Discovery of novel octahydroquinazoline scaffolds endowed with dual inhibition of tubulin polymerization/Eg5 against HCC: Apoptotic and radio-chemotherapeutic studies.

Mitotic kinesin Eg5 isozyme as a motor protein plays a critical role in cell division of tumor cells. Kinesin Eg5 selective inhibitors and Colchicine binding site suppressors are essential targets for many anticancer drugs and radio chemotherapies. On this work, a new series of octahydroquinazoline as anti-mitotic candidates 2-13 has been synthesized with dual inhibition of tubulin polymerization/Eg5 against HCC cell line. All octahydroquinazolines have been in vitro assayed against HepG-2 cytotoxicity, Eg5 inhibitory and anti-tubulin polymerization activities. The most active analogues 7, 8, 9, 10, and 12 against HepG-2 were further subjected to in vitro cytotoxic assay against HCT-116 and MCF-7 cell lines. Chalcones 9, 10, and 12 displayed the most cytotoxic potency and anti-tubulin aggregation in comparable with reference standard colchicine and potential anti-mitotic Eg5 inhibitory activity in comparison with Monastrol as well. Besides, they exhibited cell cycle arrest at the G2/M phase. Moreover, good convinced apoptotic activities have been concluded as overexpression of caspase-3 levels and tumor suppressive gene p53 in parallel with higher induction of Bax and inhibition of Bcl-2 biomarkers. Octahydroquinazoline 10 displayed an increase in caspase-3 by 1.12 folds compared to standard colchicine and induce apoptosis and demonstrated cell cycle arrest in G2/M phase arrest by targeting p53 pathway. Analogue 10 has considerably promoted cytotoxic radiation activity and boosted apoptotic induction in HepG-2 cells by 1.5 fold higher than standard colchicine.

Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies.

A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS cancer (SNB-75), and ovarian cancer (OVAR-4) with IC50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and BAX proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Novel indolyl 1,2,4-triazole derivatives as potential anti-proliferative agents: in silico studies, synthesis, and biological evaluation.

A new series of indolyl 1,2,4-triazole scaffolds was designed, synthesised, and biologically evaluated for their inhibitory activity against both CDK4 and CDK6. The results ranged from 0.049 µM to 3.031 µM on CDK4 and from 0.075 µM to 1.11 µM on CDK6 when compared to staurosporine, with IC50 values of 1.027 and 0.402 µM, respectively. Moreover, all compounds were tested for their cytotoxicity against two breast cancer cell lines, MCF-7 and MDA-MB-231. All of the synthesised compounds showed promising anti-proliferative activity, with two compounds Vf (IC50 = 2.91 and 1.914 µM, respectively) and Vg (IC50 = 0.891 and 3.479 µM, respectively) having potent cytotoxic activity in comparison to the reference staurosporine (IC50 = 3.144 and 4.385 µM, respectively). Vf and Vg were also found to significantly induce apoptosis to 45.33% and 37.26% (control = 1.91%) where Vf arrested the cell cycle at the S phase while Vg arrested the cycle at the G0/G1 phase. The binding mode and interactions of all compounds were studied and found to mimic those of the FDA approved CDK4/6 inhibitor palbociclib that was used as a reference throughout the study.

Synthesis of novel pyrimido[4,5-b]quinoline derivatives as dual EGFR/HER2 inhibitors as anticancer agents.

A series of novel N-aryl-5-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-4-amines 4a-4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3a-3c. Pyrimido[4,5-b]quinolines 4a-4l showed promising activity against the Michigan Cancer Foundation-7 (MCF-7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC50 values of 2.67, 6.82, 4.31, and 1.62 µM, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC50 values of 0.065, 0.116, and 0.052 µM, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC50 values of 0.09, 0.164, and 0.055 µM, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cell-cycle analysis and induced cell-cycle arrest at the S phase. Compound 4l induced apoptosis 60-fold compared with control untreated MCF-7 cells. 4l can inhibit cancer metastasis. It reduced MCF-7 cell infiltration and metastasis by 45% compared with control untreated cells.

Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives as novel anti-cancer, dual EGFRWT/COX-2 inhibitors with docking studies.

