. iNO has increased the partial pressure of oxygen/fraction of inspired oxygen ratio of fraction of inspired oxygen in a few patients as compared to baseline. However, in most of the studies, it does not have better outcome when compared to the baseline improvement. CONCLUSIONS: In patients with COVID-19 with acute respiratory distress syndrome, nitric oxide is linked to a slight increase in oxygenation but has no effect on mortality.

COVID-19 pandemic: A review based on current evidence.

In December 2019, severe acute respiratory syndrome-coronavirus-2, a novel coronavirus, initiated an outbreak of pneumonia from Wuhan in China, which rapidly spread worldwide. The clinical characteristics of the disease range from asymptomatic cases or mild symptoms, which include nonspecific symptoms such as fever, cough, sore throat, headache, and nasal congestion to severe cases such as pneumonia, respiratory failure demanding mechanical ventilation to multi-organ failure, sepsis, and death. As the transmission rate is quite alarming, we require an effective therapeutic strategy to treat symptomatic patients and adopt the preventive measures in order to contain the infection and prevent community transmission. Coronavirus disease 2019 (COVID-19) pandemic is a public health emergency of international concern, hence repurposing of the drugs is an attractive and a feasible option because PK/PD profile, toxicity profile, and drug interactions are already known. This review emphasizes on the different aspects of COVID-19 such as the epidemiology, etiopathogenesis, diagnosis, and preventive measures to be adopted in order to fight this pandemic. It also highlights upon the ethics preparedness and challenges faced by a developing country like India during such an outbreak. The review focuses on the various approaches adopted till date for developing effective therapeutic strategies including combination of drugs, vaccine therapy, and convalescent plasma therapy to combat this viral outbreak.

Modification of the lead molecule: Tryptophan and piperidine appended triazines reversing inflammation and hyeperalgesia in rats.

The structural optimization of the molecules making them to fit into the active site pocket of COX-2 occupying the same space as covered by the natural substrate arachidonic acid helped in the emergence of compound 10 as an efficacious anti-inflammatory agent. Selective for COX-2 over COX-1, compound 10 exhibited IC50 0.02 µM for COX-2 and reversed acetic acid induced inflammation in rats by 73% when used at 10 mg kg-1 dose and the same dose of the compound also rescued the animals from inflammatory phase of formalin induced hyperalgesia. As evidenced by the results of molecular modeling studies supported by the nuclear Overhauser enhancement data, the appropriate geometry of the molecule in the active site pocket of COX-2 contributing to its H-bond/hydrophobic interactions with Ser530, Trp387 and Tyr385 seems responsible for the enzyme inhibitory activity of the compound.

Tailoring the Substitution Pattern on 1,3,5-Triazine for Targeting Cyclooxygenase-2: Discovery and Structure-Activity Relationship of Triazine-4-Aminophenylmorpholin-3-one Hybrids that Reverse Algesia and Inflammation in Swiss Albino Mice.

Here, we report analgesic and anti-inflammatory activity of a series of compounds obtained by appending 4-aminophenylmorpholin-3-one and acyclic, cyclic, or heterocyclic moieties on 1,3,5-triazine. The structures of compounds 4b and 6b are optimized for the best inhibition of COX-2 with IC50 values of 0.06 and 0.08 µM, respectively, and selectivity over COX-1 of 166 and >125, respectively. At the dose of 5 mg kg-1, these compounds significantly reduced acetic acid induced writhings, and their ED50 values were found to be 2.2 and 1.9 mg kg-1, respectively. Besides the cell-based and animal-based experiments showing the modes of action of these compounds targeting COX-2, the interaction behavior of 4b with COX-2 was also characterized, with physicochemical experiments including ITC, NMR, UV-vis, and molecular-modeling studies. Characteristically, these compounds interact with R120, Y355, and W385, the residues responsible for holding the substrate and mediating the process of electron transfer during the metabolic phase of the enzyme.

Design and Synthesis of Aza-/Oxa Heterocycle-Based Conjugates as Novel Anti-Inflammatory Agents Targeting Cyclooxygenase-2.

A library of hybrid molecules was procured by the combination of triazine-indole adduct with morpholine/piperidine/pyrrolidine and pyrazole/pyrimidine/oxindole moieties. Enzyme immunoassays on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) identified compound 6 having an IC50 value of 20 nM for COX-2 and 3000 nM for COX-1. The significant reduction in the formation of prostaglandin E2 in the lipopolysaccharide-treated (COX-2-activated) human whole blood, almost no change in the production of thromboxane B2 in the calcium ionophore-treated (COX-1-activated) sample of human whole blood, and the mechanistic studies on Swiss albino mice ensured that compound 6 is selective for COX-2. The association constant (Ka) of compound 6 with COX-2 was found to be of the order of 0.48 × 106 M-1. The diffusion spectroscopy experiments and relaxation time (T1) calculations of compound 6 in the presence of COX-2 assisted in identifying the site-specific interactions of 6 with the enzyme, and these results fall into nice correlation with the theoretical data obtained from molecular docking and quantitative structure-activity relationship studies. With maximum tolerable dose >2000 mg kg-1, compound 6 made 68 and 32% reduction in formalin-induced analgesia and carrageenan-induced inflammation in Swiss albino mice.

