Developments of pyridodipyrimidine heterocycles and their biological activities.

The entitled review aimed to assemble and highlight the synthetic approaches and biological aspects of heterocycles with pyridodipyrimidine motifs. The recent synthetic approaches were categorized according to the accomplishments of the approaches under catalyst or catalyst-free conditions. The topic involved the synthesis of substituted tricyclic systems and spirocyclic systems. The present study offered an overview of the recent literature in addition to a scope of the preceding literature. The proposed mechanisms of the varied target products were discussed. Pyridodipyrimidine displayed potential and privileged cytotoxic, antioxidant, and antimicrobial performances. The competitions, challenges, and prospects are also deliberated.

Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies.

Apparently, tubulin inhibitors binding to the colchicine-binding site (CBS) currently have outstanding attention for cancer treatment. So, a series of benzo[b]azonin-2-one derivatives having the same pharmacophoric features as colchicine binding site inhibitors (CBSIs) were synthesized targeting the CBS of ß-tubulin. The antiproliferative activities of the newly synthesized compounds were assessed against five different cancer cell lines; HepG-2, MCF-7, MDA-MB-231, HCT-116, and Caco-2. Compounds 7a and 7d displayed promising inhibitory activities against all tested cell lines. They were further estimated towards ß-tubulin at CBS along with colchicine (Col) as a reference drug. It was shown that the assessed candidates (7a and 7d) and Col exhibited CBSI activities of 5492, 3771, and 486c.p.m./mg protein, respectively, at a concentration of 10 µM. Furthermore, compound 7d was picked out to assess its effects on apoptosis and cell-cycle profile using Annexin V-FITC and PI staining assay. In addition, the apoptotic activity of 7d was investigated using gene expression analysis of apoptosis-related genes of P53, Bax, Caspases 3 and 9, and Bcl-2 in both treated and untreated cells. Moreover, compound 7d was further assessed through in vivo studies using solid Ehrlich carcinoma (SEC)-bearing mice. Furthermore, both molecular docking and molecular dynamics simulations (for 150 ns) were performed to investigate their mechanism of action as potential CBSIs and give more insights into the behavior of the examined candidates within the ß-tubulin subunit of the CBS. On the other hand, in silico ADMET studies were carried out to assess the pharmacokinetic features, drug/lead likeness, and toxicity parameters of the newly synthesized derivatives. Finally, to anticipate the possible changes in the antimitotic activities upon future structural modifications of the investigated compounds, a structure-activity relationship study (SAR) was accomplished.

Green Synthesizing and Corrosion Inhibition Characteristics of Azo Compounds on Carbon Steel under Sweet Conditions: Experimental and Theoretical Approaches.

The deterioration of carbon steel in saline solutions enriched with carbon dioxide represents a significant challenge within the oil and gas industry. So, this study focuses on the design and structural analysis of four azo derivatives: 4-(2-quinolinylazo)-catechol (AZN-1), 4-(4-phenoxyphenylazo)-1-naphthol (AZN-2), 4-(4-pyridylazo)-1-naphthol (AZN-3), and 4-(2-pyridylazo)-1-naphthol (AZN-4), and their first application as effective corrosion inhibitors for carbon steel in a carbon dioxide saturated 3.5% sodium chloride solution. Spectroscopic methods were used to characterize the structural configurations of these compounds. The corrosion protection properties of these compounds on carbon steel in a carbon dioxide saturated 3.5% sodium chloride solution (under sweet conditions) were investigated using Tafel polarization (PDP), electrochemical impedance spectroscopy (EIS), and field emission-scanning electron microscopy (FE-SEM) studies. The results indicate that the inhibition efficiency increases as the concentration of the inhibitors increases. There is a notable agreement between the results obtained from the PDP and EIS measurements, supporting the findings. Moreover, the results displayed that these compounds had significant corrosion protection capabilities at low concentrations, ranging from 91.0 to 98.3% at an additive concentration of 5 × 10-4 M. The PDP profiles showed that these compounds acted as mixed inhibitors, and their adsorption behavior followed the Langmuir isotherm model. Besides, EIS results corroborate the adsorption of AZN compounds through a reduction in double-layer capacitance (Cdl) alongside an augmentation in polarization resistance (Rp) after the addition of AZN compounds into the corrosive solution. Field emission scanning electron microscopy (FE-SEM) and Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the formation of a protective layer on the surface of carbon steel when these inhibitors were applied. In addition, computational calculations and Monte Carlo simulations were performed to support the experimental observations, gain insights into the adsorption properties, and elucidate the corrosion inhibition mechanisms of these compounds.