A novel series of pyrimidine-5-carbonitrile derivatives was designed, synthesized, then evaluated for their cytotoxic activity as novel anti-cancer with dual EGFRWT/COX-2 inhibitors. Two compounds 4e and 4f disclosed the highest activity against all NCI60 panel cell lines. They were most potent against Colo 205 (IC50 = 1.66, and 1.83 µM), Sequentially. The most potent two compounds disturbed cell cycle of Colo-205 cells by blocking the G1 phase, coupled with increased annexin-Vstained cells which indicated the increasing in percentage of apoptosis. In addition, 4e and 4f increase the concentration of caspase-3 by 10, and 8-fold compared to control, respectively. Moreover, the two candidate compounds were screened for cytotoxicity on normal epithelial colon cells; fortunately, they were found to be safe. Molecular docking study displayed that these compounds bound to the active site as EGFRWT/COX-2 inhibitors. Furthermore, 3D pharmacophore mapping disclosed many shared features between the most potent candidates 4e and 4f and the standard EGFRWT/COX-2 inhibitors; erlotinib, and celecoxib, respectively. Finally, the physicochemical parameter was calculated for the most potent novel anticancer candidates and the SwissAdme parameter showed that the newly synthesized compounds have good drug-likeness properties.

New Phenylthiazoles: Design, Synthesis, and Biological Evaluation as Antibacterial, Antifungal, and Anti-COVID-19 Candidates.

The combination of antibacterial and antiviral agents is becoming a very important aspect of dealing with resistant bacterial and viral infections. The N-phenylthiazole scaffold was found to possess significant anti-MRSA, antifungal, and anti-COVID-19 activities as previously published; hence, a slight refinement was proposed to attach various alkyne lipophilic tails to this promising scaffold, to investigate their effects on the antimicrobial activity of the newly synthesized compounds and to provide a valuable structure-activity relationship. Phenylthiazole 4 m exhibited the most potent anti-MRSA activity with 8 µg/mL MIC value. Compounds 4 k and 4 m demonstrated potent activity against Clostridium difficile with MIC values of 2 µg/mL and moderate activity against Candida albicans with MIC value of 4 µg/mL. When analyzed for their anti-COVID-19 inhibitory effect, compound 4 b emerged with IC50 =1269 nM and the highest selectivity of 138.86 and this was supported by its binding score of -5.21 kcal mol-1 when docked against SARS-CoV-2 M pro . Two H-bonds were formed, one with His164 and the other with Met49 stabilizing phenylthiazole derivative 4 b, inside the binding pocket. Additionally, it created two arene-H bonds with Asn142 and Glu166, through the phenylthiazole scaffold and one arene-H bond with Leu141 via the phenyl ring of the lipophilic tail.

Synthesis of novel pyrimido[4,5-b]quinolines as potential anticancer agents and HER2 inhibitors.

A series of N-arylpyrimido[4,5-b]quinolines 3a-e and 2-aryl-2,3-dihydropyrimido[4,5-b]quinoline-4(1H)-ones 5a-e was designed and synthesized as potential anticancer agents against breast cancer. Compounds 3e, 5a, 5b, 5d, and 5e showed promising activity against the MCF-7 cell line. Among them, compound 5b was the most active with IC50 of 1.67 µM. Compound 5b promoted apoptosis and induced cell cycle arrest at S phase. 5b increased the level of pro-apoptotic proteins p53, Bax, and caspase-7 and inhibited the anti-apoptotic protein Bcl-2. Furthermore, all the synthesized compounds were docked into the crystal structure of HER2 (PBD: 3 pp0). Compounds 3e, 5a, 5b, 5d, and 5e showed good energy scores and binding modes. Finally, Compound 5b was evaluated on the HER2 assay and revealed good inhibition with IC50 of 0.073 µM.

Early electrophysiological study variants and their relationship with clinical presentation and outcomes of patients with Guillain-Barré syndrome.

This study compared the clinical outcomes of the two main neurophysiological types of Guillain-Barré Syndrome (GBS). Sixty-two GBS patients were examined clinically at onset using Medical Research Council (MRC), Hughes disability scales (HDS), and nerve conduction studies were evaluated in four limbs. The Modified Erasmus GBS outcome score (MEGOS) was assessed 2 weeks after onset. Outcomes were measured after 3 months using MRC and HDS scores. According to electrophysiological data two main groups identified acute inflammatory demyelinating polyneuropathy (AIDP = 31 cases) or acute axonal GBS including inexcitable forms (26 cases). The number of days between onset of weakness and admission was significantly shorter, and gastrointestinal symptoms were significantly higher among the axonal type than AIDP. MRC sum scores at onset and at nadir were significantly worse in the axonal type than in AIDP. Neck muscle weakness, impaired cough reflex, the need for mechanical ventilation, hypoalbuminemia, and hypernatremia were more common in the axonal type. At outcome, 74% of the AIDP were healthy/minor symptoms versus 38.46% of the axonal type. There was a high prevalence of the axonal variant (41.9%) compared with European and North American populations. The axonal type had a significantly worse outcome than AIDP type.

