Drug Repurposing Approach in Developing New Furosemide Analogs as Antimicrobial Candidates and Anti-PBP: Design, Synthesis, and Molecular Docking.

Multidrug-resistant microorganisms have become a global health problem, prompting research into new antimicrobials. Drug repurposing is a new technique in drug discovery used to improve drug development success. As a well-studied medication with a sulfonamide moiety, furosemide was chosen to study its antimicrobial effect on different microbial strains. In addition, a new family of furosemide analogs was investigated for their antimicrobial efficacy. According to the obtained results, the majority of the examined molecules exhibited potential antimicrobial activity. Compounds 3b and 4a had the best anti-MRSA results, with an MIC = 7.81 µg/mL. They also demonstrated potent anti-gram-negative activity against E. coli (MIC = 1.95 µg/mL and 3.91 µg/mL, respectively). A time-killing kinetics study against E. coli and MRSA showed bactericidal actions of 3b and 4a within 120-150 min. Moreover, an anti-PBP activity and an in vitro cytotoxicity evaluation were performed. Furosemide decreased the PBP2a levels in MRSA by 21.5% compared to the control. However, the furosemide analogs 3b and 4a demonstrated superior anti-PBP activity (55.9 and 57.1 % reduction in the expression of PBP2a, respectively). In addition, compound 4a was nearly nontoxic to normal WI-38 cells (IC50 = 248.60 µg /mL) indicating its high safety profile. Finally, the ability of furosemide and compounds 3b and 4a to bind to the target PBP2a enzyme has also been supported by molecular docking research.

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC50 ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

Development of novel cyanopyridines as PIM-1 kinase inhibitors with potent anti-prostate cancer activity: Synthesis, biological evaluation, nanoparticles formulation and molecular dynamics simulation.

Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b, 3b, 4b, and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC50 = 0.248, 0.13, 0.326 and 0.245 µM, respectively. The most powerful derivatives2b, 3b, 4b, and 5b, were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b-PIM-1 complex has the low binding free energy (-242.2 kJ/mol) according to the MM-PBSA calculations.

Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia.

Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hits. The 7-(4-Bromo-phenyl)-3-(3-chloro/2-chloro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamines 5 h and 5i revealed the best CDK2 inhibitory activity with comparable potency (IC50 = 22 and 24 nM, respectively) to that of dinaciclib (IC50 = 18 nM). Additionally, both analogues showed potent activities against CDK1, CDK5 and CDK9 at nanomolar concentrations (IC50 = 28-80 nM). The anti-leukemia screening of the target compounds showed strong to moderate cytotoxicity against the used leukemia cell lines (MOLT-4 and HL-60). Compound 5 h inhibited MOLT-4 and HL-60 by 1.4 and 2.3 folds (IC50 = 0.93 and 0.80 µM), respectively, compared to dinaciclib (IC50 = 1.30 and 1.84 µM). Furthermore, compound 5i was comparable to dinaciclib against MOLT-4 and exhibited twice its activity against HL-60. Besides, the cytotoxicity of the promising analogues on normal human blood cells indicated the safety of 5h and 5i as compared to the reference dinaciclib. The pharmacokinetic properties of 5h and 5i were predicted using ADME calculations revealing good oral bioavailability and high GI absorption. The molecular docking simulations indicated, as expected, that the dinaciclib analogues can well-accommodate the CDK2 binding site, forming a variety of interactions.

Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives.

