Tailored quinoline hybrids as promising COX-2/15-LOX dual inhibitors endowed with diverse safety profile: Design, synthesis, SAR, and histopathological study.

Complications of the worldwide use of non-steroidal anti-inflammatory drugs (NSAIDs) sparked scientists to design novel harmless alternatives as an urgent need. So, a unique hybridization tactic of quinoline/pyrazole/thioamide (4a-c) has been rationalized and synthesized as potential COX-2/15-LOX dual inhibitors, utilizing relevant reported studies on these pharmacophores. Moreover, we extended these preceding hybrids into more varied functionality, bearing crucial thiazole scaffolds(5a-l). All the synthesized hybrids were evaluatedin vitroas COX-2/15-LOX dual inhibitors. Initially, series4a-cexhibited significant potency towards 15-LOX inhibition (IC50 = 5.454-4.509 µM) compared to meclofenamate sodium (IC50 = 3.837 µM). Moreover, they revealed reasonable inhibitory activities against the COX-2 enzyme in comparison to celecoxib.Otherwise, conjugates 5a-ldisclosed marked inhibitory activity against 15-LOX and strong inhibitory to COX-2. In particular, hybrids5d(IC50 = 0.239 µM, SI = 8.95), 5h(IC50 = 0.234 µM, SI = 20.35) and 5l (IC50 = 0.201 µM, SI = 14.42) revealed more potency and selectivity outperforming celecoxib (IC50 = 0.512 µM, SI = 4.28). In addition, the most potentcompounds, 4a, 5d, 5h, and 5l have been elected for further in vivoevaluation and displayed potent inhibition of edema in the carrageenan-induced rat paw edema test that surpassed indomethacin. Further, compounds5d, 5h, and 5l decreased serum inflammatory markers including oxidative biomarkersiNO, and pro-inflammatory mediators cytokines like TNF-α, IL-6, and PGE. Ulcerogenic liability for tested compounds demonstrated obvious gastric mucosal safety. Furthermore, a histopathological study for compound 5l suggested a confirmatory comprehensive safety profile for stomach, kidney, and heart tissues. Docking and drug-likeness studies offered a good convention with the obtained biological investigation.

N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Design, Synthesis, In Vitro, and In Silico Studies of New N5-Substituted-pyrazolo[3,4-d]pyrimidinone Derivatives as Anticancer CDK2 Inhibitors.

CDK2 is a key player in cell cycle processes. It has a crucial role in the progression of various cancers. Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are two common cancers that affect humans worldwide. The available therapeutic options suffer from many drawbacks including high toxicity and decreased specificity. Therefore, there is a need for more effective and safer therapeutic agents. A series of new pyrazolo[3,4-d]pyrimidine analogs was designed, synthesized, and evaluated as anticancer agents against the CRC and HCC cells, HCT116, and HepG2, respectively. Pyrazolo[3,4-d]pyrimidinone derivatives bearing N5-2-(4-halophenyl) acetamide substituents were identified as the most potent amongst evaluated compounds. Further evaluation of CDK2 kinase inhibition of two potential cytotoxic compounds 4a and 4b confirmed their CDK2 inhibitory activity. Compound 4a was more potent than the reference roscovitine regarding the CDK2 inhibitory activity (IC50 values: 0.21 and 0.25 µM, respectively). In silico molecular docking provided insights into the molecular interactions of compounds 4a and 4b with important amino acids within the ATP-binding site of CDK2 (Ile10, Leu83, and Leu134). Overall, compounds 4a and 4b were identified as interesting CDK2 inhibitors eliciting antiproliferative activity against the CRC and HCC cells, HCT116 and HepG2, respectively, for future further investigations and development.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

In vivo screening and toxicity studies of indolinone incorporated thiosemicarbazone, thiazole and piperidinosulfonyl moieties as anticonvulsant agents.