Recent Modifications of Anti-dementia Agents Focusing on Tacrine and/or Donepezil Analogs.

Alzheimer's Disease (AD) is a multifactorial incurable neurodegenerative disorder. It is characterized by a decline of cholinergic function in parallel with ß-amyloid fibril deposition. Such an imbalance causes severe loss in memory and cognition, leading to behavioral disturbances, depression, and ultimately death. During the last decades, only a few approved drugs were launched onto the market with indications for treating initial and moderate stages of AD. To date, cholinesterase inhibitors (ChEI) are the mainstay line of treatment to ameliorate AD symptoms. Tacrine and Donepezil are the most commonly prescribed anti-dementia drugs, given their potent inhibitory effects. Therefore, many trials have focused on both drugs' structures to synthesize new anti-dementia agents. This paper discusses recent trends of new AD-treating anti-dementia agents focusing on Tacrine and Donepezil analogs and multifunctional hybrid ligands.

New 5-Aryl-1,3,4-Thiadiazole-Based Anticancer Agents: Design, Synthesis, In Vitro Biological Evaluation and In Vivo Radioactive Tracing Studies.

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a-g), benzyl piperidine (4i), and aryl aminothiazoles (5a-e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model.

The Anti-MRSA Activity of Phenylthiazoles: A Comprehensive Review.

Antimicrobial resistance is an aggravating global issue therefore it has been under extensive research in an attempt to reduce the number of antibiotics that are constantly reported as obsolete jeopardizing the lives of millions worldwide. Thiazoles possess a reputation as one of the most diverse biologically active nuclei, and phenylthiazoles are no less exceptional with an assorted array of biological activities such as anthelmintic, insecticidal, antimicrobial, antibacterial, and antifungal activity. Recently phenyl thiazoles came under the spotlight as a scaffold having strong potential as an anti-MRSA lead compound. It is a prominent pharmacophore in designing and synthesizing new compounds with antibacterial activity against multidrug-resistant bacteria such as MRSA, which is categorized as a serious threat pathogen, that exhibited concomitant resistance to most of the first-line antibiotics. MRSA has been associated with soft tissue and skin infections resulting in high death rates, rapid dissemination, and loss of millions of dollars of additional health care costs. In this brief review, we have focused on the advances of phenylthiazole derivatives as potential anti-MRSA from 2014 to 2021. The review encompasses the effect on biological activity due to combining this molecule with various synthetic pharmacophores. The physicochemical aspects were correlated with the pharmacokinetic properties of the reviewed compounds to reach a structure-activity relationship profile. Lead optimization of phenyl thiazole derivatives has additionally been outlined where the lipophilicity of the compounds was balanced with the metabolic stability and oral solubility to aid the researchers in medicinal chemistry, design, and synthesizing effective anti- MRSA phenylthiazoles in the future.

Effects of transcranial direct current stimulation in pain and opioid consumption after spine surgery.

BACKGROUND: Transcranial direct current stimulation (tDCS) has shown promising results in alleviating different types of pain. The present study compares the efficacy of three sessions of anodal tDCS applied over primary motor area (M1) or the left dorsolateral prefrontal cortex (DLPFC) or sham on reducing pain and the total opioid consumption in postoperative spine surgery patients. MATERIALS: Sixty-seven out of 75 eligible patients for postoperative spine surgery were randomly allocated into one of the three experimental groups. Group A received anodal tDCS applied over M1 cortex, group B over left DLPF cortex (2 mA, 20 min) and group C received sham tDCS, all for 3 consecutive postoperative days. Patients were evaluated using a visual analogue scale (VAS) and adynamic visual analogue scale (DVAS) at baseline, and on each of the treatment days. The total morphine consumption over the 3 postoperative days was assessed. RESULTS: Two-way repeated measures ANOVA showed no statistically significant difference in resting VAS between the three groups. However, there was significant pain improvement (P < 0.001) in DVAS in both active groups (group A and B) compared to the sham group (group C) in the postoperative period, with no significant difference between the active groups. Morphine consumption was significantly reduced in both active groups compared with the sham group, but there was no difference in consumption between the active groups. CONCLUSION: There was a significant postoperative reduction in morphine consumption and DVAS scores after three sessions of active tDCS. SIGNIFICANCE: tDCS is a promising tool for alleviating pain in the field of postoperative spine surgery.