Novel derivatives of the pyrazoline scaffold were synthesized and investigated for their cytotoxicity against prostate (PC-3), hepatocellular (HepG2), and breast (MDA-MB-231) carcinoma cells. The most active compounds, 4a, 4b, 5b, and 7c, revealed significant and broad-spectrum anticancer activities with IC50 values of 1.30-7.18 µM in comparison with doxorubicin (IC50 = 5.12-7.33 µM). Additionally, they exhibited lower cytotoxicity against normal WI-38 cells, indicating their high safety profiles. Aiming to enlighten the inhibitory potential on receptor tyrosine kinases (RTKs), compounds 4a, 4b, 5b, and 7c were assessed for their activities against four different RTKs (EGFR, FGFR2, HER2, and VEGFR2) and their apoptotic potencies on PC-3 cells. The results revealed that compounds 5b and 7c are potent dual EGFR and VEGFR2 inhibitors (IC50 = 0.21 and 0.23 µM, respectively, against EGFR; 0.22 and 0.21 µM, respectively, against VEGFR2), whereas they displayed moderate inhibitory activities against HER2 and FGFR2. Besides, compounds 4a, 4b, 5b, and 7c prompted apoptosis via the upregulation of Bax, p53, and caspase-3, together with the downregulation of the levels of Bcl-2. Also, it was found that compounds 5b and 7c are more potent as apoptosis inducers than the other tested derivatives. Furthermore, molecular docking analyses of compounds 4a, 4b, 5b, and 7c in the EGFR and VEGFR ATP binding sites were performed, to confirm the in vitro assays.

Synthesis of antimicrobial azoloazines and molecular docking for inhibiting COVID-19.

Diverse new azoloazines were synthesized from the reaction of fluorinated hydrazonoyl chlorides with heterocyclic thiones, 1,8-diaminonaphthalene, ketene aminal derivatives, and 4-amino-5-triflouromethyl-1,2,4-triazole-2-thiol. The mechanistic pathways and the structures of all synthesized derivatives were discussed and assured based on the available spectral data. The synthesized azoloazine derivatives were evaluated for their antifungal and antibacterial activities through zone of inhibition measurement. The results revealed promising antifungal activities for compounds 4, 5, 17a,b, 19, and 25 against the pathogenic fungal strains used; Aspergillus flavus and Candida albicans compared to ketoconazole. In addition, compounds 4, 5, 19, and 25 showed moderate antibacterial activities against most tested bacterial strains. Molecular docking studies of the promising compounds were carried out on leucyl-tRNA synthetase active site of Candida albicans, suggesting good binding in the active site forming stable complexes. Moreover, docking of the synthesized compounds was performed on the active site of SARS-CoV-2 3CLpro to predict their potential as a hopeful anti-COVID and to investigate their binding pattern.

Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design, synthesis, radiolabeling and biodistribution study.

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.

Nano-sized formazan analogues: Synthesis, structure elucidation, antimicrobial activity and docking study for COVID-19.

Three series of nanosized-formazan analogues were synthesized from the reaction of dithiazone with various types of α-haloketones (ester and acetyl substituted hydrazonoyl chlorides and phenacyl bromides) in sodium ethoxide solution. The structure and the crystal size of the new synthesized derivatives were assured based on the spectral analyses, XRD and SEM data. The antibacterial and antifungal activities were evaluated by agar diffusion technique. The results showed mild to moderate antibacterial activities and moderate to potent antifungal activities. Significant antifungal activities were observed for four derivatives 3a, 3d, 5a and 5g on the pathogenic fungal strains; Aspergillus flavus and Candida albicans with inhibition zone ranging from 16 to 20 mm. Molecular docking simulations of the synthesized compounds into leucyl-tRNA synthetase editing domain of Candida albicans suggested that most formazan analogues can fit deeply forming stable complexes in the active site. Furthermore, we utilized the docking approach to examine the potential of these compounds to inhibit SARS-CoV-2 3CLpro. The results were very promising verifying these formazan analogues as a hopeful antiviral agents.

Design, synthesis, cytotoxicity screening and molecular docking of new 3-cyanopyridines as survivin inhibitors and apoptosis inducers.

