Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review.

Lung cancer is the second most common cause of morbidity and mortality among cancer types worldwide, with non-small cell lung cancer (NSCLC) representing the majority of most cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are among the most commonly used targeted therapy to treat NSCLC. Recent years have seen the evaluation of many synthetic EGFR TKIs, most of which showed therapeutic activity in pertinent models and were classified as first, second, and third-generation. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are ineffective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism. This review covers the fourth-generation EGFR-TKIs' most recent design with their essential binding interactions, the clinical difficulties, and the potential outcomes of treating patients with EGFR mutation C797S resistant to third-generation EGFR-TKIs was also discussed. Moreover, the utilization of various therapeutic strategies, including multi-targeting drugs and combination therapies, has also been reviewed.

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC50 values from 0.74-4.62 µM against MCF-7 cell line (sunitinib IC50 = 4.77 µM) and from 1.13-8.81 µM against HepG2 cell line (sunitinib IC50 = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC50 values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC50 = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior.

Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2.

Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer. cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.

Design and synthesis of novel benzimidazole derivatives as potential Pseudomonas aeruginosa anti-biofilm agents inhibiting LasR: Evidence from comprehensive molecular dynamics simulation and in vitro investigation.

Quorum sensing (QS) inhibition is one of the potential methods to target bacterial infection. In this study, comprehensive molecular dynamics simulation (MDS) experiments were conducted on the LasR structure to understand its structural dynamic behavior either in its ligand-free form or in its ligand-bound form (i.e. agonist or antagonist). The results revealed that LasR structure is significantly unstable in its ligand-free and antagonist-bound forms and such structural instability led eventually to complete dissociation of the functioning LasR dimeric form. Accordingly, twenty-eight benzimidazole derivatives were designed, synthesized as potential LasR antagonists, and characterized in vitro as QS inhibitors. Compounds 3d and 7f disclosed the highest percentage inhibition in biofilm formation, pyocyanin, and rhamnolipids production in Pseudomonas aeruginosa (71.70%, 68.70%, 54.00%) and (68.90%, 68.00%, 51.80%), respectively. MDS experiments revealed that these compounds as inhibitors, particularly, 3d, 7f, 8a, and 9g induce LasR structure instability and complete dissociation of its functioning dimeric form similarly to the previously reported inhibitor bromophenethyl-2-nitrobenzamide (BPNB). Furthermore, gene expression assays as another mechanism targeting quorum sensing genes to prove the inhibitory activity of these compounds on virulence factors, revealed that a number of the synthesized compounds were able to downregulate lasR (e.g. 3d and 7f by 61.70% and 26.00%, respectively) and rhlR (e.g. 7f by 16.30%) expressions. The results presented here provide a functional model for LasR that could guide future design of LasR inhibitors.

Design, synthesis and mechanistic studies of novel imidazo[1,2-a]pyridines as anticancer agents.

Herein, the design, synthesis and mechanistic study of five series of imidazo[1,2-a]pyridines 8a-d, 9a-f, 11a-c, 12a-d and 14a-d as anticancer agents were discussed. The cytotoxicity of imidazo[1,2-a]pyridine derivatives was screened against NCI 60 cancer cell lines. The cytotoxicity of compounds 8b, 8c, 9e and 9f was then evaluated against leukemia K-562 cancer cell line and normal lung fibroblasts (WI38). The hydrazone derivatives 8b and 8c exhibited significant cytotoxic activities against the leukemia K-562 cancer cell line with good safety margins (IC50 = 2.91 µM, SI = 8.32 and IC50 = 1.09 µM, SI = 10.54, respectively). In addition, compounds 8b, 8c, 9e and 9f were tested for their EGFR and COX-2 inhibitory activities. The hydrazone derivatives 8b and 8c were the most active EGFR inhibitors with IC50 values of 0.123 and 0.072 µM, respectively. Compound 8c selectively inhibited COX-2 (IC50 = 1.09 µM, SI = 13.78). Moreover, the potential of compound 8c to induce apoptosis in leukemia K-562 cell line was determined. Compound 8c showed a pre-G1 apoptosis and a growth arrest of leukemia K-562 cell line at G1 phase of cell cycle. Also, compound 8c was able to induce caspase-3 overexpression (6.98 folds), if compared to control. Finally, molecular docking studies and physicochemical properties calculation of compounds 8b, 8c, 9e and 9f were carried out to explain the biological data and to predict bioavailability of the most active compounds.

Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives have been designed and synthesized as combretastatin CA-4 analogs. They were screened for anticancer and tubulin polymerization inhibition activities. The trimethoxyphenyl 1,2,4-triazolo[1,5-a]pyrimidine derivative 4c showed significant antiproliferative activity in which it exhibited IC50 = 0.53 µM against HCT-116 cancer cell line. It was further tested as a tubulin polymerization inhibitor showing an IC50 = 3.84 µM if compared to combretastatin IC50 = 1.10 µM. Further mechanism studies revealed that compound 4c could obviously inhibit the proliferation of HCT-116 cancer cells by inducing apoptosis and arresting the cell cycle at the G2/M phase. Furthermore, docking studies showed that compound 4c illustrated good fitting to the colchicine binding site of tubulin. Thus, it is considered an anticancer lead compound worthy of further development as a tubulin polymerization inhibitor.

Synthesis, biological evaluation, and molecular modeling studies of acetophenones-tethered 1,2,4-triazoles and their oximes as epidermal growth factor receptor inhibitors.

A series of 5-(4-pyridyl)-1,2,4-triazoles hybrids with acetophenones and their oxime derivatives was rationally designed and synthesized as epidermal growth factor receptor (EGFR) kinase inhibitors. Initially, drug Likeness and pharmacokinetics properties of the prepared compounds were evaluated. Afterward, the prepared compounds were in vitro screened for their ability to inhibit the growth of the NCI-60 human cancer cell lines where certain compounds showed moderate activity. Compounds 4e and 5b emerged as the most potent compounds in this series were further tested for their EGFR enzyme inhibition activity. They showed IC50 values of 0.14 and 0.18 µM, respectively, in comparison with Gefitinib as a reference with an IC50 value of 0.06 µM. Docking of compounds 4e and 5b into the binding site of EGFR tyrosine kinase was performed to explains their possible binding mode and to compare it with known inhibitors. Moreover, molecular dynamic simulations were estimated for deeper understanding of the binding mode of compounds 4e and 5b at the binding site of EGFR tyrosine kinase. The findings indicated that the novel ligands 4e and 5b were stable in the EGFR tyrosine kinase active site.

Lipophilicity study of different cephalosporins: Computational prediction of minimum inhibitory concentration using salting-out chromatography.

The chromatographic and lipophilicity characters of seven cephalosporins of different four classes (cephradine, cefaclor, cefprozil, cefixime, cefotaxime, ceftazidime and cefepime) were examined by salting out thin-layer chromatography (SOTLC). SOTLC using ammonium sulfate salt was employed to predict the lipophilicity of the proposed drugs via their retention behavior. The calculated RM0 values showed liner relationship with the molar concentration of ammonium sulfate in mobile phase in the range of 0.5-2.5 mol/L. Additionally, quantitative structure retention relationship (QSRR) was generated to figure out the relationship between the calculated chromatographic parameters (RM0 and C0) and log P of the studied cephalosporins. Good correlations were found between the chromatographically obtained retention parameters (RM0 and C0) and some molecular descriptors of the examined drugs. Furthermore, an efficient QSAR model was carried out using the calculated chromatographic parameters (RM0 and C0) and log P of the studied cephalosporins to predict minimum inhibitory concentration (MIC) and blood brain barrier (BBB) penetration of the examined drugs. The study was extended to separate and quantify the selected antibiotics in their pure forms and pharmaceutical formulations. Normal phase thin layer chromatographic (NP-TLC) method using a usable developing system of acetone: methanol: water: ammonium hydroxide: glacial acetic acid (90: 10: 18: 3: 2, by volume) was successfully applied to resolve the studied cephalosporins. Linearity was achieved in the range of 0.2-3 µg/mL for most of the studied antibiotics. The developed SOTLC method can be considered as a good start alternative to reversed phase thin layer chromatography (RP-TLC) for prediction of the lipophilic properties of examined cephalosporins. Moreover, the proposed NP-TLC densitometric method can be easily applied for quality control analysis of the chosen drugs and other structurally related components.

