New prospective insecticidal agents based on thiazolo[4,5-b]quinoxaline derivatives against cotton leafworm Spodoptera litura (Fabricius): Design, synthesis, toxicological, morphology, histological, and biomedical studies.

In this study, a new series of thiazolo[4,5-b]quinoxaline derivatives 3-8 were synthesized by treating 2,3-dichloroquinoxaline with thiosemicarbazone and thiourea derivatives under reflux conditions. The chemical structure of the newly designed derivatives was conducted using spectroscopic techniques. The insecticidal bioassay of the designed derivatives was evaluated against the 2nd and 4th larvae of S. litura after five days as toxicity agents via median lethal concentration (LC50) and the lethal time values (LT50). The results indicated that all the tested compounds had insecticidal effects against both instar larvae of S. litura with variable values. Among them, thiazolo[4,5-b]quinoxaline derivative 3 was the most toxic, with LC50 = 261.88 and 433.68 ppm against 2nd and 4th instar larvae, respectively. Moreover, the thiazolo[4,5-b]quinoxaline derivative 3 required the least time to kill the 50% population (LT50) of 2nd larvae were 20.88, 13.2, and 15.84 hs with 625, 1250, and 2500 ppm, respectively, while for the 4th larval instar were 2.75, 2.08, and 1.76 days with concentrations of 625, 1250, and 2500 ppm, respectively. Larvae's morphological and histological studies for the most active derivative 3 were investigated. According to SEM analysis, the exterior morphology of the cuticle and head capsule was affected. In addition, there were some histological alterations in the cuticle layers and the midgut tissues. Columnar cells began breaking down, and vacuolization occurred in the peritrophic membrane. Moreover, treating 4th S litura larvae hemolymph with compound 3 showed significant changes in biochemical analysis, such as total proteins, GPT, GOT, acetylcholinesterase (AChE), and alkaline phosphatase (AlP). Finally, the toxicity prediction of the most active derivative revealed non-corrosive, non-irritant to the eye, non-respiratory toxicity, non-sensitivity to the skin, non-hepatotoxic, and don't have toxicity on minnow toxicity and T. pyriformis indicating a good toxicity profile for human.

Fluorinated indeno-quinoxaline bearing thiazole moieties as hypoglycaemic agents targeting α-amylase, and α-glucosidase: synthesis, molecular docking, and ADMET studies.

Inhibition of α-glucosidase and α-amylase are key tactics for managing blood glucose levels. Currently, stronger, and more accessible inhibitors are needed to treat diabetes. Indeno[1,2-b] quinoxalines-carrying thiazole hybrids 1-17 were created and described using NMR. All analogues were tested for hypoglycaemic effect against STZ-induced diabetes in mice. Compounds 4, 6, 8, and 16 were the most potent among the synthesised analogues. These hybrids were examined for their effects on plasma insulin, urea, creatinine, GSH, MDA, ALT, AST, and total cholesterol. Moreover, these compounds were tested against α-glucosidase and α-amylase enzymes in vitro. The four hybrids 4, 6, 8, and 16 represented moderate to potent activity with IC50 values 0.982 ± 0.04, to 10.19 ± 0.21 for α-glucosidase inhibition and 17.58 ± 0.74 to 121.6 ± 5.14 µM for α-amylase inhibition when compared to the standard medication acarbose with IC50=0.316 ± 0.02 µM for α-glucosidase inhibition and 31.56 ± 1.33 µM for α-amylase inhibition. Docking studies as well as in silico ADMT were done.

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus.

A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC50 values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC50 = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC50 values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC50 = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.

Innovation of 6-sulfonamide-2H-chromene derivatives as antidiabetic agents targeting α-amylase, α-glycosidase, and PPAR-γ inhibitors with in silico molecular docking simulation.