Recently, targeting survivin proved to be an attractive strategy for developing anticancer agents. Survivin overexpression is highly correlated with cancer aggressiveness, recurrence and resistance to chemotherapeutic treatment and radiotherapy. Additionally, survivin is overexpressed selectively in most cancer types with a very little expression in completely differentiated cells, which encouraged us to design and synthesize a novel series of 3-cyanopyridine derivatives targeting survivin. The newly synthesized compounds were evaluated for their cytotoxic activities against three cancer cell lines; PC-3, HepG2 and MDA-MB-231. Compounds 4a, 4b, 5c and 6c showed significant cytotoxic activities that were more potent than the reference drug, 5-FU. Hence, these compounds were selected to be further studied regarding their apoptotic potential in PC-3 cells. Interestingly, they decreased the level of Bcl-2 by 1.9-3.8 folds and increased the level of Bax by 6.1-8.8 folds compared to the control. Moreover, they elevated the level of active caspase-3 by 7.1-8.5 folds in comparison to the control. In order to estimate the cytotoxicity level of these compounds in non-tumorigenic cells, WI38 cells were treated with these compounds. They showed high IC50 values (148.57-193.64 µM), indicating selective cytotoxicity to the tumor cells, and much less toxic effect to the normal ones. Additional studies on the mechanism of 4a, the most active compound, revealed that it induced cell cycle arrest at the G2/M phase in addition to an increase in the percentage of pre-G1 apoptotic cells. Furthermore, western blotting was carried out using different concentrations of 4a. Results showed that 4a markedly suppressed survivin expression in PC-3 cells and caused a decrease in the caspase-7/cleaved caspase-7 ratio and in Bcl-2/Bax ratio, in addition to an increase in the level of the cleaved PARP. Finally, docking study of the most active compound in the active site (dimerization site) of survivin was in agreement with the in vitro survivin inhibitory activity.

Discovery of thiazole-based-chalcones and 4-hetarylthiazoles as potent anticancer agents: Synthesis, docking study and anticancer activity.

The crucial need for novel antitumor agents with high selectivity toward cancer cells has promoted us to synthesize new series of thiazole-based chalcones and 4-hetarylthiazoles (rigid chalcones). The synthesis of thiazolyl chalcones and 4-hetarylthiazoles and the assertion of their structure are described. Their anti-proliferative activity was estimated against three human cancer cell lines; HepG-2, A549 and MCF-7. 3-(4-Methoxyphenyl)-1-(5-methyl-2-(methylamino)thiazol-4-yl)prop-2-en-1-one (chalcone derivative 3a) showed significant and broad antitumor activity that was more potent than Doxorubicin. In addition, compounds 3d, 3e and 7a displayed potent activity compared to Doxorubicin. Additionally, these compounds were less toxic on normal lung cells WI-38 with high selectivity index. Further study on 3a regarding its effect on the normal cell cycle profile in A549 cells demonstrated cell cycle arrest at the G2/M phase together with rise in the percentage of the apoptotic pre-G1 cells. CDK1/CDK2/CDK4 inhibition assays were carried out on 3a, 3d, 3e and 7a and the results revealed non selective inhibition on the tested CDKs with IC50 values of 0.78-1.97 µM. Moreover, docking study predicted that 3a, 3d, 3e and 7a can fit in the ATP binding site of CDK1 enzyme. The apoptosis induction potential of 3a, 3d, 3e and 7a was also estimated against some apoptosis markers. Interestingly, they elevated the level of Bax by 6.36-10.12 folds and reduced the expression of Bcl-2 by 1.94-4.12 folds compared to the control. Furthermore, they increased both active caspase-3 and p53 levels by 8.76-10.56 and 6.85-10.36 folds, respectively higher than the control which indicates their potential to induce apoptosis.

Novel anti-tubercular and antibacterial based benzosuberone-thiazole moieties: Synthesis, molecular docking analysis, DNA gyrase supercoiling and ATPase activity.