Design, synthesis and mechanistic study of new 1,2,4-triazole derivatives as antimicrobial agents.

Novel 5-amino-1,2,4-triazole derivatives and their cyclized 1,2,4-triazolo[1,5-a]pyrimidine analogues were designed, synthesized and evaluated for their antimicrobial activities. They were tested against five bacterial strains (Methicillin Resistant S. aureus (MRSA), E. coli, K. pneumoniae, A. baumannii and P. aeruginosa) using ciprofloxacin as a positive control and against two fungal strains (C. albicans and C. neoformans) using fluconazole and amphotericin B as positive controls. Compounds 9, 13a and 13b showed high to moderate antifungal activities against candida albicans (MIC values = 4-32 µg/ml), with considerable safety profiles; where no cytotoxicity against human embryonic kidney or red blood cells were detected at concentrations up to 32 µg/mL. Furthermore, compound 9 showed significant inhibitory activity against lansterol 14α-demethylase (IC50 = 0.27 µM), compared to the reference drug fluconazole (IC50 = 0.25 µM). Molecular docking of compound 9 into the active site of the cytochrome P450 enzyme revealed comparable binding modes and docking scores to those of fluconazole. Finally, in silico ADME studies prediction and drug-like properties of these compounds revealed favorable oral bioavailability results.

Charge-Transfer Complex of Linifanib with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone: Synthesis, Spectroscopic Characterization, Computational Molecular Modelling and Application in the Development of Novel 96-microwell Spectrophotometric Assay.

BACKGROUND: Linifanib (LFB) is a multi-targeted receptor tyrosine kinase inhibitor used in the treatment of hepatocellular carcinoma and other types of cancer. The charge-transfer (CT) interaction of LFB is important in studying its receptor binding mechanisms and useful in the development of a reliable CT-based spectrophotometric assay for LFB in its pharmaceutical formulation to assure its therapeutic benefits. PURPOSE: The aim of this study was to investigate the CT reaction of LFB with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ) and its application in the development of a novel 96-microwell spectrophotometric assay for LFB. METHODS: The reaction was investigated, its conditions were optimized, the physicochemical and constants of the CT complex and stoichiometric ratio of the complex were determined. The solid-state LFB-DDQ complex was synthesized and its structure was analyzed by UV-visible, FT-IR, and 1H-NMR spectroscopic techniques, and also by the computational molecular modeling. The reaction was employed in the development of a novel 96-microwell spectrophotometric assay for LFB. RESULTS: The reaction resulted in the formation of a red-colored product, and the spectrophotometric investigations confirmed that the reaction had a CT nature. The molar absorptivity of the complex was linearly correlated with the dielectric constant and polarity index of the solvent; the correlation coefficients were 0.9526 and 0.9459, respectively. The stoichiometric ratio of LFB:DDQ was 1:2. The spectroscopic and computational data confirmed the sites of interaction on the LFB molecule, and accordingly, the reaction mechanism was postulated. The reaction was utilized in the development of the first 96-microwell spectrophotometric assay for LFB. The assay limits of detection and quantitation were 1.31 and 3.96 µg/well, respectively. The assay was successfully applied to the analysis of LFB in its bulk and tablets with high accuracy and precision. CONCLUSION: The assay is simple, rapid, accurate, eco-friendly as it consumes low volumes of organic solvent, and has high analysis throughput.

Bacterial virulence factors: a target for heterocyclic compounds to combat bacterial resistance.

Antibiotic resistance is one of the most important challenges of the 21st century. However, the growing understanding of bacterial pathogenesis and cell-to-cell communication has revealed many potential strategies for the discovery of drugs that can be used for the treatment of bacterial infections. Interfering with bacterial virulence and/or quorum sensing could be a particularly interesting approach, because it is believed to exert less selective pressure on the bacterial resistance than with traditional strategies, geared toward killing bacteria or preventing their growth. Here, we discuss the mechanism of bacterial virulence, presenting promising strategies and recently synthesized heterocyclic compounds to combat future bacterial infections.