Synthesis and biological activities of bicyclic pyridines integrated steroid hybrid.

Reports on structural modification of heterosteroids through various reactions, and developed synthetic routes have considerably increased over the last decade. The present review encompasses the applicable approaches dealing with the utility of reactive moieties in various steroids for the synthesis of fused bicyclic pyridines, and binary bicyclic pyridines all over the years. The different sections include the synthesis of steroids-fused, and binary quinolines, pyridopyrimidines, imidazopyridines, spirocyclic imidazopyridines, pyrazolopyridines, thienopyridines, pyridinyl-thiazoles, and tetrazolopyridine hybrids, as well as, the diverse biological applications of these heterocyclic steroids. The researchers' interest was principally focused on investigating the flexibility of synthetic strategies for various derivatives of natural steroids and building proposals based on heterocyclic steroids for drug discovery, biological assessments, and synthetic applications.

Synthetic strategies of heterocycle-integrated pyridopyrimidine scaffolds supported by nano-catalysts.

Nano-catalysts are of special character for the synthesis of organic molecules with high efficiency, and exceptional physicochemical properties. The objective of this study was to present an overview of the literature reports concerning the synthetic strategies supported by nano-catalysts and the biological features of heterocycle-integrated pyridopyrimidine scaffolds. The basic topics include the strategies that were adopted to prepare pyrido[2,3-d]pyrimidines and pyrido[1,2-a]pyrimidines. The synthesis of pyrido[2,3-d]pyrimidines was attained through two-, three-, or four-component reactions. The synthesis of spirocyclic systems, including spiro[indoline-pyridopyrimidine] derivatives and arylation reactions, was investigated. The anticipated mechanisms of the diverse target products, in addition to the preparation of the nanocatalysts, were scrutinized. The privileged antimicrobial characteristics, challenges, literature overview, and future prospectives were consistently investigated.

One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAFV600E Inhibitors.

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1H)-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67-79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a-e, 7a, and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b, 6e, and 7b. Compounds 6b and 7b inhibited EGFR with IC50 values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAFV600E (IC50 = 108 and 96 nM, respectively) and cancer cell proliferation (GI50 = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAFV600E inhibitory properties and showed promising antiproliferative and apoptotic activity.

Synthesis, biological activities, and future perspectives of steroidal monocyclic pyridines.

Steroidal pyridines are a class of compounds that have been the subject of extensive research in recent years due to their potential biological activities. The introduction of a pyridine ring into the steroid skeleton can significantly alter the chemical and biological properties of the compound, making it more potent and/or selective for a particular target. Different synthetic methods have been developed for the preparation of steroidal pyridines. This review provides an overview of the synthesis, biological activities, and future perspectives of steroidal monocyclic dihydropyridines, tetrahydropyridines, and pyridines from 2005 to the present. The different synthetic methods that have been developed for the preparation of these steroids are discussed, as well as the proposed mechanisms and the biological activities that have been reported. Finally, the potential of steroidal monocyclic pyridines for the development of new drugs is discussed. This review is intended to provide a comprehensive overview of the field of steroidal monocyclic pyridines for researchers and scientists who are interested in this area of research. It is also hoped that this review will stimulate further research into the synthesis and biological activities of steroidal pyridines to develop new and improved drugs for the treatment of diseases.

Perspectives on Corrosion Inhibition Features of Novel Synthesized Gemini-Fluorinated Cationic Surfactants Bearing Varied Spacers for Acid Pickling of X60-Steel: Practical, and In Silico Calculations.

