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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 novel series of 1,2,3-triazole/quinazoline-4-one hybrids (8a-t) were designed and synthesized as dual-targeted antiproliferative agents. Compounds 8a-t were evaluated for their antiproliferative efficacy against a panel of four cancer cell lines. The results indicated that most of the evaluated compounds exhibited strong antiproliferative activity, with 8f, 8g, 8h, 8j, and 8l demonstrating the highest potency. These five compounds were investigated as EGFR and BRAF V600E inhibitors. The in vitro tests showed that compounds 8g, 8h, and 8j are strong antiproliferative agents that might work as dual EGFR/BRAF V600E inhibitors. Compounds 8g and 8h were further examined as activators of caspases 3, 8, and Bax and down-regulators of the anti-apoptotic protein Bcl2. The results indicated that the studied compounds had considerable apoptotic antiproliferative action. The investigation of the cell cycle and apoptosis revealed that compound 8g induces cell cycle arrest during the G1 phase transition. Molecular docking experiments are thoroughly examined to validate the binding interactions of the most active hybrids with the active sites of EGFR and BRAF V600E . The data indicated that the examined compounds can efficiently engage with essential amino acid residues in both kinases., Competing Interests: The author reported no potential conflicts of interest(s)., (This journal is © The Royal Society of Chemistry.)

A series of 1,2,4-triazolo[1,5- a ]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a - p with 3-phenyl-1,2,4-triazole-5-amine ( 5 ). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds ( 9d , 9n , 9o , and 9p ) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin's 10-90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than fluconazole's 11.50-17.50 μM values. Compounds 9n and 9o , in particular, showed excellent bactericidal activity. Compounds 9n and 9o , the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that 9n and 9o demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds 9n and 9o demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of E. coli DNA gyrase and DHFR enzymes., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC 50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Dual targeting of EGFR and HER2 is a valid anti-cancer approach for treating solid tumors. We designed and synthesized a new series of EGFR/HER-2 dual-target inhibitors based on quinoline derivatives. The structure of the newly synthesized compounds was verified using 1 H NMR, 13 C NMR, and elemental analysis. The targeted compounds were tested for antiproliferative efficacy against four cancer cell lines. All the compounds had GI 50 s ranging from 25 to 82 nM, with breast (MCF-7) and lung (A-549) cancer cell lines being the most sensitive. Compound 5a demonstrated the most significant antiproliferative action. With inhibitory (IC 50 ) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC 50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC 50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the anti-apoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends., Competing Interests: The authors reported no potential conflicts of interest(s)., (This journal is © The Royal Society of Chemistry.)

COX-2-selective drugs were withdrawn from the market just a few years after their development due to cardiovascular side effects. As a result, developing a selective COX-2 inhibitor as an anti-inflammatory agent with cardioprotective characteristics has become a prominent objective in medicinal chemistry. New 15 diaryl-1,2,4-triazolo[3,4- a ]pyrimidine hybrids 8a - o were synthesized and investigated in vitro as dual COX-2/sEH inhibitors. Compounds 8b , 8m , and 8o have the highest potency and selectivity as COX-2 inhibitors (IC 50 = 15.20, 11.60, and 10.50 μM, respectively; selectivity index (COX-1/COX-2) = 13, 20, and 25, respectively), compared to celecoxib (COX-2; IC 50 = 42 μM; SI = 8). The 5-LOX inhibitory activity of compounds 8b , 8m , and 8o was further examined in vitro . Compounds 8m and 8o , the most effective COX-2 selective inhibitors, demonstrated stronger 5-LOX inhibitory action than the reference quercetin, with IC 50 values of 2.90 and 3.05 μM, respectively. Additionally, compounds 8b , 8m , and 8o were the most potent dual COX-2/sEH inhibitors, with IC 50 values against sEH of 3.20, 2.95, and 2.20 nM, respectively, and were equivalent to AUDA (IC 50 = 1.2 nM). In vivo investigations also demonstrated that these compounds were the most efficacious as analgesic/anti-inflammatory derivatives with a high cardioprotective profile against cardiac biomarkers and inflammatory cytokines. The docking data analysis inquiry helped better understand the binding mechanisms of the most active hybrids within the COX-2 active site and supported their COX-2 selectivity. Compounds 8b , 8m , and 8o exhibited a similar orientation to rofecoxib and celecoxib, with a larger proclivity to enter the selectivity side pocket than the reference compounds., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

A new series of 1,3,4-thiadiazin-3-ium bromide derivatives 9a-g were prepared as a six-member ring by interactions between 4-substituted thiosemicarbazides 8a-e and α-halo ketones 2a,b. The reaction was conducted using hydrazine-NH 2 and yielded a hexagonal shape. The structures of all obtained compounds have been verified using IR, NMR spectra, mass spectrometry, elemental analysis, and X-ray crystallography. The X-ray crystallographic analysis of compounds 9a and 9b has revealed that the salt is formed with the nitrogen atom N3 when the aromatic substituents 9a and 9d are present, but in the case of compounds 9b, 9c, 9e, 9f, and 9g with the aliphatic substituent, the salt is formed outside the ring. Compounds 9a-g were evaluated for antiproliferative activity as multitargeted inhibitors. Results revealed that targets 9a-g displayed good antiproliferative activity, with GI 50 ranging from 38 nM to 66 nM against a panel of four cancer cell lines compared to the reference Erlotinib (GI 50 = 33 nM). Compounds 9a, 9c, and 9d were the most potent antiproliferative derivatives, with GI 50 values of 43, 38, and 47 nM, respectively. Compounds 9a, 9c, and 9d were evaluated for their inhibitory activity against EGFR, BRAF V600E , and VEGFR-2. The in vitro experiments demonstrated that the compounds being examined exhibit potent antiproliferative properties and have the potential to function as multitargeted inhibitors. In addition, the western blotting investigation demonstrated the inhibitory effects of 9c on EGFR, BRAF V600E , and VEGFR-2., Competing Interests: The authors state that they do not have any known competing financial interests or personal links that could appear to have influenced the work disclosed in this study., (This journal is © The Royal Society of Chemistry.)

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a-j) with apoptotic antiproliferative effects as dual EGFR/BRAF V600E inhibitors were designed and synthesized. Compounds 5a-j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a-j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a-j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI 50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI 50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAF V600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAF V600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAF V600E , with high docking scores of -8.55 kcal mol -1 and -8.22 kcal mol -1 , respectively. Furthermore, the ADME analysis of compounds 5a-j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation., Competing Interests: The authors reported no potential conflicts of interest(s)., (This journal is © The Royal Society of Chemistry.)