A new series of 2-imino or 2-oxo-2H-chromene-6-sulfonamide derivatives 2-9 with potential anti-diabetic activity were designed and synthesized. The new 6-sulfonamide chromenes were synthesized by reacting 3-formyl-4-hydroxybenzenesulfonyl chloride with activated methylene derivatives in the presence of ammonium acetate as a catalyst. The structure of the products was confirmed by spectroscopic analysis. All the designed derivatives 2-9 were evaluated for their activity against α-amylase and exhibited inhibitory percentage values higher than 93% at 100 µg mL-1. Additionally, the IC50 values represented a variable degree of activity with two derivatives 2 and 9 exhibiting the most promising derivative results with IC50 values of 1.76 ± 0.01 and 1.08 ± 0.02 µM, respectively, compared to Acarbose (IC50 = 0.43 ± 0.01 µM). Additionally, these derivatives showed potency against the α-glucosidase enzyme with IC50 values of 0.548 ± 0.02 and 2.44 ± 0.09 µg mL-1, compared to Acarbose (0.604 ± 0.02 µg mL-1). Moreover, the in vitro PPAR-γ transactivation assay revealed that chromene-6-sulfonamide derivatives 2 and 9 exhibited potential PPAR-γ activity with IC50 values of 3.152 ± 0.03 and 3.706 ± 0.32 µg mL-1, respectively, compared to Pioglitazone (4.884 ± 0.29 µg mL-1). This indicates that these derivatives have insulin sensitivity and glucose metabolism activity. The in silico ADMET prediction showed that these derivatives have an acceptable range of oral bioavailability, drug-likeness, and a safe toxicity profile, including being non-cytotoxic, non-mutagenic, non-immunotoxic, and non-carcinogenic. Finally, computational docking analysis demonstrated the ability of these derivatives to interact with α-amylase, α-glucosidase, and PPAR-γ enzymes, with confirmed successful placement due to good binding energy values and various interactions within the pocket.

Developing a new multi-featured chitosan-quinoline Schiff base with potent antibacterial, antioxidant, and antidiabetic activities: design and molecular modeling simulation.

A new chitosan Schiff base was developed via the reaction of chitosan (CH) with 2-chloro-3-formyl-7-ethoxy quinoline (Q) derivative. The alteration in the chemical structure and morphology of CHQ derivative was confirmed by 1H NMR, FT-IR spectroscopy and SEM analysis. The antibacterial activity was considerably promoted with increasing quinoline concentration up to 1 M with maximal inhibition reached 96 and 77% against Staphylococcus haemolyticus and Escherichia coli, respectively. Additionally, CHQ derivative afforded higher ABTS·+ radical scavenging activity reached 59% compared to 13% for native chitosan, approving its acceptable antioxidant activity. Moreover, the developed CHQ derivative can stimulate the glucose uptake in HepG-2 and yeast cells, while better inhibition of α-amylase and α-glucosidase was accomplished with maximum values of 99.78 and 92.10%, respectively. Furthermore, the molecular docking simulation clarified the binding mode of CHQ derivative inside the active site of α-amylase and α-glucosidase, suggesting its potential use as diabetes mellitus drug. The DFT calculations indicated an improvement in the electronic properties of CHQ with a lower energy band gap reached 4.05eV compared to 5.94eV for CH. The cytotoxicity assay revealed the safety of CHQ towards normal HSF cells, hypothesizing its possible application as non-toxic antibacterial, antioxidant, and antidiabetic agent for biomedical applications.

Design, green synthesis, and quorum sensing quenching potential of novel 2-oxo-pyridines containing a thiophene/furan scaffold and targeting a LasR gene on P. aeruginosa.

