Inhibition of paraoxonase 1 by coumarin‐substituted N‐heterocyclic carbene silver(I), ruthenium(II) and palladium(II) complexes

We synthesized three coumarin‐substituted benzimidazolium chlorides and their silver(I), ruthenium(II) and palladium(II) N‐heterocyclic carbene (NHC) complexes. All compounds were characterized using appropriate spectroscopic techniques and elemental analyses. Single‐crystal X‐ray structure of a Pd(II)–NHC complex ( 6b ) was also determined. The inhibitory properties of all compounds were tested on the activity of human paraoxonase 1 (PON1). All complexes exhibited weaker inhibitory properties than their corresponding benzimidazolium salts except for complex 6b which is the most active inhibitor with an IC₅₀ value of 3.01 μM among the compounds reported in this study. A kinetic evaluation showed that this complex inhibits PON1 activity in a non‐competitive manner. Molecular docking studies were also performed for 6b in order to obtain more insight into the binding mode.     

Design,Synthesis, and Biological and In Silico Study of Fluorine‐Containing Quinoline Hybrid Thiosemicarbazide Analogues

A novel series of fluorine‐containing quinoline hybrid thiosemicarbazide analogues ( 8a–8l ) were synthesized and tested for their biological activities. The antibacterial results demonstrated that compounds 8d and 8l [minimal inhibitory concentration (MIC) 62.5 μg/mL] were shown to have higher biological activity than ampicillin against Escherichia coli. Compound 8b (MIC 25 μg/mL) was shown to have the highest activity than was ampicillin against Staphylococcus aureus. The antifungal results demonstrated that compound 8j (MIC 100 μg/mL) has shown good activity. Most of the targeted compounds have shown potent antimalarial activity. Compounds 8d (0.19 μg/mL), 8g (0.30 μg/mL), 8h (0.36 μg/mL), 8k (0.10 μg/mL), 8l (0.28 μg/mL), 8k (0.10 μg/mL), and 8l (0.28 μg/mL) have notable activity than does the reference drug quinine. Compounds 8d (0.27 μg/mL), 8g (0.30 μg/mL), and 8k (0.17 μg/mL) have shown excellent activity against chloroquine‐resistant strain. The MTT assay performed on peripheral blood lymphocyte cultures showed a high percentage of lymphocyte viability [ 8d (99.64), 8g (99.46), 8h (98.83), and 8k (99.51)] at a maximum dose (10 μg/mL), depicting no cytotoxicity of these compounds on human lymphocytes in vitro. A molecular docking study was performed on Pf‐DHFR‐TS inhibitor. A molecular dynamics study has shown compound 8g to have better affinity with protein. ADME‐Tox and pharmacophore study of synthesized compounds suggested prediction of active site.     

Indolyl Linked Meta‐Substituted Benzylidenes as Novel Ligands: Synthesis,Biological Evaluation,and Molecular Docking Studies

Synthesis of indolyl linked benzylidene based meta‐substituted phenyl containing thiazolidinediones ( 4a – b ), rhodanine ( 5a – b ), and 1,3‐dicarbonyl based acyclic analogs of isoxazolidinediones ( 6a – 7b ) in an effort to develop novel α‐glucosidase inhibitors in the management of hyperglycemia for the treatment of type 2 diabetes is reported. The structure of all the novel synthesized compounds was confirmed through the spectral studies (LC–MS, ¹H‐NMR, ¹³C‐NMR, and FTIR). Comparative evaluation of these compounds revealed that the compound 5b showed maximum inhibitory potential against α‐amylase and α‐glucosidase giving an IC₅₀ value of 0.28 ± 0.01 μM. Furthermore, binding affinities in terms of G score values and hydrogen bond interactions between all the synthesized compounds and the AA residues in the active site of the protein (PDB code: 3TOP) to that of Acarbose (standard drug) were explored with the help of molecular docking studies. Compound 5b was considered as promising candidate of this series.     

