Search

Introduction: Bacteria have acquired resistance to almost all antibiotics currently in use due to their extensive, broad, and improper utilization over a prolonged period. DNA gyrase and DHFR exhibit significant promise as targets for antibacterial therapeutics. Methods: We have developed a series of disalicylic acid methylene/Schiff bases hybrids (6a-l) that function as antibacterial agents by targeting DNA gyrase and DHFR. Results and discussion: The findings showed that 6a-l have significant antibacterial activity against both Gram-positive and Gram-negative bacteria, with inhibition zones (IZ) comparable to or even higher than the reference Ciprofloxacin. MIC testing revealed that 6h and 6l were 1.5 times as effective than ciprofloxacin against S. aureus. Compounds 6h and 6l had MBC values of 28 and 33 nM for S. aureus , compared to Ciprofloxacin's 45 nM, indicating that they are more potent bactericidal agents. The MIC values for compounds 6c , 6e , 6h , 6j , and 6l against A. flavus were between 14.50 and 19.50 µM, while the MIC value for fluconazole was 11.50 µM. Also, the studied compounds had MIC values between 18.20 and 22.90 µM against C. albicans , while Fluconazole had a MIC value of 17.50 µM. Compound 6h showed a MIC value of 1.70 µM against the clinical strain S. aureus (ATCC 43300) (MRSA), making it an effective antibacterial agent. Compounds 6h , 6j , and 6l inhibited E. coli DNA gyrase with IC50 values of 79, 117, and 87 nM, respectively, compared to the reference novobiocin (IC50 = 170 nM). Additionally, compounds 6h and 6l , the most potent E. coli gyrase inhibitors, showed encouraging results on DHFR. Compounds 6h and 6l exhibit IC50 values of 3.80 µM and 4.25 µM, respectively. These values are significantly lower and hence more effective than Trimethoprim's IC50 of 5.20 µM. [ABSTRACT FROM AUTHOR]

Introduction: We developed and produced a new series of 4,6-diaryl-pyrimidines 9–29 as antiproliferative agents targeting EGFR/VEGFR-2. Methods: The antiproliferative efficacy of the novel targets was assessed against a panel of 60 NCI cancer cell lines and four cancer cell lines in vitro. Results and Discussion: Compounds 14 , 17 , 19 , 22 , 25 , and 29 demonstrated the greatest potency among the derivatives, with GI50 values between 22 and 33 nM; compounds 22 and 29 exhibited the highest potency, with GI50 values of 22 and 24 nM, respectively. We subsequently examined the most efficient derivatives as dual EGFR/VEGFR-2 inhibitors, finding that compounds 22 and 29 functioned as dual inhibitors. Moreover, 22 and 29 can act as apoptotic inducers by increasing Bax levels and decreasing levels of the anti-apoptotic protein Bcl2. At both 24- and 48-h intervals, the cell migration rates of compounds 22 and 29 were lower than those of untreated cells, according to the migration rate and wound closure percentage assessment. The wound closure rate reached 100% after 72 h of therapy with compound 22 but only 80% with compound 29. The docking study showed that compounds 22 and 29 had docking scores similar to those of Erlotinib and Sorafenib, co-crystallized ligands, for the EGFR and VEGFR-2 proteins. The experiments on lipophilicity showed that the new pyrimidines had a consistent result. This group of compounds has better biological activity in all the biological systems studied with low lipophilicity. [ABSTRACT FROM AUTHOR]

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors. [ABSTRACT FROM AUTHOR]

The present study details the design, synthesis, and bio-evaluation of indoles 3-16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS) with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3-16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7,12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids' 12and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8-16, highlighting their potential as therapeutic agents with reduced toxicity. [ABSTRACT FROM AUTHOR]

Introduction: The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors. Methods: The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents. Results and Discussion: The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAF[sup V600E] inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAF[sup V600E] inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFR[sup T790M]), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents. [ABSTRACT FROM AUTHOR]