Synthesis and biological evaluation of halogenated phenoxychalcones and their corresponding pyrazolines as cytotoxic agents in human breast cancer.

Novel halogenated phenoxychalcones 2a-f and their corresponding N-acetylpyrazolines 3a-f were synthesised and evaluated for their anticancer activities against breast cancer cell line (MCF-7) and normal breast cell line (MCF-10a), compared with staurosporine. All compounds showed moderate to good cytotoxic activity when compared to control. Compound 2c was the most active, with IC50 = 1.52 µM and selectivity index = 15.24. Also, chalcone 2f showed significant cytotoxic activity with IC50 = 1.87 µM and selectivity index = 11.03. Compound 2c decreased both total mitogen activated protein kinase (p38α MAPK) and phosphorylated enzyme in MCF-7 cells, suggesting its ability to decrease cell proliferation and survival. It also showed the ability to induce ROS in MCF-7 treated cells. Compound 2c exhibited apoptotic behaviour in MCF-7 cells due to cell accumulation in G2/M phase and elevation in late apoptosis 57.78-fold more than control. Docking studies showed that compounds 2c and 2f interact with p38alpha MAPK active sites.

Pre- and in-hospital delays in the use of thrombolytic therapy for patients with acute ischemic stroke in rural and urban Egypt.

Background: Reducing pre- and in-hospital delays plays an important role in increasing the rate of intravenous thrombolysis (IVT) in patients with acute ischemic stroke. In Egypt, the IVT rate has increased steadily but is still far away from an ideal rate. Aim: The study aimed to investigate the factors associated with pre- and in-hospital delays of IVT among patients with acute ischemic stroke coming from urban and rural communities. Methods: This prospective, multicenter, observational cohort study was conducted from January 2018 to January 2019. Patients with acute ischemic stroke, who did not receive IVT, were included in the study. Patients were recruited from three large university stroke centers in Egypt, Assiut (south of Egypt), Tanta (north of Egypt), both serving urban and rural patients, and the University Hospital in Cairo (capital city), only serving an urban community. All participants underwent the National Institutes of Health Stroke Scale and full neurological assessment, urgent laboratory investigations, and computed tomography or magnetic resonance imaging to confirm the stroke diagnosis. The patients were subjected to a structured questionnaire that was designed to determine the parameters and time metrics for the pre- and in-hospital delays among patients from rural and urban regions. Results: A total of 618 patients were included in the study, of which 364 patients (58.9%) lived in rural regions and 254 (41.1%) in urban regions. General demographic characteristics were similar between both groups. Approximately 73.3% of patients who arrived within the therapeutic time window were urban patients. The time from symptom onset till hospital arrival (onset to door time, ODT) was significantly longer among rural patients (738 ± 690 min) than urban patients (360 ± 342 min). Delayed onset to alarm time (OAT), initial misdiagnosis, and presentation to non-stroke-ready hospitals were the most common causes of pre-hospital delay and were significantly higher in rural patients. For patients arriving within the time window, the most common causes of in-hospital delays were prolonged laboratory investigations and imaging duration. Conclusion: The limited availability of stroke-ready hospitals in rural Egypt leads to delays in stroke management, with subsequent treatment inequality of rural patients with acute stroke.

Design, Synthesis, and Antipoliferative Activities of Novel Substituted Imidazole-Thione Linked Benzotriazole Derivatives.

A new series of benzotriazole moiety bearing substituted imidazol-2-thiones at N1 has been designed, synthesized and evaluated for in vitro anticancer activity against the different cancer cell lines MCF-7(breast cancer), HL-60 (Human promyelocytic leukemia), and HCT-116 (colon cancer). Most of the benzotriazole analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, BI9 showed potent activity against the cancer cell lines such as MCF-7, HL-60 and HCT-116 with IC50 3.57, 0.40 and 2.63 µM, respectively. Compound BI9 was taken up for elaborate biological studies and the HL-60 cells in the cell cycle were arrested in G2/M phase. Compound BI9 showed remarkable inhibition of tubulin polymerization with the colchicine binding site of tubulin. In addition, compound BI9 promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2. These results provide guidance for further rational development of potent tubulin polymerization inhibitors for the treatment of cancer.

Case Report: Guillain-Barré Syndrome Associated With COVID-19.