Based on the biological importance of the thiazole nucleus, we decided to prepare and evaluate the biological activity of some new isatin derivatives containing thiazole moiety. The 5-(piperidin-1-ylsulfonyl)indoline-2,3-dione (1) was prepared and used as a starting material in the synthesis of many isatin derivatives for anticonvulsant evaluation. All the newly synthesized thiazlidino/thiosemicarbazide-indolin-2-one derivatives screened in vivo for their anticonvulsant activity against pentylenetetrazole-induced convulsions in mice. The results were compared with phenobarbitone sodium as a standard anticonvulsant drug. Most of the tested compounds exhibited anticonvulsant activity with relative potency ranging from 0.02 to 0.2 in comparison to standard drug phenobarbitone. The most active compounds 3, 6a, 6c and 8, were exposed to further investigations in rats to evaluate the effect of most active derivatives on the haematological, liver, kidney functions as well as histopathological studies of the liver and kidney tissues. Finally, the most potent compounds 3, 6a, 6c and 8 observed good toxic properties for both liver and kidney function with mild variability changes on RBCs, WBCs, Platelets, Hb, AST, ALT, and creatinine level, as well as kidney and liver tissue and these good results obtained rather than used low dose from phenobarbitone.

Design, Synthesis, biological Evaluation, and molecular docking studies of novel Pyrazolo[3,4-d]Pyrimidine derivative scaffolds as potent EGFR inhibitors and cell apoptosis inducers.

A series of novel hybrid pyrazolo[3,4-d]pyramidine derivatives was designed and chemically synthesized in useful yields. The synthesized compounds were structurally characterized by the usual techniques. All the new synthesized compounds were biologically screened in vitro for their antiproliferative activities against a panel of four cancer cell lines, namely HepG-2, MCF-7, HCT-116, and Hela. The results of cytotoxic evaluation indicated that compound 14d was appeared to be the most prominent broad-spectrum cytotoxic activity and significantly more potent than sorafenib with IC50 values of 4.28, 5.18, 3.97, and 9.85 µM against four cell lines (HePG2, Hela, HCT-116 and MCF-7). In addition, compound 15 was displayed promising antiproliferative effect against all tested cell lines with IC50 value less than 11 µM compared with sorafenib as a control drug. Besides, structurally pharmacophoric features indicated that pyrazolo[3,4-d]pyrimidine scaffold having an amide linker and substituted with phenyl moiety at the 5-position was more potent than those possessing azomethine methyl, azomethine proton and carbomethene linkers, which lead to significant decrease in antiproliferative activity. The most potent compounds were further selected and evaluated for their activities against epidermal growth factor receptor (EGFR) kinase inhibitors according to homogenous time resolved fluorescence (HTRF) assay. The most potent compound 14d exhibited the most promising inhibitory activity against EGFRWT with IC50 value of 56.02 ± 1.38 µM compared with gefitinib as control drug with IC50 value of 41.79 ± 1.07 µM. Moreover, the inhibition of cell cycle progression and induction of apoptosis in the A549 cell line at G2/M and pre-G1 phases of cell cycle might contribute to cancer treatment that evaluated by Annexin V-FITC/PI double staining detection method. Finally, molecular docking studies were conducted to investigate that probable binding conformations of these anticancer agents and ADME properties were calculated to predict pharmacokinetics and toxic properties of the target compounds.

Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies.

Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4-d]pyrimidine is a versatile scaffold that has been exploited for developing potential anticancer agents. On the basis of fragment-based drug discovery, considering the essential pharmacophoric features of potent EGFR tyrosine kinase (TK) inhibitors, herein, we report the design and synthesis of new hybrid molecules of the pyrazolo[3,4-d]pyrimidine scaffold linked with diverse pharmacophoric fragments with reported anticancer potential. These fragments include hydrazone, indoline-2-one, phthalimide, thiourea, oxadiazole, pyrazole, and dihydropyrazole. The synthesized molecules were evaluated for their anticancer activity against the human breast cancer cell line, MCF-7. The obtained results revealed comparable antitumor activity with that of the reference drugs doxorubicin and toceranib. Docking studies were performed along with EGFR-TK and ADMET profiling studies. The results of the docking studies showed the ability of the designed compounds to interact with key residues of the EGFR-TK through a number of covalent and noncovalent interactions. The obtained activity of compound 25 (IC50 = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.