Herein, molecular hybridization strategy was utilized in the design of new benzosuberone-thiazole derivatives. The structures of the synthesized hybrids were determined on the basis of elemental and spectral analyses. These compounds were evaluated for their antibacterial activities against five bronchitis causing bacteria in addition to their anti-tubercular activities. Most compounds revealed promising activities. Amongst active compounds, benzosuberone-dithiazole derivatives 22a and 28 with MIC value = 1.95 µg/ml against H. influenza, M. pneumonia, and B. pertussis displayed four times the activity of ciprofloxacin (MIC = 7.81 µg/ml) against H. influenza, twice the activity of ciprofloxacin (MIC = 3.9 µg/ml) against M. pneumonia and were equipotent to ciprofloxacin against B. pertussis (MIC = 1.95 µg/ml). Additionally, benzosuberone-dithiazole derivatives 22a and 27 were the most promising anti-tubercular among the tested compounds with MIC values of 0.12 and 0.24 µg/ml, respectively against sensitive M. tuberculosis in addition to high activity against resistant strain of M. tuberculosis (MIC = 0.98 and 1.95 µg/ml, respectively) compared to isoniazid (MIC = 0.12 µg/ml against sensitive M. tuberculosis and no activity against resistant M. tuberculosis). Cytotoxicity study of the active dithiazole derivatives 22a, 27 and 28 against normal human lung cells (WI-38) indicated their high safety profile as showed from their high IC50 values (IC50 = 107, 74.8, and 117 µM, respectively). Furthermore, DNA gyrase supercoiling and ATPase activity assays showed that 22a, 27 and 28 have the potential to inhibit DNA gyrase at low micromolar levels (IC50 = 3.29-15.64 µM). Molecular docking analysis was also carried out to understand the binding profiles of the synthesized compounds into the ATPase binding sites of bacterial and mycobacterial DNA gyraseB.

Apoptosis: A target for anticancer therapy with novel cyanopyridines.

One of the many methods of treating cancer is to terminate the uncontrolled growth of cancer cells. So, aiming the apoptotic pathway is an exciting approach to finding new anticancer agents. A novel series of cyanopyridines was designed and synthesized for antiproliferative evaluation. 2-Amino-6-(4-(benzyloxy)phenyl)-4-(4-(dimethylamino)phenyl) nicotinonitrile 10f was the most potent inhibitor against the growth of PC-3, and HepG-2 cancer cell lines with IC50 values of 2.04 uM (selectivity index, SI = 78.63, 43, respectively). Also, 10f was safe against the growth of normal human diploid lung fibroblasts cell line (WI-38) with an IC50 value of 160.04 uM. Its analogs, 10b, 10d, 10g, and 11b, were also active against the growth of PC-3, and HepG-2 while against MCF-7 cell line, they displayed good cytotoxic activity compared to the reference standard 5-FU. Remarkably, mechanistic studies indicated that compounds 10b, 10d, 10f, 10g, and 11b stimulated the level of active caspase 3 and boosted the BAX/BCL2 ratio 20-95 folds in comparison to the control. Our results have also indicated that 10b, 10d, 10f, 10g, and 11b exhibited a very potent inhibitory activity against PIM-1 kinase enzyme, where the IC50 values unraveled very potent molecules in the micromolar range (0.47-1.27 µM). Further investigations have shown that 10f, the most potent PIM-1 kinase inhibitor, induced a cell cycle arrest at the G2/M phase. Moreover, in silico evaluation of ADME properties indicated that all the cyanopyridine compounds are orally bioavailable with no permeation to the blood brain barrier.

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers.

The overexpression of survivin is usually accompanied by an increased resistance of cancer cells to chemotherapeutic agents in addition to cancer aggressiveness. Consequently, survivin is considered as an attractive target to develop new promising anticancer candidates. A series of novel 3-cyanopyridine derivatives was synthesized and assessed for their cytotoxic activity against three human cancer cell lines: prostate carcinoma (PC-3), breast cancer (MDA-MB-231) and hepatocellular carcinoma (HepG2). In addition, their activities were evaluated in comparison with a standard anticancer drug 5-FU. Compounds 5c and 5e both exhibited promising cytotoxicity against all the tested cell lines; especially, 5e showed better cytotoxic effect than the reference drug 5-FU. In order to evaluate the safety of these compounds, they were tested on the normal cell line WI-38, revealing their toxic selectivity toward cancer cells over normal ones. Further studies were performed in order to understand their mechanism of action; we examined the ability of our promising compounds 5c and 5e to induce cell cycle arrest. Both resulted in a notable induction of cell cycle arrest at the G2/M phase, along with an increase in the DNA content in the pre-G1 phase, giving us an indication of the incidence of apoptosis. 5c and 5e were further subjected to additional study using Annexin V-FITC assay in order to evaluate their ability to induce apoptosis. The results showed a marked increase in the early and late apoptotic cells, as well as an increase in the percentage of necrosis. Furthermore, Western blotting assay was accomplished using different concentrations of 5c and 5e. The results revealed a striking reduction in survivin expression through proteasome-dependent survivin degradation in addition to a decrease in the expression of some other inhibitor of apoptosis proteins (IAP) family proteins: Livin, XIAP, and C-IAP1 in a concentration-dependent manner. A docking study of 5c and 5e compounds in the dimerization site of survivin was also performed, showing agreement with the in vitro anti-survivin activity.