The current trend in fighting bacteria is attacking the virulence and quorum-sensing (QS) signals that control bacterial communication and virulence factors, especially biofilm formation. This study reports new Schiff bases and tetracyclic rings based on a pyridine pharmacophore by two methods: a green approach using CAN and a conventional method. The structure of designed derivatives was confirmed using different spectroscopies (IR and 1H/13C NMR) and elemental analysis. The designed derivatives exhibited good to moderate inhibition zones against bacterial and fungal pathogens. In addition, six compounds 2a,b, 3a,b, and 6a,b displayed potency against tested pathogens with eligible MIC and MBC values compared to standard antimicrobial agents. Compound 2a displayed MIC values of 15.6 µg mL-1 compared to Gentamicin (MIC = 250 µg mL-1 against K. pneumoniae), while compound 6b exhibited super-potent activity against P. aeruginosa, and K. pneumoniae with MIC values of 62.5 and 125 µg mL-1, as well as MBC values of 31.25 and 15.6 µg mL-1 compared to Gentamicin (MIC = 250 and 125 µg mL-1 and MBC = 62.5 µg mL-1), respectively. Surprisingly, these six derivatives revealed bactericidal and fungicidal potency and remarkable anti-biofilm activity that could significantly reduce the biofilm formation against MRSA, E. coli, P. aeruginosa, and C. albicans. Furthermore, the most active derivatives reduced the LasR gene's production between 10-40% at 1/8 MICs compared with untreated P. aeruginosa. Besides, they demonstrated promising safety profile on Vero cells (normal cell lines) with IC50 values ranging between (175.17 ± 3.49 to 344.27 ± 3.81 µg mL-1). In addition, the in silico ADMET prediction was carried out and the results revealed that these compounds could be used with oral bioavailability with low toxicity prediction when administered as a candidate drug. Finally, the molecular docking simulation was performed inside LasR and predicted the key binding interactions responsible for the activity that corroborated the biological results.

A new class of anti-proliferative activity and apoptotic inducer with molecular docking studies for a novel of 1,3-dithiolo[4,5-b]quinoxaline derivatives hybrid with a sulfonamide moiety.

A new series of 6-(pyrrolidin-1-ylsulfonyl)-[1,3]dithiolo[4,5-b]quinoxaline-2-ylidines 10a-f, 12, 14, 16, and 18 were designed, synthesized, and evaluated for their in vitro anticancer activity. The structures of the novel compounds were systematically characterized by 1H NMR, 13C NMR, and elemental analysis. The synthesized derivatives were evaluated for their in vitro antiproliferative activity against three human cancer cell lines (HepG-2, HCT-116, and MCF-7) with more sensitivity to MCF-7. Moreover, three derivatives 10c, 10f, and 12 were the most promising candidates with sub-micromole values. These derivatives were further evaluated against MDA-MB-231, and the results displayed significant IC50 values ranging from 2.26 ± 0.1 to 10.46 ± 0.8 µM and showed low cellular cytotoxicity against WI-38. Surprisingly, the most active derivative 12 revealed sensitivity towards the breast cell lines MCF-7 (IC50 = 3.82 ± 0.2 µM) and MDA-MB-231 (IC50 = 2.26 ± 0.1 µM) compared with doxorubicin (IC50 = 4.17 ± 0.2 and 3.18 ± 0.1 M). Cell cycle analysis showed that compound 12 arrests and inhibits the growth of MCF-7 cells in the S phase with values of 48.16% compared with the untreated control 29.79% and exhibited a significantly higher apoptotic effect in MCF-7 with a value of 42.08% compared to control cell at 1.84%. Furthermore, compound 12 decreased Bcl-2 protein 0.368-fold and activation on pro-apoptotic genes Bax and P53 by 3.97 and 4.97 folds, respectively, in MCF-7 cells. Compound 12 exhibited higher inhibitory activity to EGFRWt, EGFRL858R, and VEGFR-2 with IC50 values (0.19 ± 0.009, 0.026 ± 0.001, and 0.42 ± 0.021 µM) compared with erlotinib (IC50 = 0.037 ± 0.002 and 0.026 ± 0.001 µM) and sorafenib (IC50 = 0.035 ± 0.002 µM). Finally, in silico ADMET prediction presented that 1,3-dithiolo[4,5-b]quinoxaline derivative 12 obeys the Lipinski rule of five and the Veber rule with no PAINs alarms and moderately soluble properties. Additionally, toxicity prediction revealed that compound 12 demonstrated inactivity to hepatotoxic carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Moreover, molecular docking studies showed good binding affinity with lower binding energy inside the active site of Bcl-2 (PDB: 4AQ3), EGFR (PDB: 1M17), and VEGFR (PDB: 4ASD).

Antibiofilm and Anti-Quorum-Sensing Activities of Novel Pyrazole and Pyrazolo[1,5-a]pyrimidine Derivatives as Carbonic Anhydrase I and II Inhibitors: Design, Synthesis, Radiosterilization, and Molecular Docking Studies.