Pyrazine based Pt(II) bis‐alkynyl organometallic complexes: Synthesis,characterization, and cytotoxic effect on A549 human lung carcinoma cells

A facile and efficient synthesis of a series of five new pyrazine‐based organometallic complexes is being reported. The complexes ( 2 – 6 ) have been fully characterized. Molecules 2 , 3 and 6 were structurally characterized by single crystal X‐ray crystallographic analyses. Additionally, anticancer properties of these organometallic complexes have been studied against A549 human lung carcinoma cells. Biological studies suggest that complex 5 (with pendant pyridine moieties) exhibited maximal growth inhibitory cytotoxic effect even at lower concentration (nearly 0.5–1 μM) whereas the other four compounds ( 2 , 3 , 4 and 6 ) were non‐toxic below 1 μM concentration. Two complexes ( 4 and 6) were effective only at higher doses (approx 30 μM) while the remaining two organometallic complexes ( 2 and 3) were able to inhibit 50% cell growth at slightly lower concentration (nearly 10 μM). As far as IC₅₀ is concerned, 5 exhibited a minimum value ranging between 3–5 μM which is comparable with cisplatin under similar conditions.     

Trifluoromethylpyridine‐Substituted N‐Heterocyclic Carbenes Related to Natural Products: Synthesis,Structure, and Potential Antitumor Activity of some Corresponding Gold(I), Rhodium(I), and Iridium(I) Complexes

This work presents the synthesis, characterization, and application of several new metal(I) complexes with trifluoromethylpyridine‐containing N‐heterocyclic carbene (NHC) ligands. The metal of choice was gold(I) for compounds 7  –  10 , rhodium(I) for 11  –  12 , and iridium(I) for 13  –  14 , respectively. The trifluoromethylpyridine moiety was incorporated, along with other biologically active moieties, with the intention of modifying the lipophilicity of the complexes, so that the transport of the active units (M–NHC) through the cell wall barrier is facilitated. The biological activity of the complexes was investigated. In vitro assessment of antitumor activity in a panel of 12 human tumor cell lines by a monolayer assay revealed good potency (mean IC₅₀ 12.6 μm ) and tumor selectivity for one compound. The solid‐state structures of two solvates of compound 7 , one with MeOH and one with THF, were determined by X‐ray diffraction analysis.     

Synthesis,in vitro urease inhibitory activity and molecular docking of 3,5‐disubstituted thiadiazine‐2‐thiones

A series of 3,5‐disubstituted‐tetrahydro‐thiadiazine‐2‐thione ( 1 ‐ 16 ) have been synthesized, characterized by elemental analysis, infrared (IR), UV‐visible, ¹H NMR, ¹³C NMR, and MS spectroscopic techniques, and screened against jack bean urease. Among 16 compounds, compounds ( 1 ), ( 2 ), ( 3 ), ( 4 ), ( 6 ), ( 7 ), and ( 9 ) demonstrated excellent urease inhibitory activity with IC₅₀ values (9.8 ± 0.5, 11.0 ± 0.6, 16.0 ± 1.5, 17.2 ± 0.5, 15.4 ± 0.5, 19.7 ± 0.4, and 15.8 ± 0.2μM), respectively, even better than the standard thiourea (IC₅₀ = 21 ± 0.01μM). However, compound ( 8 ) shows an almost same level of inhibition (IC₅₀ = 22.9 ± 0.3μM), as like standard. In this work, we reported for the first time urease inhibitory activity of thiadiazine thiones and its molecular docking studies.     

Design,Synthesis, and Anticancer Activity of Novel Benzothiazole Analogues

On the pharmaceutical account of the reported anticancer activity of benzothiazole derivatives, differently substituted benzothiazole derivatives 2a – c to 34a , b , attached at 2‐position to different heterocyclic moieties, were synthesized via different chemical reactions. Thirteen of the newly synthesized compounds were selected by the National Cancer Institute, Bethesda, Maryland, USA, and evaluated for their in vitro antitumor activity against 60 human tumor cell lines in a one‐dose screening panel among which two compounds 4 and 17 showed high activity and were selected for further evaluation in the five‐dose full panel assay, in which compound 4 exerted powerful growth inhibitory activity against all cell lines with GI₅₀ ranging from 0.683 to 4.66 μM/L in addition to excellent lethal activity against most of the cell lines.     