Design, synthesis, biological assessment and in silico ADME prediction of new 2-(4-(methylsulfonyl) phenyl) benzimidazoles as selective cyclooxygenase-2 inhibitors.

A novel series of benzimidazole derivatives wherein 4-(methylsulfonyl) phenyl pharmacophore attached via its C-2 position was designed and synthesized. These compounds were evaluated in vitro as cyclooxygenase-1(COX-1)/cyclooxygenese-2(COX-2) inhibitors. Furthermore, the synthesized compounds were also in vivo evaluated for their anti-inflammatory activity and ulcerogenic liability. Examination of histopathological lesions was also performed to evaluate the cariogenic effect of most active compounds. In silico prediction of physicochemical properties, ADME, and drug-likeness profiles were also studied. Several compounds as 11b, 11k, 12b, and 12d showed selective inhibition to (COX-2) isozyme. Compound 11b showed the most potent (COX-2) inhibitory activity with (IC50 = 0.10 µM) and selectivity index (SI = 134); the tested compounds also have shown good anti-inflammatory activity. Regarding the ulcerogenic liability, compound 11b was also safest one (Ulcer Index) (UI = 0.83). The results of the molecular docking studies is closely related to the results of the in vitro COX-2 inhibitory activities.

Design, synthesis and molecular modeling studies of 2-styrylquinazoline derivatives as EGFR inhibitors and apoptosis inducers.

Herein, we report the synthesis of novel 2-substituted styrylquinazolines conjugated with aniline or sulfonamide moieties, anticipated to act as potent anticancer therapeutic agents through preferential EGFR inhibition. In doing so, all the synthesized compounds were screened for their in vitro anticancer activities (nine subpanels) at the National Cancer Institute (NCI), USA. The resulting two most active anticancer compounds (7b and 8c) were then chemically manipulated to investigate feasible derivatives (12a-e and 15a-d). MTT cytotoxicity, in vitro cell free EGFR and anti-proliferative activity against EGFR/ A549 cell line evaluation for the most active broadly spectrum candidates (7a/b, 8c/e, 12b and 15d) was conducted. Promising results were obtained for the styrylquinazoline-benzenesulfonamide derivative 8c (IC50 = 8.62 µM, 0.190 µM and = 79.25%), if compared to lapatanib (IC50 = 11.98 µM, 0.190 µM, and 79.25%), respectively. Moreover, its apoptotic induction potential was studied through cell cycle analysis, Annexin-V and caspase-3 activation assays. Results showed a clear cell arrest at G2/M phase, a late apoptotic increase (76 folds) and a fruitful caspase-3 expression change (8 folds), compared to the control. Finally, molecular docking studies of compounds 7a/b, 8c/e, 12b and 15d revealed proper fitting into the active site of EGFR with a low binding energy score for compound 8c (-13.19 Kcal/mole), compared to lapatanib (-14.54 Kcal/mole).

Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents.

Herein, novel three series of benzimidazole scaffold bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole moieties 1-3, 4a-j, 6a-c and 7 derivatives were designed, synthesized and evaluated for their antimicrobial activity. The structures of the prepared compounds were assigned using different spectroscopic techniques such as IR, 1H NMR, 13C NMR and elemental analyses. Compounds 3, 4a, 4e and 4f exhibited remarkable antifungal activity against C. albicans and C. neoformans var. grubii with MIC values ranging from 4 to 16 µg/mL. Furthermore, they were not cytotoxic against red blood cells and human embryonic kidney cells at concentration up to 32 µg/mL. The study was expanded to forecast the mechanism of action of the prepared compounds and determine sterol quantitation method (SQM) by spectrophotometric assay. On the other hand, compound 4e showed the highest inhibitory activity against lanosterol 14α-demethylase (CYP51) with IC50 value = 0.19 µg/mL compared to fluconazole as reference IC50 value = 0.62 µg/mL. Also, compounds 4d and 4f exhibited mild to moderate antibacterial activity. Moreover, molecular docking of the active target compound 4e in active site of lanosterol 14α-demethylase (CYP51) revealed that docking scores and binding mode are comparable to that of co-crystallized ligand confirming their antifungal activity. In silico ADME prediction investigations also forecasting the drug-like characters of these compounds.