Nowadays, searching for new anti-infective agents with diverse mechanisms of action has become necessary. In this study, 16 pyrazole and pyrazolo[1,5-a]pyrimidine derivatives were synthesized and assessed for their preliminary antibacterial and antibiofilm activities. All these derivatives were initially screened for their antibacterial activity against six clinically isolated multidrug resistance by agar well-diffusion and broth microdilution methods. The initial screening presented significant antibacterial activity with a bactericidal effect for five compounds, namely 3a, 5a, 6, 9a, and 10a, compared with Erythromycin and Amikacin. These five derivatives were further evaluated for their antibiofilm activity against both S. aureus and P. aeruginosa, which showed strong biofilm-forming activity at their MICs by >60%. The SEM analysis confirmed the biofilm disruption in the presence of these derivatives. Furthermore, anti-QS activity was observed for the five hybrids at their sub-MICs, as indicated by the visible halo zone. In addition, the presence of the most active derivatives reduces the violacein production by CV026, confirming that these compounds yielded anti-QS activity. Furthermore, these compounds showed strong inhibitory action against human carbonic anhydrase (hCA-I and hCA-II) isoforms with IC50 values ranging between 92.34 and 168.84 nM and between 73.2 and 161.22 nM, respectively. Finally, radiosterilization, ADMET, and a docking simulation were performed.

Development of novel pyrazole, imidazo[1,2-b]pyrazole, and pyrazolo[1,5-a]pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential.

Searching for new compounds with anti-inflammatory properties is a significant target since inflammation is a major cause of pain. A series of pyrazole, imidazopyrazolone, and pyrazolopyrimidine derivatives were designed and synthesized by reaction of 3,5-diamino-1H-pyrazole derivative with cyclic and acyclic carbonyl reagents. The structure of the newly synthesized derivatives were fully characterized using different spectroscopic data and elemental analysis, and therefore, evaluated as COX-2 inhibitors. The in vitro COX-2 activity of the tested derivatives 2-13 displayed moderate to good potency with two derivatives 8 and 13 that exhibiting high potency to COX-2 with IC50 values of 5.68 ± 0.08 and 3.37 ± 0.07 µM compared with celecoxib (IC50 = 3.60 ± 0.07 µM) and meloxicam (IC50 = 7.58 ± 0.13 µM). Furthermore, the most active pyrazolo[1,5-a]pyrimidine derivatives 8 and 13 were evaluated to measure the levels of pro-inflammatory proteins such as TNF-α and IL-6 using qRT-PCR in RAW264.7 cells, and the results showed down-regulation of two immunomodulatory proteins. Surprisingly, these derivatives 8 and 13 revealed a decrease in IL-6 level with inhibition percentages of 65.8 and 70.3%, respectively, compared with celecoxib (% = 76.8). Further, compounds 8 and 13 can regulate and suppress the TNF-α with percentage inhibition of 63.1 and 59.2% to controls, while celecoxib displayed an inhibition percentage of 72.7. The Quantum chemical calculation was conducted, and data explained the structural features crucial to the activity. The molecular docking simulation and ADMET predictions revealed that the most active derivatives have good binding affinity, possess appropriate drug-likeness properties and low toxicity profiles. Finally, compounds 8 and 13 demonstrated COX-2 inhibitors with α-TNF and IL-6 suppression capabilities as a dual-action strategy to get more effective treatment.

Development of new spiro[1,3]dithiine-4,11'-indeno[1,2-b]quinoxaline derivatives as S. aureus Sortase A inhibitors and radiosterilization with molecular modeling simulation.