Pyrano[3,2-c]quinoline-3-carboxylate derivatives 3a-j were synthesized efficiently by the microwave–irradiated condensation of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 4a-j with ethyl cyanoacetate (2) in the presence of ethanol and a catalytic amount of piperidine. The structures of the products were confirmed by a combination of spectral techniques including infra-red (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and elemental analyses in addition to X-ray structure analysis. The synthesized compounds 3a-j were tested for their in vitro antiproliferative activity against four human cancer cell lines using the MTT assay and doxorubicin as the reference drug: pancreas (Panc-1) cancer cell line, breast cancer (MCF-7) cell line, colon cancer (HT-29) cell line, and epithelial cancer (A-549) cell line. In comparison to the standard doxorubicin (GI50 = 1.10 µM), compounds 3a-j demonstrated promising antiproliferative action, with GI50 values ranging from 1.30 to 5.90 µM. The most effective derivatives were compounds 3c, 3g, 3h, and 3i with GI50 values ranging from 1.30 to 2.20 µM. The most potent antiproliferative derivative, compound 3c (R1 = OCH3, R2 = R3 = H), was also the most potent EGFR inhibitor, with an IC50 value of 105 ± 08 nM, 1.3-fold less potent than erlotinib (IC50 = 80 ± 05 nM). Compounds 3g (R1 = Br, R2 = R3 = H) and 3h (R1 = Cl, R2 = R3 = H) were the second and third most active, with IC50 values of 124 ± 10 nM and 195 ± 13 nM, respectively. Molecular docking calculations were conducted to inspect the docking scores and poses of the most promising compounds against EGFR and BRAFV600E. Based on the docking computations, compounds 3c and 3g revealed promising docking scores against the EGFR and BRAFV600E with values of − 7.9 and − 8.3 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine‐carboxamide derivatives 7a‐q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF‐10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated in vitro against four panels of cancer cell lines A‐549, MCF‐7, Panc‐1, and HT‐29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of 0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A‐549 (epithelial cancer cell line), MCF‐7 (breast cancer cell line), and HT‐29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform. [ABSTRACT FROM AUTHOR]

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds. [ABSTRACT FROM AUTHOR]

A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc, VIf, VIg, VIi, and VIk have the highest antiproliferative activity. Compounds VIc, VIf, VIg, VIi, and VIk inhibited EGFR with IC50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAFV600E (IC50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI50 = 44 and 35 nM against four cancer cell lines, respectively). Compound VIk, the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC50 value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, VIc, VIf, and VIk have a high capacity to inhibit LOX-IMVI cell line survival. A series of piperine-carboximidamide hybrids VIa-k was designed and synthesised. The new compounds were evaluated as antiproliferative agent targeting EGFR, BRAF, and CDK2. Antiproliferative activities were evaluated against four human cancer cell lines. Molecular docking studies were carried out against EGFR, mutated BRAF and CDK2-TK. In silico ADME/pharmacokinetic analysis was considered. [ABSTRACT FROM AUTHOR]

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects. [ABSTRACT FROM AUTHOR]

New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

Introduction: One of the most robust global challenges and difficulties in the 21st century is cancer. Treating cancer is a goal which continues to motivate researchers to innovate in design and development of new treatments to help battle the disease. Objectives: Our objective was developing new antiapoptotic hybrids based on biologically active heterocyclic motifs "benzimidazole?oxadiazole-chalcone hybrids'' that had shown promising ability to inhibit EGFR and induce apoptosis. We expected these scaffolds to display anticancer activity via inhibition of BRAF, EGFR, and Bcl-2 and induction of apoptosis through activation of caspases. Methods: The new hybrids 7a-x were evaluated for their anti-proliferative, EGFR & BRAFV600E inhibitory, and apoptosis induction activities were detected. Docking study & dynamic stimulation into EGFR and BRAFV600E were studied. Results: All hybrids exhibited remarkable cell growth inhibition on the four tested cell lines with IC50 ranging from 0.95 μM to 12.50 μM. which was comparable to Doxorubicin. Compounds 7k-m had the most potent EGFR inhibitory activity. While, compounds 7e, 7g, 7k and 7l showed good inhibitory activities against BRAFV600E. Furthermore, Compounds 7k, 7l, and 7m increased Caspases 3,8 & 9, Cytochrome C and Bax levels and decreased Bcl-2 protein levels. Compounds 7k-m received the best binding scores and showed binding modes that were almost identical to each other and comparable with that of the co-crystalized Erlotinib in EGFR and BRAF active sites. Conclusion: Compounds 7k-m could be used as potential apoptotic anti-proliferative agents upon further optimization. [ABSTRACT FROM AUTHOR]

A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects. [ABSTRACT FROM AUTHOR]