Design and synthesis of novel sugar‐based nitrogen‐containing heterocycles as potential anticancer agents under microwave in water

A series of novel glycosyl nitrogen‐containing heterocycles derivatives were designed and synthesized. With the help of microwave, the reaction was carried out in water rapidly and afforded the target compounds in good yields. The acid catalysts that were essential for this kind of reaction under traditional heating method were avoided through this strategy. Preliminary biological evaluation showed that most of the compounds could inhibit the growth of A549 cells, but the inhibition of HepG‐2 cells was relatively poor. Notably, compound 2i displayed the best potency with an IC₅₀ value of 3.42 μM against A549 cell lines, which is comparable with the common anticarcinogen paclitaxel (5.12 μM). Molecular modeling studies suggested that 2i may bind to the ATP‐binding site of epidermal growth factor receptor (EGFR), indicating a rational design strategy. These results provide a starting point for designing glycosyl nitrogen‐containing heterocycles as the potential drugs in lung cancer therapy.     

Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents

A new strategy for the preparation of 8‐quinolyl ethers 3 ( a – g ), 5 ( a – g ), and 7 ( a – d ) was studied by copper (II)‐catalyzed methodology in the presence of Cs₂CO₃ and acetone–water mixture (1:1). Screening of quinolinyl‐8‐ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF‐7), skin cancer (G‐361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide‐3‐kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a – c were inactive (IC₅₀ > 5 μM), while 3e – g , 5a , 5c – e , 5g , 7a , and 7d showed a moderate activity (IC₅₀ ≥ 0.05 μM). Compounds ( 5b , 5f , 7b , and 7c ) showed significant activity (IC₅₀ < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF‐7); 5b , 5f , 7b , and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC₅₀ values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC₅₀ = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b , 5f , 7b , and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure–activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer‐related diseases.     

Synthesis,cytotoxicity, topoisomerase I inhibition and molecular docking of novel phosphoramide mustard sophoridinic acid analogues

A series of novel phosphoramide mustard sophoridinic acid analogues, consisting of nitrogen mustard group and sophoridinic acid scaffold, have been designed, synthesized and evaluated for their topoisomerase inhibitory activity as well as cytotoxicity against six tumor cell lines (SMMC‐7721, LoVo, MCF‐7, K562, S180 and H22) and a normal cell line (L929). Among the compounds tested, five were found to be potent inhibitors and exhibited potent cytotoxicity against S180 and H22 cell lines with IC₅₀ values of 1–4 μM. Further mechanistic studies showed that this class of compounds acted as novel topoisomerase I (Topo I) catalytic inhibitors by preventing the binding of Topo I to DNA and inhibiting the cleavage of DNA, and molecular docking studies revealed that the binding energy for these compounds was comparable to that for classic Topo I inhibitors CPT and HCPT, indicating that the compounds have an interaction with DNA and Topo I.     

Design,synthesis and antiviral activities of chalcone derivatives containing pyrimidine

A series of chalcone derivatives (T1-T23) containing pyrimidine were synthesized, characterized, and assessed for their antiviral activity against tobacco mosaic virus (TMV) activities. Most target compounds displayed better antiviral activities against TMV than commercial ningnanmycin. Among them, the EC₅₀ value of curative activities of compounds T1, T7, T9 and T19 (219.2, 228.2, 279.9 and 234.9 μg/mL, respectively) were superior to that of ningnanmycin (320.1 μg/mL). In addtion, the EC₅₀ value of protective activities of compounds T5, T9, T19 and T23 (235.0, 220.0, 199.5 and 187.2 μg/mL, respectively) were superior to that of ningnanmycin (307.4 μg/mL). Then, the antiviral mechanism of T19 and TMV coat protein (TMV-CP) was preliminarily investigated by microscale thermophoresis (MST) and molecular docking technology. The results showed that T19 had a strong binding affinity for TMV coat protein, and its dissociation constant (K_d) was 0.00310 ± 0.000916 μM, which was superior to ningnanmycin(0.165 ± 0.0799 μM). This study suggests that chalcone derivatives containing pyrimidine could be used as novel antiviral agents for controlling the plant viruses.     

