ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

Titania/graphene nanocomposites from scalable gas-phase synthesis for high-capacity and high-stability sodium-ion battery anodes.

In sodium-ion batteries (SIBs), TiO2or sodium titanates are discussed as cost-effective anode material. The use of ultrafine TiO2particles overcomes the effect of intrinsically low electronic and ionic conductivity that otherwise limits the electrochemical performance and thus its Na-ion storage capacity. Especially, TiO2nanoparticles integrated in a highly conductive, large surface-area, and stable graphene matrix can achieve an exceptional electrochemical rate performance, durability, and increase in capacity. We report the direct and scalable gas-phase synthesis of TiO2and graphene and their subsequent self-assembly to produce TiO2/graphene nanocomposites (TiO2/Gr). Transmission electron microscopy shows that the TiO2nanoparticles are uniformly distributed on the surface of the graphene nanosheets. TiO2/Gr nanocomposites with graphene loadings of 20 and 30 wt% were tested as anode in SIBs. With the outstanding electronic conductivity enhancement and a synergistic Na-ion storage effect at the interface of TiO2nanoparticles and graphene, nanocomposites with 30 wt% graphene exhibited particularly good electrochemical performance with a reversible capacity of 281 mAh g-1at 0.1 C, compared to pristine TiO2nanoparticles (155 mAh g-1). Moreover, the composite showed excellent high-rate performance of 158 mAh g-1at 20 C and a reversible capacity of 154 mAh g-1after 500 cycles at 10 C. Cyclic voltammetry showed that the Na-ion storage is dominated by surface and TiO2/Gr interface processes rather than slow, diffusion-controlled intercalation, explaining its outstanding rate performance. The synthesis route of these high-performing nanocomposites provides a highly promising strategy for the scalable production of advanced nanomaterials for SIBs.

Outbreaks of SARS-CoV-2 Infections in Nursing Homes during Periods of Delta and Omicron Predominance, United States, July 2021-March 2022.

SARS-CoV-2 infections among vaccinated nursing home residents increased after the Omicron variant emerged. Data on booster dose effectiveness in this population are limited. During July 2021-March 2022, nursing home outbreaks in 11 US jurisdictions involving >3 infections within 14 days among residents who had received at least the primary COVID-19 vaccine(s) were monitored. Among 2,188 nursing homes, 1,247 outbreaks were reported in the periods of Delta (n = 356, 29%), mixed Delta/Omicron (n = 354, 28%), and Omicron (n = 536, 43%) predominance. During the Omicron-predominant period, the risk for infection within 14 days of an outbreak start was lower among boosted residents than among residents who had received the primary vaccine series alone (risk ratio [RR] 0.25, 95% CI 0.19-0.33). Once infected, boosted residents were at lower risk for all-cause hospitalization (RR 0.48, 95% CI 0.40-0.49) and death (RR 0.45, 95% CI 0.34-0.59) than primary vaccine-only residents.

Intravascular Ultrasound Versus Computed Tomography Angiography in Sizing and Operative Management of Endovascular Aortic Aneurysm Repair.

OBJECTIVES: An abdominal aortic aneurysm (AAA) is a potentially life-threatening condition, the management of which has dramatically evolved over the past 2 decades with an increasing tendency toward endovascular repair (EVAR) rather than open surgical repair. Classically, contrast-enhanced multislice computed tomography (CT) angiography (CTA) is performed preoperatively for procedure sizing and EVAR planning. This entails voluminous contrast injection with risk of allergic reaction, nephropathy, and radiation exposure. Intra-vascular ultrasound (IVUS) has been increasingly used to guide EVAR procedures intraoperatively. The aim of this study is to investigate the accuracy of IVUS in sizing AAAs, device selection, and EVAR planning compared to the gold standard CTA. DESIGN: This is a prospective observational study enrolling 10 patients who underwent standard infrarenal EVAR procedures performed for unruptured infrarenal AAAs over the course of 1 year. All patients had a preoperative CTA done upon which aneurysm sizing and device planning were performed, and the measurements obtained were compared to those obtained from intraoperative IVUS. METHODS: All participating patients had unruptured infrarenal AAA, had no renal impairment, and had anatomical suitability for EVAR according to the instructions for use (IFU) of the device manufacturer. Primary endpoint was comparing anatomical measurements recorded by IVUS with those obtained from the preoperative CTA. RESULTS: Mean age was 65.6 (±6.19), all patients were males and hypertensives and 4 (40%) had a positive family history for AAA. On comparing mean measurements taken by CTA and IVUS, there was no statistically significant differences with exception of maximal aortic diameter and aortic diameter at site of bifurcation (both p-values <.001). There were no statistically significant differences in length measurements between the 2 imaging modalities. Computed tomography angiography was more associated with neck thrombus detection, and IVUS was more associated with calcification detection. CONCLUSION: Although CT angiography is still the gold standard imaging modality for AAA, IVUS use is very beneficial in EVAR sizing and planning, in addition to intra-operative guidance of the procedure, saving the patient significant time, contrast administration, and radiation exposure, especially in patients with renal impairment and contrast allergy. CLINICAL IMPACT: A preoperative CT angiogram is the gold standard required investigation for planning and sizing EVARs, with subsequent contrast injection entailing a risk of contrast induced nephropathy and allergic reactions. IVUS has been used as an adjuvant technique to guide EVAR stent graft deployment. However, our study concluded that it can also be reliably used in sizing and planning of the EVAR stent graft along with complementary non contrast imaging, especially in patients with high risk for contrast induced nephropathy and contrast allergy.

Multicomponent Domino Reaction for Concise Access to 2-Amino-Substituted 1,3,4 Oxadiazoles via Smiles Rearrangement.

A multicomponent domino reaction has been developed for the preparation of N-substituted 2-amino-1,3,4-oxadiazoles directly from various hydrazides (32 examples). The formation of 2-amino-1,3,4-oxadiazole involves the Smiles rearrangement of thiazolidinone, which results in the formation of carbodiimide intermediate that concomitantly undergoes amide-imidic acid tautomerism followed by cyclization. The protocol developed has wide applicability and provides the desired 2-amino-1,3,4-oxadiazole in excellent yields. The GSD studies of NMR spectra of aliphatic substrates (4di, 4dh) revealed the formation of three products, whereas, in the case of allylic and benzylic substrates, thiazolidinones were obtained as the sole products. Furthermore, to elucidate the plausible mechanism, DFT studies were performed affirming carbodiimide as the crucial intermediate for the interconversion of thiazolidinone to oxadiazole.

Helicobacter pylori eradication rates using clarithromycin and levofloxacin-based regimens in patients with previous COVID-19 treatment: a randomized clinical trial.

BACKGROUND: Helicobacter pylori (H. pylori) is affecting half of the globe. It is considered a main causative organism of chronic gastritis, peptic ulcer disease, and different gastric maliganacies. It has been also correlated to extraintestinal diseases, including refractory iron deficiency anaemia, vitamin B12 deficiency, and immune thrombocytopenic purpura. The misuse of antibiotics during the coronavirus diseases 2019 (COVID-19) pandemic time can affect H. pylori eradication rates. Our aim was to compare the efficacy of clarithromycin versus levofloxacin-based regimens for H. pylori treatment in naïve patients after the COVID-19 pandemic misuse of antibiotics. METHODS: A total of 270 naïve H. pylori infected patients with previous treatment for COVID-19 more than 3 months before enrolment were recruited. Patients were randomized to receive either clarithromycin, esomeprazole, and amoxicillin, or levofloxacin, esomeprazole, and amoxicillin. RESULTS: A total of 270 naïve H. pylori infected patients with previous treatment for COVID-19 more than 3 months before enrolment were included, 135 in each arm. In total, 19 patients in the clarithromycin group and 18 patients in the levofloxacin group stopped treatment after 2-4 days because of side effects or were lost for follow-up. Finally, 116 subjects in the clarithromycin group and 117 in the levofloxacin group were assessed. The eradication rates in intention to treat (ITT) and per protocol (PP) analyses were: group I, 55.56% and 64.66%; and Group II, 64.44% and 74.36% respectively (p = 0.11). CONCLUSION: As COVID-19 pandemic has moved forward fast, high resistance rates of H. pylori to both clarithromycin and levofloxacin were developed after less than two years from the start of the pandemic. Molecular & genetic testing is highly recommended to identify antimicrobial resistance patterns. Strategies to prevent antibiotic misuse in the treatment of COVID-19 are needed to prevent more antibiotic resistance. TRIAL REGISTRATION: The trial was registered on Clinicaltrials.gov NCT05035186. Date of registration is 2-09-2021.

Synthesis, biological evaluation and mechanistic studies of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as a new structural class of antimicrobials.

In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benzimidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide spectrum of microbes. Herein, we report the design and synthesis of a new structural class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as antimicrobial agents. The most potent analog, 6g shows IC50 of 1.3 µM, 2.7 µM, 10.8 µM, 5.4 µM and 10.8 µM against Cryptococcus neoformans, Candida albicans, Candida parapsilosis, Escherichia coli and Staphylococcus aureus, respectively. Interestingly 6g exhibits selectivity towards the cryptococcal cells with fungicidal behavior. Propidium iodide uptake study shows permeabilization of pathogenic cells in the presence of 6g. Flow cytometric analysis confirms that cell death is predominantly due to apoptosis. Moreover, electron microscopic analysis specifies that it shrinks, disrupts and initiate pore(s) formation in the cell membrane leading to cell lysis.

Benzimidazole-linked pyrazolo[1,5-a]pyrimidine conjugates: synthesis and detail evaluation as potential anticancer agents.

A library of benzimidazole briged pyrazolo[1,5-a]pyrimidine (6a-q) was designed, synthesized and subjected for evaluation for cytotoxic potential. Antiproliferative activity, ranging from 3.1-51.5 µM, was observed against a panel of cancer cell lines which included MCF-7 (breast cancer), A549 (lung cancer), HeLa (cervical cancer) and SiHa (cervical cancer). Among them, 6k, 6l, 6n and 6o have shown significant cytotoxicity and were investigated further to study their probable mechanism of action against MCF-7 cell line. Accumulation of cells at sub-G1 phase was observed in flow cytometric analysis. The detachment of cells from substratum and membrane blebbing seen under bright field microscopy supports the ability of these conjugates to induce apoptosis. Immunostaining and western blot analysis showed EGFR, p-EGFR, STAT3, and p-STAT3 significant downregulation. Western blot analysis demonstrated an elevated level of apoptotic proteins such as p53, p21, Bax, whereas a decrease in the antiapoptotic protein Bcl-2 and procaspase-9, confirming the ability of these conjugates to trigger cell death by apoptosis. EGFR kinase assay confirms the specific activity of conjugates. Molecular docking simulation study disclosed that these molecules fit well in ATP-binding pocket of EGFR. The analysis of docking poses and the atomic interactions of different conjugates rationalize the structural-activity relationship in this series. Benzimidazole-linked pyrazolo[1,5-a]pyrimidine conjugates were synthesized and evaluated for their anticancer potential. All the conjugates have significant anticancer potential. Further mechanistic studies revealed that these conjugates arrest cancer cell growth by EGFR/STAT3 inhibition.

Complicated urachal cyst in two pediatric patients: a case report.

BACKGROUND: A urachal cyst has a rare incidence that has been reported as 1/5,000 live birth. CASE PRESENTATION: We report two patients with a complicated urachal cyst, a 5-year-old female who presented to the emergency department with severe abdominal pain and a 3-year-old female presenting with abdominal pain and constipation. Upon laparoscopic exploration both patients had complicated urachal cysts which were adherent to the urinary bladder. CONCLUSION: Complicated urachal cysts can present with acute abdominal pain.

Management of pediatric blunt abdominal trauma with split liver or spleen injuries: a retrospective study.

BACKGROUND: Blunt abdominal trauma is a prevailing cause of pediatric morbidity and mortality. It constitutes the most frequent type of pediatric injuries. Contrast-enhanced sonography (CEUS) and contrast-enhanced computed tomography (CECT) are considered pivotal diagnostic modalities in hemodynamically stable patients. AIM: To report the experience in management of pediatric split liver and spleen injuries using CEUS and CECT. PATIENTS AND METHODS: This study included 246 children who sustained blunt abdominal trauma, and admitted and treated at three tertiary hospitals in the period of 5 years. Primary resuscitation was offered to all children based on the advanced trauma and life support (ATLS) protocol. A special algorithm for decision-making was followed. It incorporated the FAST, baseline ultrasound (US), CEUS, and CECT. Patients were treated according to the imaging findings and hemodynamic stability. RESULTS: All 246 children who sustained a blunt abdominal were studied. Patients' age was 10.5 ± 2.1. Road traffic accidents were the most common cause of trauma; 155 patients (63%). CECT showed the extent of injury in 153 patients' spleen (62%) and 78 patients' liver (32%), while the remaining 15 (6%) patients had both injuries. CEUS detected 142 (57.7%) spleen injury, and 67 (27.2%) liver injury. CONCLUSIONS: CEUS may be a useful diagnostic tool among hemodynamically stable children who sustained low-to-moderate energy isolated blunt abdominal trauma. It may be also helpful for further evaluation of uncertain CECT findings and follow-up of conservatively managed traumatic injuries.

Enhancing Heat Transfer Behaviour of Ethylene Glycol by the Introduction of Silicon Carbide Nanoparticles: An Experimental and Molecular Dynamics Simulation Study.

As the critical component of automotive engine coolant, ethylene glycol (E.G.) significantly matters in heat dissipation. In this study, the key aim is to investigate the heat transfer behaviour of E.G. as nano-additives base fluid. The heat transfer capability of E.G./SiC nanofluid (N.F.) was experimentally and theoretically evaluated via transient hot wire methods and equilibrium molecular dynamics (EMD) simulation, respectively. M.D. simulation exhibited a great ability to accurately forecast the thermal conductivity of N.F. compared with the experiment results. The results confirmed that the thermal stability of N.F. is relatively greater than that of E.G. base fluids. An improvement mechanism of thermal conductivity and thermal stability under an atomic scale via the analysis of mean square displacement (MSD) and radial distribution function (RDF) calculation was elaborately presented. Ultimately, the results indicated that the diffusion effect and the increasing transition rate of liquid atoms are responsible for thermal conductivity enhancement.

The Role of Methylene Blue Spray to Keep Parathyroid Gland and Recurrent Laryngeal Nerve Safe During Thyroidectomy.

Background: The main postoperative complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve (RLN) palsy. Methylene blue, which is a drug and dye, is safe and easy to get, and we can use it to avoid complications during thyroidectomy. Objectives: We aim to assess that we can spray Methylene blue to allow the identification of important structures intraoperative which are the parathyroid gland and recurrent laryngeal nerve. Also, to evaluate that this technique is safe, effective, technically feasible, and less dangerous than other techniques. Methods: Our study is a prospective cohort study of patients, patients who presented with simple nodular goiter, solitary thyroid nodule, controlled toxic goiter, and failed medical treatment with the indication for thyroidectomy, suspected malignancy, and retrosternal goiters at El-Demerdash Hospital from the period of August 2021 to August 2022. In the specified study period of 1 year from 1/8/2021 to 31/7/2022. Results: Sixty patients underwent thyroidectomy 54 underwent total while 6 only underwent hemithyroidectomy. The time taken to wash out the dye over the thyroid gland was 15 to 25 minutes, the parathyroid gland was 4 to 7 minutes and the recurrent laryngeal nerve (RLN) was almost 0 to 1 minute and this indicated that the RLN almost did not take the dye. In the controlled group, two patients had symptoms and signs of hypocalcemia only one of them had signs of tetany, 8 patients had laboratory hypocalcemia, two patients suffered from a change of voice and another two patients suffered difficulty breathing one of which needed temporary tracheostomy while in the interventional group, only one patient had symptoms and signs of hypocalcemia no one had signs of tetany, two patients had laboratory hypocalcemia, one patient suffered from the change of voice and another two patients suffered the difficulty of breathing but no one needed a tracheostomy tube. Conclusions: It is safe, useful, and suitable to use Methylene blue spraying to keep the parathyroid gland and RLN during thyroidectomy, which led us to reduce the percentage of incidence of postoperative complications. Also, it helped us to find the parathyroid gland and RLN during the surgery, despite some surgeons seeing that searching for the parathyroid and RLN can lead to harmful effects and increase the incidence of injury.

The relationship between types of life events and the onset of functional neurological (conversion) disorder in adults: a systematic review and meta-analysis.

Adverse life events precede the onset of functional neurological disorder (FND, also known as conversion disorder) more commonly than other neuropsychiatric conditions, but their aetiological role is unclear. We conducted a systematic review and quantitative analysis of the type, timing and number of life events preceding the onset of FND in adults, and a meta-analysis of the proportions of types of events in controlled studies. Fifty-one studies of different designs, covering 4247 patients, were eligible for inclusion. There was no clear majority of any type of preceding event. Family problems were the most common category of events, followed by relationship problems. Females were more likely to experience preceding family/relationship problems than males, who reported more work problems. Family problems were the commonest type of preceding event in studies in developing countries, whereas family and health problems were equally common in developed countries. Abuse was associated with early symptom onset, while patients with later onset were more likely to report family problems. The median number of events was one, and the events occurred closer to onset than in controls. Meta-analysis found that family, relationship and work events were all relatively more common in patients than pathological controls, as were events where symptoms might provide a solution to the stressor. In conclusion, although a range of events precede the onset of FND, they do not appear to do so uniformly. This may support a different aetiological role for stressors than in other disorders, although the support is indirect and the quality generally low.

COVID-19 Incidence and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster Doses During Periods of Delta and Omicron Variant Emergence - 25 U.S. Jurisdictions, April 4-December 25, 2021.

Previous reports of COVID-19 case, hospitalization, and death rates by vaccination status† indicate that vaccine protection against infection, as well as serious COVID-19 illness for some groups, declined with the emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, and waning of vaccine-induced immunity (1-4). During August-November 2021, CDC recommended§ additional primary COVID-19 vaccine doses among immunocompromised persons and booster doses among persons aged ≥18 years (5). The SARS-CoV-2 B.1.1.529 (Omicron) variant emerged in the United States during December 2021 (6) and by December 25 accounted for 72% of sequenced lineages (7). To assess the impact of full vaccination with additional and booster doses (booster doses),¶ case and death rates and incidence rate ratios (IRRs) were estimated among unvaccinated and fully vaccinated adults by receipt of booster doses during pre-Delta (April-May 2021), Delta emergence (June 2021), Delta predominance (July-November 2021), and Omicron emergence (December 2021) periods in the United States. During 2021, averaged weekly, age-standardized case IRRs among unvaccinated persons compared with fully vaccinated persons decreased from 13.9 pre-Delta to 8.7 as Delta emerged, and to 5.1 during the period of Delta predominance. During October-November, unvaccinated persons had 13.9 and 53.2 times the risks for infection and COVID-19-associated death, respectively, compared with fully vaccinated persons who received booster doses, and 4.0 and 12.7 times the risks compared with fully vaccinated persons without booster doses. When the Omicron variant emerged during December 2021, case IRRs decreased to 4.9 for fully vaccinated persons with booster doses and 2.8 for those without booster doses, relative to October-November 2021. The highest impact of booster doses against infection and death compared with full vaccination without booster doses was recorded among persons aged 50-64 and ≥65 years. Eligible persons should stay up to date with COVID-19 vaccinations.

COVID-19: Vaccines and therapeutics.

Coronavirus disease 2019 (COVID-19) is a communicable disease triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged as leading cause of death from a single infectious agent globally. Despite of rigorous protective measures, availability of multiple vaccines and with few approved therapeutics, the virus effect on the humankind throughout the world is perennial. COVID-19 has become the most urgent health concern with emergence of new challenging variants which outnumbered all other health issues and ensued in overwhelming number of reported deaths. In this unprecedented period of COVID-19 pandemic, scientists work round the clock for rapid development of efficient vaccines for prevention of infection and effective therapeutics for treatment. Here, we report the status of COVID-19 and highlight the ongoing research and development of vaccines and therapeutic strategies. It is necessary to know the present situation and available options to fight against the COVID-19 pandemic.

Novel linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents.

The quest for new antifungal and antitubercular drugs is a need of the hour because of morbid co-pathogenesis and an increase in immunocompromised patients. One of the ways forward is to explore and repurpose the established pharmacophores for the desired application. Oxazolidinones are well-known antibacterial agents, with few investigations reported to exploit their antifungal properties. Herein, we report the design and synthesis of a series of linezolid-based oxazolidinones as potent anticandidiasis and antitubercular agents. Studies revealed that two of the novel oxazolidinones 2 and 3a exhibited excellent anticandidiasis activity against different Candida fungus strains, superior to standard drugs. Mechanistic and docking studies revealed that oxazolidinones were better inhibitors of the ergosterol biosynthesis pathway than the controls used. In addition, the oxazolidinones 2 and 3a also exhibited prominent inhibitory activity against M. tuberculosis H37Rv with MIC values of 1 and 2 µg/ml, respectively. Computational studies demonstrated the binding of the compounds to the transcriptional regulatory repressor protein, which was reinforced by the molecular dynamics simulations. The pharmacophore modeling experiments validated the molecular docking results in both the target proteins.

Clinicopathological evaluation of intralesional methotrexate in different subtypes of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common malignant skin tumor. While slowly growing, it can cause major skin disfigurement. Therefore, novel cosmetically acceptable treatment options, other than surgery require investigation. The aim of the study was to evaluate efficacy and safety of intralesional methotrexate (MTX) as a convenient modality for BCC treatment clinically and pathologicaly. A total of 20 patients with BCC of any clinical variant underwent intralesional MTX injection at a maximum 1 mL of 25 mg/mL MTX per session. Histopathological assessments were performed before and 1 month after treatment. Forty percent of patients showed >50% clinical improvement after 1-4 sessions. Intralesional MTX is a suitable and safe treatment modality for BCC and may be used as an adjuvant to surgery.

Synthesis and Cytotoxic Activity of 1,2,4-Triazolo-Linked Bis-Indolyl Conjugates as Dual Inhibitors of Tankyrase and PI3K.

A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a-r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 µM) and 15r (IC50 = 0.85 µM) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 µM) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G0/G1 phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 µM and 1 µM, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, ß-catenin, TAB-182, ß-actin, AXIN-2, and NF-κB markers that are involved in the ß-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.

New indenopyrazole linked oxadiazole conjugates as anti-pancreatic cancer agents: Design, synthesis, in silico studies including 3D-QSAR analysis.

To continue the quest of newer anticancer agents, herein a novel class of 1,4-Dihydroindenopyrazole linked oxadiazole conjugates 9(a-r) was designed, synthesized and experimented for their anti-proliferative activities against four different cancer cell lines (human) such as MDA MB-231 (breast), PANC-1 (pancreatic), MCF-7 (breast), and Caco-2 (Colorectal) by using MTT assay. Among the series compound 9h and 9 m demonstrated significant potency against the PANC-1 (human pancreatic cancer cells) with IC50 value 7.4 µM and 4.3 µM respectively. While compound 9 m was found to be equipotent to standard Gomitabine (IC50 = 4.2 µM). The detailed biological assays revealed S phase cell cycle arrest and their ability to propagate apoptosis by activating caspase 3 and 9 enzymes which was confirmed by Annexin-FITC assay and caspase assay. Moreover, docking study suggested their binding modes and interactions with caspase-3. In addition, in silico studies revealed that they exhibit good pharmacokinetics and drug likeliness properties. Furthermore, 3D-QSAR was carried out to achieve a pharmacophoric model with CoMFA (q2 = 0.631, r2 = 0.977) and CoMSIA (q2 = 0.686, r2 = 0.954) on PANC-1 cancer cells which were established, generated and validated to be reliable models for further design and optimization of newer molecules with enhanced anticancer activity.

ß-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies.

The effect of ß-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of ß-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug Entinostat for in vitro enzymatic assay. Among the tested compounds, 7h displayed a noteworthy potency with an IC50 value of 0.70 ± 0.15 µM against HCT-15 cell line when compared to the standard drug Entinostat (IC50 of 3.87 ± 0.62 µM). The traditional apoptosis assays such as nuclear morphological alterations, AO/EB, DAPI, and Annexin-V/PI staining revealed the antiproliferative activity of 7h while depolarization of mitochondrial membrane potential by JC-1 was observed in dose-dependent manner. Cell cycle analysis also unveiled the typical accumulation of cells in G2M phase and sub-G1/S phase arrest. In addition, immunoblot analysis for compound 7h on HCT-15 indicated selective inhibition of the protein expression of class I HDAC 2 and 3 isoforms. Molecular docking analysis of compound 7h revealed that it can prominent binding with the active pocket of the HDAC 2. These finding suggest that the compound 7h can be a promising lead candidate for further investigation in the development of novel anti-cancer drug potentially inhibiting HDACs.