Guillain-Barré syndrome (GBS) is a potentially fatal, immune-mediated disease of the peripheral nervous system that is usually triggered by infection. Only a small number of cases of GBS associated with COVID-19 infection have been published. We report here five patients with GBS admitted to the Neurology, Psychiatry, and Neurosurgery Hospital, Assiut University/Egypt from July 1 to November 20, 2020. Three of the five patients were positive for SARS-CoV-2 following polymerase chain reaction (PCR) of nasopharyngeal swabs on day of admission and another one had a high level of IgM and IgG; all had bilateral ground-glass opacities with consolidation on CT chest scan (GGO) and lymphopenia. All patients presented with two or more of the following: fever, cough, malaise, vomiting, and diarrhea with variable duration. However, there were some peculiarities in the clinical presentation. First, there were only 3 to 14 days between the onset of COVID-19 symptoms and the first symptoms of GBS, which developed into flaccid areflexic quadriplegia with glove and stocking hypoesthesia. The second peculiarity was that three of the cases had cranial nerve involvement, suggesting that there may be a high incidence of cranial involvement in SARS-CoV-2-associated GBS. Other peculiarities occurred. Case 2 presented with a cerebellar hemorrhage before symptoms of COVID-19 and had a cardiac attack with elevated cardiac enzymes following onset of GBS symptoms. Case 5 was also unusual in that the onset began with bilateral facial palsy, which preceded the sensory and motor manifestations of GBS (descending course). Neurophysiological studies showed evidence of sensorimotor demyelinating polyradiculoneuropathy, suggesting acute inflammatory polyneuropathy (AIDP) in all patients. Three patients received plasmapheresis. All of them had either full recovery or partial recovery. Possible pathophysiological links between GBS and COVID-19 are discussed.

Design, synthesis and assessment of new series of quinazolinone derivatives as EGFR inhibitors along with their cytotoxic evaluation against MCF7 and A549 cancer cell lines.

New acetamide (IV a-e) and 1,3-thiazolidinone derivatives (VII a-e) were designed, synthesized and assessed for their cytotoxic activity against MCF-7 and A549 cell lines along with their lead compounds (erlotinib and gefitinib). The newly designed compounds were prepared according to the adopted procedures in schemes 1 and 2 from their quinazolinone parents. 3D QSAR pharmacophore and docking molecular modeling protocols were conducted using Discovery Studio program, beside a full biological assay for these compounds. The cytotoxicity evaluation demonstrated that compounds IVb, IVc, VIIa, VIIb, VIId exhibited potent cytotoxic activities against both MCF-7 and A549 cell lines. Moreover, the molecular modeling studies corroborated to the affinity of the compounds towards EGFR. Consequently, these five compounds were then screened for their EGFR inhibition and evaluated as well for their toxicity to normal cells, which revealed that the acetamide derivative IVc and the thiazolidinone derivative VIIa were the most potent and least toxic. DNA flow cytometry analysis was conducted for compounds IVc and VIIa, which indicated that they both induced arrest at G2/M phase of the cell cycle.

Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors.

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC50 values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.

Evaluation of N-phenyl-2-aminothiazoles for treatment of multi-drug resistant and intracellular Staphylococcus aureus infections.

The increasing emergence of antibiotic-resistant bacterial pathogens calls for additional urgency in the development of new antibacterial candidates. N-Phenyl-2-aminothiazoles are promising candidates that possess potent anti-MRSA activity and could potentially replenish the MRSA antibiotic pipeline. The initial screen of a series of compounds in this novel class against several bacterial strains revealed that the aminoguanidine analogues possessed promising activities and superior safety profiles. The determined MICs of these compounds were comparable to, if not better than, those of the control drugs (linezolid and vancomycin). Remarkably, compounds 3a, 3b, and 3e possessed potent activities against multidrug resistant staphylococcal isolates and several clinically important pathogens, such as vancomycin-resistant enterococci (VRE) and Streptococcus pneumoniae. In addition, the compounds were superior to vancomycin in the rapid killing of MRSA and the longer post-antibiotic effects. Furthermore, low concentrations of compounds 3a, 3b, and 3e reduced the intracellular burden of MRSA by greater than 90%. Initial in vitro PK/toxicity assessments revealed that compound 3e was highly tolerable and possessed a low metabolic clearance rate and a highly acceptable half-life.

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX-2/5-LOX inhibitors.

A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising anti-inflammatory activity. Compound 3j was found to be the most promising derivative, with IC50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.