Design,synthesis and biological evaluation of isoxazole-naphthalene derivatives as anti-tubulin agents

In this study, a novel series of isoxazole-naphthalene derivatives as tubulin polymerization inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against human breast cancer cell line MCF-7. Most of the synthesized compounds exhibited moderate to potent antiproliferative activity (IC₅₀ < 10.0 μM), as compared to cisplatin (15.24 ± 1.27 μM). Among them, compound 5j containing 4-ethoxy substitution at phenyl ring was found to be the most active compound with IC₅₀ value of 1.23 ± 0.16 μM. Mechanistic studies revealed that compound 5j arrested cell cycle at G2/M phase and induces apoptosis. Furthermore, in vitro tubulin polymerization assay showed that compound 5j displayed better inhibition activity on tubulin polymerization (IC₅₀ = 3.4 μM) than colchicine (IC₅₀ = 7.5 μM). Molecular docking study also revealed that compound 5j binds to the colchicine binding site of tubulin.     

Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

Synthesis,characterization, biological applications,and molecular docking studies of amino-phenol-derived mixed-ligand complexes with Fe(III), Cr(III), and La(III) ions

A new series of Fe(III), Cr(III), and La(III) mixed-ligand complexes, resulting from the interaction of 2-aminophenol with 2-hydroxy acetophenone (HL₁) as primary ligand and L- histidine (L₂) as a secondary ligand, has been investigated using various physicochemical studies such as elemental analyses, molar conductivity, magnetic moment, infrared, UV/Vis, ¹H NMR, and mass spectroscopic techniques. The microanalytical results indicate that the mixed ligand complexes were designed in a 1:1:1 M ratio. The electronic spectral data indicated that all the synthesized complexes have an octahedral structure. The disc diffusion assay was used to determine the disc inhibition zone (IZ, mm) and minimum inhibitory concentration (MIC, g/mL) of the investigated compounds against the growth of the pathogenic bacterial strains S. aureus, E. faecalis, P. aeruginosa, Klebsiella sp., and E. coli. The MTT test was used to determine the cytotoxicity of these reported compounds against the human hepatocellular liver cancer (HEPG-2) cell lines. The molecular docking study for the compounds against the EGFR tyrosine kinase receptor (PDB code: 1 M17) was conducted to examine the interactions in protein–ligand complexes. Furthermore, the biological activity of the ligand was investigated using quantitative structure–activity relationship studies (QSAR).     

Regioselective Reactions,Spectroscopic Characterization,and Cytotoxic Evaluation of Spiro‐pyrrolidine Thiophene

Spiro‐oxo‐indole/pyrrolidine‐thiophene base possessed significant pharmacological activity. The [3 + 2] cycloaddition reactions of thia‐methine ylide respected through multi‐component reaction affording regioselective and stereoselective spiroindoline‐3,2′‐tetrahydrothiophene derivative 3 . Reaction of such compound with different electrophilic and nucleophilic reagents afforded bioactive heterocyclic compounds 4 – 16 . Biological evaluation showed that these synthesized spiro‐pyrrolidine exhibited moderate to good cytotoxic activity. Among them, compounds 7 and 14 displayed the best cytotoxic activity against MCF‐7 and Wl‐38 cells with the IC₅₀ values of 7.02 ± 0.6 and 8.97 ± 0.9 μm (very strong), respectively. Compounds 4 , 5 , and 12 exhibited strong cytotoxicity's with IC₅₀ 16.28 ± 1.7, 11.16 ± 1.1, and 19.14 ± 1.7 μm, respectively, against MCF‐7 mammary gland cell line. All compound structures were supported by spectroscopic data and elemental analysis.     

Antioxidant properties,anti- SARS-CoV-2 study,collagenase and elastase inhibition effects,anti-human lung cancer potential of some phenolic compounds

Lung cancer is one of the main reasons for death worldwide. The natural compounds with anti-lung cancer potential are of main interest and are considered a very promising alternative to replace or raise the efficiency of conventional drugs. Diethylstilbestrol, Enterodiol, Enterolactone, Flavokawain A, Flavokawain B, and Flavokawain C compounds showed excellent to good inhibitory activities against studied these enzymes with IC₅₀ values in ranging between 9.66 ± 1.52 to 121.20 ± 15.87 μM for collagenase and 11.06 ± 1.87 to 27.31 ± 4.673 μM for elastase. Also, these compounds had In vitro anti-lung cancer activities. Comparison of the chemical and biological activities of the studied molecules was made by theoretical calculations. Gaussian sofware program was used for chemical activity. The Maestro molecular docking calculations were made to compare their biochemical activities. Afterwards, ADME/T calculations of the molecules were made.     