Multi-drug resistant microbes have become a severe threat to human health and arise a worldwide concern. A total of fifteen spiro-1,3-dithiinoindenoquinoxaline derivatives 2-7 were synthesized and evaluated for their biological activities against five standard and MDRB pathogens. The MIC and MBC/MFC for the most active derivatives were determined in vitro via broth microdilution assay. These derivatives showed significant activity against the tested strains with microbicidal behavior, with compound 4b as the most active compound (MIC range between 0.06 and 0.25 µg/mL for bacteria strains and MIC = 0.25 µg/mL for C. albicans). The most active spiro-1,3-dithiinoindenoquinoxaline derivatives were able to inhibit the activity of SrtA with IC50 values ranging from 22.15 ± 0.4 µM to 37.12 ± 1.4 µM. In addition, the active spiro-1,3-dithiinoindenoquinoxaline attenuated the in vitro virulence-related phenotype of SrtA by weakening the adherence of S. aureus to fibrinogen and reducing the biofilm formation. Surprisingly, compound 4b revealed potent SrtA inhibitory activity with IC50 = 22.15 µM, inhibiting the adhesion of S. aureus with 39.22 ± 0.15 % compared with untreated 9.43 ± 1.52 %, and showed a reduction in the biofilm biomass of S. aureus with 32.27 ± 0.52 %. We further investigated the effect of gamma radiation as a sterilization method on the microbial load and found that a dose of 5 kGy was sufficient to eradicate the microbial load. The quantum chemical studies exhibited that the tested derivatives have a small energy band gap (ΔE = -2.95 to -3.61 eV) and therefore exert potent bioactivity by interacting with receptors more stabilizing.

A new exploration toward adamantane derivatives as potential anti-MDR agents: Design, synthesis, antimicrobial, and radiosterilization activity as potential topoisomerase IV and DNA gyrase inhibitors.

Developing novel antimicrobial agents has become a necessitate due to the increasing rate of microbial resistance to antibiotics. All the newly adamantane derivatives were evaluated for their antimicrobial activities against six MDR clinical pathogenic isolates. The results exhibited that 13 compounds have from potent to good activity. Among those, five derivatives (6, 7, 9, 14a, and 14b) displayed the potent activities against the different isolates tested (MIC < 0.25 µg/ml with bacteria and <8 µg/ml with fungi) compared with Ciprofloxacin (CIP) and Fluconazole (FCA). Additionally, the potent adamantanes showed bactericidal and fungicidal effects based on (MBCs and MFCs) and the time-kill assay. The most active adamantane derivatives 7 and 14b exhibited a synergistic effect of ΣFIC ≤ 0.5 with CIP and FCA against the bacterial and fungal isolates. Moreover, no antagonistic effect appeared for the tested derivatives. Additionally, the interaction of DNA gyrase and topoisomerase IV enzymes with the compounds 6, 7, 9, 14a, and 14b exhibited potent antimicrobial activity using in vitro biochemical assays and gel-based DNA-supercoiling inhibition method. The activity of DNA gyrase and topoisomerase IV enzymes showed inhibitory activity (IC50 ) of 6.20 µM and 9.40 µM with compound 7 and 10.14 µM and 13.28 µM with compound 14b, respectively. Surprisingly, exposing compound 7 to gamma irradiation sterilized and increased its activity. Finally, the in-silico analysis predicted that the most active derivatives had good drug-likeness and safe properties. Besides, molecular docking and quantum chemical studies revealed several important interactions inside the active sites and showed the structural features necessary for activity.

Hybridized Quinoline Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and Molecular Docking.

OBJECTIVE: Conjugating quinolones with different bioactive pharmacophores to obtain potent anticancer active agents. METHODS: Fused pyrazolopyrimidoquinolines 3a-d, Schiff bases 5, 6a-e, two hybridized systems: pyrazolochromenquinoline 7 and pyrazolothiazolidinquinoline 8, different substituted thiazoloquinolines 13-15 and thiazolo[3,2-a]pyridine derivatives 16a-c were synthesized. Their chemical structures were characterized through spectral and elemental analysis, cytotoxic activity on five cancer cell lines, caspase-3 activation, tubulin polymerization inhibition and cell cycle analysis were evaluated. RESULTS: Four compounds 3b, 3d, 8 and 13 showed potent activity than doxorubicin on HCT116 and three compounds 3b, 3d and 8 on HEPG2. These promising derivatives showed increase in the level of caspase-3. The trifloromethylphenyl derivatives of pyrazolopyrimidoquinolines 3b and 3d showed considerable tubulin polymerization inhibitory activity. Both compounds arrested cell cycle at G2/M phase and induced apoptosis. CONCLUSION: Compounds 3b and 3d can be considered as promising anticancer active agents with 70% of colchicine activity on tubulin polymerization inhibition and represent hopeful leads that deserve further investigation and optimization.