A note on mixed coccidian and Capillaria infection in pigeons.

Two adult pigeons were presented to the Teaching Veterinary Hospital (TVH), GADVASU, Ludhiana, Punjab with the history of weakness, anorexia, ruffled feathers and intermittent diarrhoea. Coproscopic examination revealed the presence of coccidian oocysts alongside eggs of Capillaria spp. Based on the morphological characters the eggs were designated as C. obsignata. Sporulation studies on the coccidian oocysts revealed mixed infection of Eimeria columbae and E. columbarum.

TNF-α and IL-6 inhibitors: Conjugates of N-substituted indole and aminophenylmorpholin-3-one as anti-inflammatory agents.

The conjugates obtained by the combination of indole and aminophenyl morpholinone were screened for TNF-α and IL-6 inhibition in microglial cells. Compound 4 was found to be the most potent anti-inflammatory agent as it reduced LPS induced level of inflammatory cytokines TNF-α and IL-6 by 71% and 53%, respectively. A significant decrease in NO and MMPs release from BV2 cells in culture pretreated with this compound as well as inhibition of nuclear translocation of NF-κB and AP-1 was observed. 75% inhibition of acetic acid induced algesia in swiss albino mice was noticed in the presence of compound 4. Experimental data and molecular docking studies indicate that the compounds are targeting TNF-α, iNOS and IL-6.

Rational modification of the lead molecule: Enhancement in the anticancer and dihydrofolate reductase inhibitory activity.

By using molecular docking studies, the practice of fragment based drug discovery is conceptualized by introducing oxindole and iso-propanol moieties in our previous lead molecule 1. The resulting compound 2 exhibited competitive inhibition and favorable Ka and Ki for hDHFR. The screening of compound 2 at 60 cell line panel of human tumor cell lines showed its considerably better efficacy than compound 1 and hence put the candidature of 2 on stronghold for further studies.

Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent.

Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg(-1) dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 10(4) M(-1) and ΔG of -100.3 kJ mol(-1) in comparison to a Ka 0.41 × 10(3) ± 0.09 M(-1) and ΔG of -19.2 ± 0.06 kJ mol(-1) for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg(-1) dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.

The bioinspired design of a reagent allows the functionalization of Cα-H of α,ß-unsaturated carbonyl compounds via the Baylis-Hillman chemistry under ambient conditions.

A rationally designed reagent capable of affecting alkylation at Cα of α,ß-unsaturated carbonyl compounds is reported. The reaction proceeded at room temperature without any additives. The pH and H-bond formation during the reaction play a key role in the working of the reagent.

Correction: Thymidylate synthase inspired biomodel reagent for the conversion of uracil to thymine.

Correction for 'Thymidylate synthase inspired biomodel reagent for the conversion of uracil to thymine' by Palwinder Singh et al., Chem. Commun., 2015, 51, 9961-9964.

Thymidylate synthase inspired biomodel reagent for the conversion of uracil to thymine.

Inspired by TSase catalysis for dUMP conversion to dTMP, a biomodel reagent is developed. The presence of NH2, Gly-(S)-Cys and (S)-oxiran methyl, at C5, C4 and N-10 of acridine, respectively, in addition to the pH of the reaction mixture, allows for good complementary inter- and intra-molecular interactions and chiral discrimination for the reagent to achieve conversion of uracil to thymine.

Strategically designed biomodel: engineering C3-C4 cleavage of D-fructose.

Amongst a library of aldolase inspired, rationally designed compounds, the acridine derivative carrying a (S)-Tyr-Gly-(S)-Lys tripeptide selectively effected C3-C4 scissoring of D-fructose and produced D-glyceraldehyde and dihydroxyacetone.

Transformation of gas-phase amino acid clusters to dipeptides: a nice approach to demonstrate the formation of prebiotic peptides.

RATIONALE: Exploring prebiotic developments is a fascinating area of research which is continually drawing the attention of the scientific community. It is probable that first the biomolecules were formed and then they became aggregated to generate life. Formation of one such biomolecules (peptide ions) is shown in the present experiments. METHODS: All amino acid solutions for recording mass spectra were prepared in 3:6.9:0.1 (v/v/v) acetonitrile/water/formic acid at a concentration of 50 µM. The studies were performed using a Bruker MicroTOF QII mass spectrometer. Before carrying out experiments in the collision cell, atmospheric pressure in-source fragmentations were also performed. The formation of different chemical species was detected with high-resolution mass spectrometry. RESULTS: Here, we show experimentally the formation of amino acid cluster ions of varied populations, when a solution of an amino acid was injected into an electrospray ionization quadrupole time-of-flight (ESI-QTOF) mass spectrometer. During in-source fragmentation/collision cell fragmentation, the non-covalent interaction between two identical amino acids forms either the [M2 + H](+) dimer cluster ion and/or the [M2 + K](+) adduct ion which, by elimination of one molecule of water, form the covalent linked dipeptide. CONCLUSIONS: After the formation of the amino acid cluster, it was established that the creation of the dipeptides, by a covalent bond resulting from the loss of a water molecule, was the initial step towards the formation of the primordial peptides.