Synthesis and biological evaluation of 2-(4-methylsulfonyl phenyl) indole derivatives: multi-target compounds with dual antimicrobial and anti-inflammatory activities.

Three series of 2-(4-methylsulfonylphenyl) indole derivatives have been designed and synthesized. The synthesized compounds were assessed for their antimicrobial, COX inhibitory and anti-inflammatory activities. Compound 7g was identified to be the most potent antibacterial candidate against strains of MRSA, E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii, respectively, with safe therapeutic dose. Compounds 7a-k, 8a-c, and 9a-c showed good anti-inflammatory activity with excessive selectivity towards COX-2 in comparison with reference drugs indomethacin and celecoxib. Compounds 9a-c were found to release moderate amounts of NO to decrease the side effects associated with selective COX-2 inhibitors. A molecular modeling study for compounds 7b, 7h, and 7i into COX-2 active site was correlated with the results of in vitro COX-2 inhibition assays.

Saccharomonosporine A inspiration; synthesis of potent analogues as potential PIM kinase inhibitors.

Saccharomonosporine A was recently reported as a natural anti-cancer agent working through inhibition of a Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) kinase. Structural bioisosteres of this natural product were synthesized and tested against PIM kinase enzymes. They showed potent inhibitory activity against all the known PIM kinases (PIM-1, 2 and 3) with IC50 values ranging from 0.22 to 2.46 µM. Compound 5 was the most potent pan-inhibitor with IC50 values of 0.37, 0.41, and 0.3 µM, against PIM-1, 2, 3 respectively. Compounds 4-6 were tested for their cytotoxic activities against 3 cell lines: H1650, HT-29, and HL-60. Compound 5 exhibited significant cytotoxic activity against human colon adenocarcinoma HT-29 and the human promyelocytic leukemia HL-60, with IC50 µM values of 1.4 and 1.7 respectively. Molecular docking and homology modeling studies were carried out to confirm the affinity of these synthesized compounds to the three different PIM kinases. Additionally, a number of in silico predictions, ADME/Tox, were adopted to evaluate their drug-likeness.

Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins.

The 2019 coronavirus (COVID-19) pandemic is spreading worldwide, with a dramatic increase in death without any effective therapeutic treatment available up to now. We previously reported quinazoline-trihydroxyphenyl Schiff base conjugates as phosphodiesterase 4B (PDE 4B) inhibitors (an enzyme that plays an essential role in the early stages of COVID-19 pneumonia). Additionally, the structural similarity between these conjugates and identified anti-severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 flavonoids inspired us to in silico study their possible binding interactions with essential SARS-CoV-2 proteins. Thus, this study provides an insight into the potential bindings between quinazoline-Schiff base conjugates and SARS-CoV-2 proteins, including spike glycoprotein (SGp), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), to offer an opportunity to find an effective therapy. Besides this, based on the role that COVID-19 plays in iron dysmetabolism, the conjugate trihydroxyphenyl moiety should be reconsidered as an iron chelator. Moreover, molecular dynamics simulations of quinazoline derivative Ic bound to the mentioned targets were carried out. Finally, ADMET calculations were performed for the studied compounds to predict their pharmacokinetic profiles.

Synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives: Antimicrobial activity, DNA Gyrase inhibition and molecular docking.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized and screened for their antibacterial and antifungal activities as well as their safety profile. Compounds 2b, 3a, 6b, 8b, 8c, 8h, 9a,b, 10b, 11a,b and 12a,b showed high activity against Gram-positive and Gram-negative bacteria with MIC values ranging from 0.25 to 2.0 µg/mL. Many compounds were safe with no cytotoxicity against human embryonic kidney and red blood cells at concentration up to 32 µg/mL. Moreover, compound 9a showed the highest inhibitory activity against DNA Gyrase with IC50 = 0.68 µM compared to ciprofloxacin IC50 = 0.85 µM. Molecular docking at DNA Gyrase active site revealed binding mode and docking scores comparable to that of ciprofloxacin confirming their antibacterial activity via DNA Gyrase inhibition.