Design, synthesis and biological evaluation of novel 1,3,4-trisubstituted pyrazole derivatives as potential chemotherapeutic agents for hepatocellular carcinoma.

A series of novel 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their cytotoxic activity against three different cancer cell lines namely HCT116, UO-31 and HepG2. Compounds 3b, 3d, 7b and 9 showed excellent anticancer activity against all the tested cancer cell lines and had better cytotoxic activities than the reference drug, Sorafenib. Therefore, these compounds were chosen to be further evaluated in a panel of HCC cell lines. Among them, 3b and 7b were the most active compounds against HCC cells used here. Further studies on the mechanism demonstrated that 3b and 7b induced apoptosis in addition to induction of cell cycle arrest at G2/M phase in HepG2 and Huh7 cells. Consistent with these results, caspase-3 assay was done and the results revealed that the pro-apoptotic activity of the target compounds could be due to the stimulation of caspases-3. In addition, CDK1 inhibition assay was done and it was found that compounds 3b and 7b inhibited CDK1 activities with IC50 values of 2.38 and 1.52 µM, respectively. Finally, pyrazole derivatives 3b and 7b showed potent bioactivities, indicating that these compounds could be potent anticancer drugs in the future.

Design and Synthesis of New bis-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity.

BACKGROUND: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development. METHODS: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride. RESULTS: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 µM) and MDA-MB-231 (IC50 = 3.23-7.98 µM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 µM against MCF-7 and 5.71 µM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 µM) compared to palbociclib (IC50 = 0.071 µM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation. CONCLUSION: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.

Chitosan-Aspirin Combination Inhibits Quorum-Sensing Synthases (lasI and rhlI) in Pseudomonas aeruginosa.

BACKGROUND: Quorum sensing (QS) controls the virulence of P. aeruginosa. This study aims to determine the anti-QS activity of aspirin alone and in combination with chitosan to reach maximum inhibition. We tested ten virulent Pseudomonas aeruginosa (P. aeruginosa) isolates and screened for N-acyl homoserine lactone (AHL) production using Agrobacterium tumefaciens as a biosensor. P. aeruginosa isolates were treated with sub-minimum inhibitory concentrations (MICs) of aspirin and chitosan-aspirin. We used broth microdilution and checkerboard titration methods to determine the MICs and the synergistic effect of these two compounds, respectively. Real-time polymerase chain reaction (PCR) was used to estimate the anti-QS activity of the aspirin-chitosan combination on the expression of lasI and rhlI genes. RESULTS: Aspirin decreased the motility and production of AHLs, pyocyanin, and biofilm. Chitosan potentiated the inhibitory effect of aspirin. The chitosan-aspirin combination inhibited lasI and rhlI gene expression in PAO1 (ATCC 15692) by 7.12- and 0.92-fold, respectively. In clinical isolates, the expression of lasI and rhlI was decreased by 1.76 × 102- and 1.63 × 104-fold, respectively. Molecular docking analysis revealed that aspirin could fit into the active sites of the QS synthases lasI and rhlI with a high binding affinity, causing conformational changes that resulted in their inhibition. CONCLUSIONS: The chitosan-aspirin combination provides new insights into treating virulent and resistant P. aeruginosa.