From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity.

Inhibition of PCAF bromodomain has been validated as a promising strategy for the treatment of cancer. In this study, we report the bioisosteric modification of the first reported potent PCAF bromodomain inhibitor, L-45 to its triazoloquinazoline bioisosteres. Accordingly, three new series of triazoloquinazoline derivatives were designed, synthesized, and assessed for their anticancer activity against a panel of four human cancer cells. Three derivatives demonstrated comparable cytotoxic activity with the reference drug doxorubicin. Among them, compound 22 showed the most potent activity with IC50 values of 15.07, 9.86, 5.75, and 10.79 µM against Hep-G2, MCF-7, PC3, and HCT-116 respectively. Also, compound 24 exhibited remarkable cytotoxicity effects against the selected cancer cell lines with IC50 values of 20.49, 12.56, 17.18, and 11.50 µM. Compounds 22 and 25 were the most potent PCAF inhibitors (IC50, 2.88 and 3.19 µM, respectively) compared with bromosporine (IC50, 2.10 µM). Follow up apoptosis induction and cell cycle analysis studies revealed that the bioisostere 22 could induce apoptotic cell death and arrest the cell cycle of PC3 at the G2/M phase. The in silico molecular docking studies were additionally performed to rationalize the PCAF inhibitory effects of new triazoloquinazoline bioisosteres.

Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies.

A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).

In vivo and in vitro anti-inflammatory, antipyretic and ulcerogenic activities of pyridone and chromenopyridone derivatives, physicochemical and pharmacokinetic studies.

Throughout this study, we present the victorious synthesis of a novel class of 2(1H)-pyridone molecules, bearing a 4-hydroxyphenyl moiety through a one-pot reaction of 2-cyano-N-(4-hydroxyphenyl)acetamide with cyanoacetamide, acetylacetone or ethyl acetoacetate, and their corresponding aldehydes. In addition, the chromene moiety was introduced into the pyridine skeleton through the cyclization of the cyanoacetamide 2 with salicylaldehyde, followed by treatment with malononitrile, ethyl cyanoacetate, and cyanoacetamide, in order to improve their biological behaviour. Due to their anti-inflammatory, ulcerogenic, and antipyretic characters, the target molecules have undergone in-vitro and in-vivo examination, that display promising results. Moreover, in order to predict the physicochemical and ADME traits of all synthesized compounds and standard reference drugs, paracetamol and phenylbutazone, the in-silico prediction methodology was provided.

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists.

Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC50 values ranging from 1.9 to 6.4 µM on MDA-MB 231 cell line. Additionally, molecular docking for all synthesized compounds was performed to predict their binding affinity toward the homology model of A2B receptor as a proposed mode of their cytotoxic activity. Results of molecular docking were strongly correlated with those of the cytotoxic study. Finally, structure activity relationship analyses of the new compounds were explored.

Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies.

The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC50 = 3.61 µM), followed by 21 which displayed IC50 value of 3.93 µM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand-protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles.

Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives.

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 µg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 µg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 µM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.

Novel 1,2,4-triazole derivatives: Design, synthesis, anticancer evaluation, molecular docking, and pharmacokinetic profiling studies.