Through our present study, three novel Gemini-fluorinated cationic surfactants bearing different spacers (FSG6-2, FSG6-4, and FSG6-6) were synthesized, and their structures were explained via different spectroscopic instruments such as 1H, 13C, and 19F NMR spectra. The surface activity of the as-prepared surfactants was examined. The inhibiting influence of FSG6 molecules on the X60 steel corrosion in the pickling solution (HCl) was examined by diverse methods comprising electrochemical impedance spectroscopy (EIS), potentiodynamic polarization (PDP), and X-ray photoelectron spectroscopy (XPS) experimentations, and computational calculations. The inhibition effectiveness of FSG6 surfactants followed the order of 93.37% (FSG6-2) < 96.74% (FSG6-4) < 98.37% (FSG6-6) at 2.0 × 10-4 M. The FSG6 surfactants function as mixed-type inhibitors, according to PDP investigations. The H2O molecules that adsorbed on the steel interface were substituted with surfactant molecules, and the surfactant's inhibitory activity is likely caused by the improvement in an adsorptive layer on the steel substrate, as specified by the EIS results. The Langmuir isotherm describes the absorption of FSG6 molecules on the metal surface. The XPS investigations validate the steel interface's extremely protective nature. The mechanism of interaction between FSG6 molecules with an X60-steel employing the DFT calculations and MC simulations methods was also examined and discussed.

Synthesis of novel benzopyrimido[4,5-d]azoninone analogs catalyzed by biosynthesized Ag-TiO2 core/shell magnetic nanocatalyst and assessment of their antioxidant activity.

The present work reported the synthesis of novel benzopyrimido[4,5-d]azoninone analogs using a biosynthesized Ag-TiO2 core/shell magnetic nanocatalyst. Accordingly, three-component one-pot reactions of benzoazonine-dione with thiourea and aryl aldehyde derivatives under nanocatalytic and optimized conditions afforded reasonable to brilliant yields of the target products (57-91%). The nanocatalyst was synthesized by a facile method using turmeric ethanol extract as a reducing and chelating agent. The synthesized nanocatalyst was verified by FT-IR, XRD, zeta potential, EDX, SEM, and TEM. The nanocatalyst presented remarkable catalytic activity for the synthesis of the target products. The procedure provided biosynthesis of the nanocatalyst, accessible reagents, high yields and rates of the reactions, nanocatalyst recyclability, and ease of product isolation and purification. The novel products were characterized by FT-IR, 1H-NMR, 13C-NMR, mass spectra, and 2D NMR analysis (COSY, NOESY, HMQC & HSQC) spectral analyses. The antioxidant activity was assessed by DPPH and phosphomolybdate assays, in which the compounds exhibited excellent potency. Overall, this approach could be used to develop new and sustainable methods for the synthesis of antioxidants and other biologically active molecules.

Novel fused imidazotriazines acting as promising top. II inhibitors and apoptotic inducers with greater selectivity against head and neck tumors: Design, synthesis, and biological assessments.

Although the great effectiveness of doxorubicin (Dox) in the treatment of many types of tumors, it showed limited effectiveness against the head and neck squamous cell carcinoma (HNSCC) subtype which is attributed to its reported multiple drug resistance (MDR). In the current study, we considered the essential pharmacophoric features of Dox as an effective Top. II inhibitor and sought to develop a novel set of imidazo[1,2-a] [1,3,5]triazin-2-amines (2a-2p) as a suggested anticancer option that could intercalate the DNA base pairs. We evaluated the % inhibition of the newly synthesized compounds on thirteen cancer cell lines and the analysis of structure-activity relationships revealed that the human head and neck cancer cell line (HNO97) was the most sensitive to their growth inhibition effect. Then, the IC50 values were recorded against the most sensitive cancer cell lines (HNO97, MDA-MB-231, and HEPG2), and compared to the normal cell line OEC (human oral epithelial cells). Compounds 2f and 2g showed very strong activities against HNO97 with IC50 values of (4 ± 1 and 3 ± 1.5 µg/mL), respectively, compared to that of Dox (9 ± 1.6 µg/mL). Next, a quantitative determination of human DNA Top. II concentrations in the most sensitive cell line (HNO97) were recorded for the most active anticancer derivatives. Again, compound 2f showed a superior Top. II inhibition with 87.86% compared to that of Dox (86.44%), while compound 2g achieved an inhibition of 81.37% which was close to the effect of Dox. To further investigate their effects on cell cycle progression and apoptosis induction in HNO97 cells, both 2f and 2g were selected for analysis. Both candidates arrested cell cycle progression at both the S and G2-M phases, as well as increased the early and late apoptosis phase ratios. Besides, both 2f and 2g were subjected to protein expression analysis of apoptosis-related genes (p53, BAX, IL-6, and BCL2). Moreover, the antioxidant effect of 2f and 2g was evaluated by measuring GSH, MDA, and NO markers in HNO97 cells. Furthermore, molecular docking for the newly designed tricyclic derivatives against both the Top. II and DNA double helix was carried out.