Targeting EGFR/PI3K/AKT/mTOR signaling in lung and colon cancers: synthesis, antitumor evaluation of new 1,2,4-oxdiazoles tethered 1,2,3-triazoles.

The EGFR/PI3K/Akt/mTOR pathway is important for metastasis, medication resistance, apoptosis prevention, and malignant transformation. Mutations in lung and colon cancer typically change this pathway's expression. As a result, a novel class of 1,2,4-oxdiazoles that are attached to 1,2,3-triazoles, 5-11, were created as possible anticancer drugs. The produced compounds are all examined by spectroscopic and micro-analytical techniques. MTT assay results on lung (A549) colon (Caco-2) and normal lung fibroblast (WI38) revealed that compounds 6a, 6b, 8a, and 11b demonstrated strong and selective antiproliferative activities against lung (A549) and colon (Caco-2) cancer cell lines while the remaining derivatives showed moderate to low activity. qPCR data revealed that the potential hits had large fold changes in the downregulation of EGFR, mTOR, and PI3K; they upregulate the amount of p53 to support their mode of action even more. Interestingly, docking investigations validated the biological outcomes by demonstrating a strong affinity of our compounds against EGFR active regions. Computational predictions of all the synthesized compounds' pharmacokinetic profiles, physicochemical characteristics, and drug-likeness data indicated that the promising hits might be taken into consideration as drug-like prospects.

Correction: Targeting EGFR/PI3K/AKT/mTOR signaling in lung and colon cancers: synthesis, antitumor evaluation of new 1,2,4-oxdiazoles tethered 1,2,3-triazoles.

[This corrects the article DOI: 10.1039/D4RA02222J.].

A Literature Review Focusing on the Antiviral Activity of [1,2,4] and [1,2,3]-triazoles.

Out of a variety of heterocycles, triazole scaffolds have been shown to play a significant part in a wide array of biological functions. Many drug compounds containing a triazole moiety with important antimicrobial, anticancer and antidepressant properties have been commercialized. In addition, the triazole scaffold exhibits remarkable antiviral activity either incorporated into nucleoside analogs or non-nucleosides. Many synthetic techniques have been produced by scientists around the world as a result of their wide-ranging biological function. In this review, we have tried to summarize new synthetic methods produced by diverse research groups as well as provide a comprehensive description of the function of [1,2,4] and [1,2,3]-triazole derivatives as antiviral agents. Antiviral triazole compounds have been shown to target a wide variety of molecular proteins. In addition, several strains of viruses, including the human immunodeficiency virus, SARS virus, hepatitis B and C viruses, influenza virus, Hantavirus, and herpes virus, were discovered to be susceptible to triazole derivatives. This review article covered the reports for antiviral activity of both 1,2,3- and 1,2,4-triazole moieties up to 2022.

Design, synthesis, and anti-hepatocellular carcinoma of thiopyrimidine/chalcone hybrids as dual STAT3/STAT5 inhibitors.

Among the promising therapeutic targets for treating cancer are the continuously active STAT proteins, which are important in the progression of many malignancies. Here, we detail the STAT3/5 inhibitory action and thiopyrimidine/chalcone hybrid design, production, and anti-hepatocellular carcinoma activity. The prepared hybrids were assessed for their cytotoxic effect on HepG2 and Huh7 liver cancer cells. The most active compounds 5e and 5h (IC50 range from 0.55 to 2.58 µM) were further evaluated against normal THLE cells to examine their safety profiles. The hybrids 5e and 5h were additionally tested for their potential to inhibit STAT3 and STAT5a. They showed dual inhibitory action, with a decrease in the level of STAT3 by 65 and 87 times, respectively, and a decrease in the level of STAT5 by 60 and 79.5 times, respectively, compared to the control. Additionally, western blot analysis of compound 5h revealed inhibition of STAT3 and STAT5 phosphorylation at Tyr705 and Tyr694, respectively, with only a slight decrease in the total expression of STAT3 and STAT5 proteins. And lastly, molecular docking research provided additional insight on the 5h binding mechanism in the STAT3 and STAT5 SH2 domains.