Three novel series of 1,2,4-triazole derivatives were designed and synthesized as potential adenosine A2B receptor antagonists. The design of the new compounds depended on a virtual screening of a previously constructed library of compounds targeting the human adenosine A2B protein. Spectroscopic techniques including 1 H nuclear magnetic resonance (NMR) and 13 C NMR, and infrared and mass spectroscopy were used to confirm the structures of the synthesized compounds. The in vitro cytotoxicity evaluation was carried out against a human breast adenocarcinoma cell line (MDA-MB-231) using the MTT assay, and the obtained results were compared with doxorubicin as a reference anticancer agent. In addition, in silico studies to propose how the two most active compounds interact with the adenosine A2B receptor as a potential target were performed. Furthermore, a structure-activity relationship analysis was performed, and the pharmacokinetic profile to predict the oral bioavailability and other pharmacokinetic properties was also explained. Four of our designed derivatives showed promising cytotoxic effects against the selected cancer cell line. Compound 15 showed the highest activity with an IC50 value of 3.48 µM. Also, compound 20 revealed an equipotent activity with the reference cytotoxic drug, with an IC50 value of 5.95 µM. The observed IC50 values were consistent with the obtained in silico docking scores. The newly designed compounds revealed promising pharmacokinetic profiles as compared with the reference marketed drug.

Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects.

The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10-32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83-13.97 µM), similar to doxorubicin (IC50, 4.17-8.87 µM) and afatinib (IC50, 5.4-11.4 µM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06-10.5 µM), similar to doxorubicin (IC50, 4.50 µM) and afatinib (IC50, 5.4 µM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83-10.36 and 5.69-11.36 µM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 µM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56-12.28 µM) compared with doxorubicin (IC50, 8.87 µM) and afatinib (IC50 7.7 µM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 µM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 µM, respectively) compared with bromosporine (IC50, 5.00 µM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 µM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.

Novel triazolophthalazine-hydrazone hybrids as potential PCAF inhibitors: Design, synthesis, in vitro anticancer evaluation, apoptosis, and molecular docking studies.

Three novel series of triazolophthalazine derivatives bearing hydrazone moiety were designed, synthesized, and evaluated for their anticancer activity against four human cancer cell lines by MTT assay. Six derivatives demonstrated comparable activity with Doxorubicin reference drug against the selected cancer cells. Especially, compound 16 showed the most potent activity with IC50 values of 5.70, 8.04, 11.15, and 4.25, µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Also, compound 26 exhibited comparable inhibitory effect with that of Doxorubicin against the selected cancer cell lines with IC50 values of 6.45, 8.63, 12.28, and 7.03 µM against HePG2, MCF-7, PC3, and HCT-116 respectively. Investigation of the apoptotic activity of the two most active compounds revealed that compounds 16 and 26 could induce both the early and the late apoptosis of HePG2. Further mechanistic study of the HePG2 cell cycle confirmed the spectacular cytotoxic and apoptotic effects of both compounds. Compounds 16 and 26 showed a pronounced increase in cells in G2/M and Pre G1 phases with a concomitant reduction of cells in G0-G1 and S phases. A follow up enzymatic assay indicated that these two compounds have comparable activities with that of bromosporine as PCAF inhibitors with IC50 values of 8.13 and 5.31 µM respectively. Moreover, molecular docking study for all the synthesized compounds was performed to predict their binding affinities toward the active site of histone acetyltransferase GCN5. Results of molecular docking were strongly correlated with that of the cytotoxicity study.

Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B.

A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.

tert-Butylphenylthiazoles with an oxadiazole linker: a novel orally bioavailable class of antibiotics exhibiting antibiofilm activity.

The structure-activity and structure-kinetic relationships of a new tert-butylphenylthiazole series with oxadiazole linkers were conducted with the objective of obtaining a new orally available antibacterial compounds. Twenty-two new compounds were prepared, purified and identified. Their activity against methicillin-resistant Staphylococcus aureus were examined. Compound 20 with 3-hydroxyazetidine as a nitrogenous side chain showed promising activity against twenty-four clinical isolates, including vancomycin-resistant staphylococcal and enterococcal species with MIC values ranging from 4-8 µg mL-1. Additional advantages of this compound include an ability to eradicate staphylococcal biofilm mass in a dose-dependent manner as well as high metabolic stability after an oral dose of 25 mg kg-1 with a biological half-life that exceeds 5 hours and a plasma concentration (C max) that exceeds the MIC values.

Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents.

3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H-pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver carcinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64-7.73 µg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated.