Design, synthesis and biological evaluation of Helicobacter pylori inosine 5'-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2.

Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDHs, microbial IMPDHs are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated ≥70% HpIMPDH inhibition at 10 µM concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 µM) in the series. The study reaffirmed the utility of 5-aminoisobenzofuran-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.

Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2.

During cancer chemotherapy, certain cancers may become cross-resistant to structurally diverse antineoplastic agents. This so-called multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transport proteins. These membrane-bound efflux pumps export a broad range of structurally diverse endo- and xenobiotics, including chemically unrelated anticancer agents. This translocation of drugs from the inside to the outside of cancer cells is mediated at the expense of ATP. In the last 40 years, three ABC transporters - ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) - have mainly been attributed to the occurrence of MDR in cancer cells. One of the strategies to overcome MDR is to inhibit the efflux transporter function by small-molecule inhibitors. In this work, we investigated new chalcone- and flavone-based compounds for selective as well as broad-spectrum inhibition of the stated transport proteins. These include substituted chalcones with variations at rings A and B, and flavones with acetamido linker at position 3. The synthesized molecules were evaluated for their inhibitory potential against ABCB1, ABCC1, and ABCG2 in calcein AM and pheophorbide A assays. In further investigations with the most promising candidates from each class, we proved that ABCB1- and ABCG2-mediated MDR could be reversed by the compounds. Moreover, their intrinsic toxicity was found to be negligible in most cases. Altogether, our findings contribute to the understanding of ABC transport proteins and reveal new compounds for ongoing evaluation in the field of ABC transporter-mediated MDR.

Discovery of novel human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.

The enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, and thus regulates the guanine nucleotide pool required for cell proliferation. Of the two isoforms, human IMPDH type 2 (hIMPDH2) is a validated molecular target for potential immunosuppressive, antiviral and anticancer chemotherapy. In search of newer hIMPDH2 inhibitors as potential anticancer agents, three novel series (A: 5-aminoisobenzofuran-1(3H)-one, B: 3,4-dimethoxyaniline and C: benzo[d]-[1,3]dioxol-5-ylmethanamine) were synthesized and evaluated for in vitro and cell-based activities. A total of 37 molecules (29-65) were screened for their in vitro hIMPDH2 inhibition, with particular emphasis on establishing their structure-activity relationship (SAR) trends. Eight compounds (hits, 30, 31, 33-35, 37, 41 and 43) demonstrated significant enzyme inhibition (>70% @ 10 µM); especially the A series molecules were more potent than B series (<70% inhibition @ 10 µM), while C series members were found to be inactive. The hIMPDH2 IC50 values for the hits ranged from 0.36 to 7.38 µM. The hits displaying >80% hIMPDH2 inhibition (30, 33, 35, 41 and 43) were further assessed for their cytotoxic activity against cancer cell lines such as MDA-MB-231 (breast adenocarcinoma), DU145 (prostate carcinoma), U87 MG (glioblastoma astrocytoma) and a normal cell line, NIH-3T3 (mouse embryonic fibroblast) using MTT assay. Most of the compounds exhibited higher cellular potency against cancer cell lines and notably lower toxicity towards NIH-3T3 cells compared to mycophenolic acid (MPA), a prototypical hIMPDH2 inhibitor. Two of the series A hits (30 and 35) were evaluated in human peripheral blood mononuclear cells (hPBMC) assay and found to be better tolerated than MPA. The calculated/predicted molecular and physicochemical properties were satisfactory with reference to drug-likeness. The molecular docking studies clearly demonstrated crucial interactions of the hits with the cofactor-binding site of hIMPDH2, further providing critical information for refining the design strategy. The present study reports the design and discovery of structurally novel hIMPDH2 inhibitors as potential anticancer agents and provides a guide for further research on the development of safe and effective anticancer agents, especially against glioblastoma.

Newer human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents.

Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.

Efficacy and safety of the intensive dose of rosuvastatin 40mg/day in patients with acute coronary syndrome and at high risk of cardiovascular disease-ROSUVEES-2.

BACKGROUND: Randomized clinical trials have established the benefits of statin therapy in acute coronary syndromes (ACS) via their pleiotropic effects. AIM OF THE STUDY: This was a 12-week, open-label, multicenter, postmarketing observational study evaluating the efficacy and safety of rosuvastatin 40 mg/day in very high-risk or high-risk Indian patients according to NCEP ATP III guidelines. METHODOLOGY: One hundred and sixty two patients (age: 30 to 69 years) with evidence of coronary artery disease, hospitalized with chest pain with/without electrocardiogram changes and with non-ST segment elevation ACS and ST segment elevation ACS who received optimal reperfusion therapy were enrolled. The primary endpoint was the percent change from baseline in low-density lipoprotein cholesterol (LDL-C) levels at 6 and 12 weeks of treatment. Other lipid parameters, high sensitive C-reactive protein (hsCRP), glycosylated hemoglobin, and clinical biochemical parameters were also assessed. RESULTS: At 12 weeks, intensive therapy with rosuvastatin 40mg/day significantly reduced LDL-C (p<0.001), total cholesterol (TC) (p<0.001), triglyceride (p<0.01), TC/high density lipoprotein cholesterol (HDL-C) ratio (p<0.001), non-HDL-C (p<0.001), LDL-C/HDL-C ratio (p<0.001), and hsCRP (p=0.034) in very high-risk and high-risk patients with ACS. Overall, 54.5% (61/112) patients achieved LDL-C goal of <70mg/dL. However, the change in HDL-C and very low density lipoprotein cholesterol (VLDL-C) were not significant. Few adverse events including myalgia were reported during the study. CONCLUSION: Results of this study showed that 40mg dose of rosuvastatin, initiated early and continued for 12 weeks, was effective in terms of reducing LDL cholesterol and was well tolerated.

Inosine 5'-monophosphate dehydrogenase inhibitors as antimicrobial agents: recent progress and future perspectives.

Inosine 5'-monophosphate dehydrogenase (IMPDH), a crucial enzyme required for de novo synthesis of guanine nucleotides, is an important target for cancer, bacterial, parasitic and viral infections and autoimmune disorders. Several classes of IMPDH inhibitors are known in the literature. The current review succinctly summarizes the progress made in the design and development of IMPDH inhibitors as antimicrobial agents in last five years or so. The focus is on the inhibitor and enzyme structural features responsible for imparting selectivity for the microbial over the host enzyme. Future perspectives clearly outline the inhibitor design opportunities available in this area to address the present challenges of drug resistance and re-emergence of newer and deadly strains of microbes, posing a serious threat to public.

Design, synthesis and antistaphylococcal activity of marine pyrrole alkaloid derivatives.

A novel set of 16 hybrids of bromopyrrole alkaloids with aroyl hydrazone were designed, synthesized and evaluated for antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43866), methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 35556) and Staphylococcus epidermidis (SE, S. epidermidis ATCC 35984). Of the 16 tested hybrids, 14 exhibited equal or superior antibiofilm activity against MSSA and MRSA relative to standard vancomycin. Compound 4m showed highest potency with antibiofilm activity of 0.39 µg/mL and 0.78 µg/mL against MSSA and MRSA, respectively. Thus, this compound could act as a potential lead for further development of new antistaphylococcal drugs.

Synthesis and evaluation of novel marine bromopyrrole alkaloid-based hybrids as anticancer agents.

A series of twenty three novel hybrids of marine bromopyrrole alkaloids with chalcone, isoxazole and flavone structural features were synthesized and evaluated for in vitro anticancer activity by MTT assay against five human cancer cell lines. Among the synthesized chalcones, hybrids 4a and 4h (IC50 range: 0.18 µM-12.00 µM) showed anticancer activity against all the tested cancer cell lines. Promising cytotoxic activities were exhibited by flavones derivatives, 5a and 5b (0.41 µM-1.28 µM) against cell lines PA1 and KB403. Isoxazole hybrids, 6b-6e selectively inhibited oral and mouth cancer cell line KB403, among which 6c (IC50 = 2.45 µM) was found to be most active.

Synthesis and antibiofilm activity of marine natural product-based 4-thiazolidinones derivatives.

4-Thiazolidinones derivatives of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compounds. Among the synthesized compounds, some showed promising antibiofilm activity. Biological data revealed that 1,3-thiazolidin-4-one derivatives are more potent antibiofilm agents compared to 1,3-thiazinan-4-ones. Antibiofilm activity of compound 4b, 4c (MIC=0.78 µg/ml) was 3-fold superior than standard vancomycin (MIC=3.125 µg/ml) while activity of compound 4d, 4f, 4g and 4h was 2-fold (MIC=1.56 µg/ml) against Staphylococcus aureus biofilm. Compound 4b-4h showed equal antibiofilm activity against Staphylococcus epidermidis compared to standard Vancomycin (MIC=3.125 µg/ml).

Precursor concentration and temperature controlled formation of polyvinyl alcohol-capped CdSe-quantum dots.

Polyvinyl alcohol-capped CdSe quantum dots, with a size within their quantum confinement limit, were prepared in aqueous solution at room temperature, by a simple and environmentally friendly chemical method. The size of the CdSe quantum dots was found to be dependent on the concentrations of the precursors of cadmium and selenium ions, as well as on the aging time and the reaction temperature; all of which could be used conveniently for tuning the size of the particles, as well as their optical properties. The synthesized quantum dots were characterized by optical absorption spectroscopy, fluorescence spectroscopy, X-ray diffraction, atomic force microscopy and transmission electron microscopy. The samples were fluorescent at room temperature; the green fluorescence was assigned to band edge emission, and the near-infrared fluorescence peaks at about 665 and 865 nm were assigned to shallow and deep trap states emissions, respectively. The quantum dots were fairly stable up to several days.

Adenosine induced ventricular fibrillation in Wolff-Parkinson-White syndrome.

VF was observed in four patients (group A) with preexcited AF presenting to the emergency department who had been given 12 mg of adenosine. These patients were resuscitated and underwent electrophysiological study and catheter ablation of the accessory pathway (AP). In a control (group B) of five patients with manifest AP, sustained AF was induced by rapid atrial pacing during electrophysiological study and 12 mg of adenosine was administered. The ECG and electrophysiologic features in the two groups were compared. All patients had a single manifest AP. In group A, three patients had a left free-wall AP and one patient had a posteroseptal AP, while in the control group all had left free-wall APs. The antegrade AP effective refractory period (ERP) in groups A and B was 227 +/- 29 and 289 +/- 37 ms, respectively (P < 0.05). The atrial ERP was 210 +/- 17 versus 219 +/- 21 ms, respectively, in groups A and B (P > 0.05). The shortest R-R interval during AF in group A was 246 +/- 51 ms and 301 +/- 60 ms in group B (P value < 0.05). After adenosine, no patient in group B developed VF. Adenosine may cause VF when administered during preexcited AF. This phenomenon is seen in patients having APs with short refractory periods.