Design and synthesis of novel pyrazolopyrimidine candidates as promising EGFR-T790M inhibitors and apoptosis inducers.

Aim: Our objective was to design and synthesize a new range of pyrazolopyrimidines while maintaining the key pharmacophoric features of EGFR tyrosine kinase inhibitors. Materials & methods: Percentage inhibition in 14 human cancer cell lines and IC50 values were recorded. Compounds 6c, 7e and 7f were examined against both wild and mutant (T790M) EGFR subtypes. Apoptosis markers, cell cycle arrest, apoptosis assay and molecular docking were performed. Results: Compounds 6c, 7e and 7f demonstrated superior inhibitory potentials against wild and mutant (T790M) EGFR subtypes. A molecular docking study showed that compounds 6c and 7e had the best fit. Conclusion: The designed candidates demonstrated superior inhibitory potential as promising EGFR-T790M inhibitors that agrees with the proposed rationale.

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold.

Pyrazolo[1,5-a]pyrimidines are the dominant motif of many drugs; for instance, zaleplon and indiplon are sedative agents and ocinaplon was identified as an anxiolytic agent. The importance of this class of compounds lies in its varied and significant biological activities, and accordingly, considerable methods have been devised to prepare these compounds. Hence, other derivatives of this class of compounds were prepared by substitution reactions with different nucleophiles exploiting the activity of groups linked to the ring carbon and nitrogen atoms. The methods used vary through the condensation reactions of the aminopyrazoles with 1,2-allenic, enaminonitriles, enaminones, 1,3-diketones, unsaturated nitriles, or unsaturated ketones. Alternatively, these compounds are prepared through the reactions of acyclic reagents, as these methods were recently developed efficiently with high yields. The current review highlighted the recent progress of the therapeutic potential of pyrazolo[1,5-a]pyrimidines as antimicrobial, anticancer, antianxiety, anti-proliferative, analgesic, and antioxidant agents, carboxylesterase, translocator protein and PDE10A inhibitors, and selective kinase inhibitors.

Recent progress in the chemistry of ß-aminoketones.

The ß-aminoketone moiety has been found to be the basic skeleton of several drugs such as the amine salts "tolperisone (vasodilation)" and "oxyfedrine (therapeutic coronary disease)", and fluoroaryl derivatives such as "sitagliptin (antidiabetic)". The objective of this review is to summarize and highlight the chemistry of compounds reported with a ß-aminoketone core in the last five years regarding their synthetic strategies, chemical reactivity, and mechanistic synthetic pathways. In the different sections, we categorize the synthesis of ß-aminoketones by Mannich reactions via catalytic, non-catalytic, and one-pot procedures. Also, the synthesis of the investigated compounds is accomplished by condensation reactions, from propargylic alcohols, reductive hydroamination, alkylation, carbonylative coupling, and acid hydrolysis of metal complexes. The aim of this review is to provide details for the synthesis of piperidines, morpholinones, piperazinones, dihydroxy-2-oxopyrroles, spirocyclic systems, imidazolines, indolizines, pyrido-isoindoles, aminoalcohols, metal complexes, fluoxetine, sotolon, (S)-ketamine, indolines, and benzoazepinones.