Synthesis and evaluation of new pyrazoline‐thiazole derivatives as monoamine oxidase inhibitors

A novel series of 1,3,5‐trisubstituted‐2‐pyrazoline derivatives ( 4a ‐ 4k ) was synthesized and their chemical structures characterized by ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds were evaluated as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes. The most common inhibitors of MAO enzymes used to treat depression and anxiety such as selegiline and moclobemide drugs were used as reference agents. A result of biological evaluation of these compounds revealed compounds 4c , 4d , and 4? as potent and selective MAO A inhibitors. The most active compound 4? , which is 2,4‐dimethoxy at phenyl ring, showed strong inhibitory activity at MAO A (IC₅₀ of 0.0445 ± 0.0018μM). Furthermore, compounds 4c and 4d showed significant inhibition profile on MAO A with the IC₅₀ values 0.1423 ± 0.0051μM and 0.2148 ± 0.0067μM, respectively.     

Synthesis,Characterization, and Investigation of Cholinesterase Inhibitory Properties of Novel Phthalocyanines

In this study, 4‐{2‐(2‐thienyl)ethoxy}phthalonitrile ( 3 ) and its tetra substituted peripherally metal‐free ( 4 ), lead (II) ( 5 ), magnesium (II) ( 6 ), and cobalt (II) ( 7 ) phthalocyanines were synthesized. The structural characterization of the obtained compounds was performed by a combination of FTIR, ¹H‐NMR, UV–vis, and MALDI‐TOF techniques. The inhibitory properties of these compounds were determined using Ingkaninan's methods against cholinesterase enzymes. Compound ( 7 ) had the highest enzyme inhibitory effect toward AChE and BuChE enzymes with IC₅₀ values of 23.71 ± 0.39 and 27.29 ± 0.22 μM, respectively. The enzyme kinetic study of compound ( 7 ) demonstrated noncompetitive AChE inhibition and uncompetitive BuChE inhibition. The K_i values of compound ( 7 ) against AChE and BuChE were found to 39.15 and 7.25 μM, respectively. In the tested compounds, ( 7 ) deserves further investigation for potential therapeutic candidates of Alzheimer's disease.     

Glycerol Mediated Synthesis,Biological Evaluation,and Molecular Docking Study of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines as Potent Antitubercular Agents

A series of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines were synthesized through one‐pot four‐component Hantzsch condensation of 1,3‐diphenyl‐1H‐pyrazole‐4‐carbaldehydes, ammonium acetate, dimedone, and alkyl acetoacetate in glycerol as a green reaction medium. The structures of the compounds are verified by spectroscopic methods and screened for their antimicrobial activity against Mycobacterium tuberculosis H37RV strain. Almost all the synthesized derivatives reveal excellent antitubercular activity based on minimum inhibitory concentration. Especially the compounds 5h and 5k exhibit outstanding antitubercular activity with minimum inhibitory concentration 1.6 μg/mL. In addition, molecular docking study of synthesized scaffolds against enoyl‐acyl carrier protein reductase from M. tuberculosis was performed to propose the binding modes.     

Thiazolidinones: Synthesis,Reactivity, and Their Biological Applications

Thiazolidinone is a biologically important five‐membered heterocyclic ring having almost all types of biological activities. This review covers various types of thiazolidinones, such as 2‐thiazolidinones, 4‐thiazolidinones, 5‐thiazolidinones, 2‐thioxo‐4‐thiazolidinones, and thiazolidiene‐2,4‐dione. The literature related to the physical properties, chemical reactions, and synthesis for these derivatives has been included. Recent advances in the biological activities reported for 4‐thiazolidinone derivatives, such as peroxisome proliferator‐activated receptor γ binders, follicle‐stimulating hormone agonists, cystic fibrosis transmembrane conductance regulator inhibitors, and antioxidants, have been covered in this review. Thus, this study may help in further optimizing these thiazolidinone derivatives as more effective drug agents.