Synthesis of 2-{[5-(aralkyl/aryl)-1,3,4-oxadiazol-2- yl]sulfanyl}-N-(4-methyl-1,3-thiazol-2-yl)acetamides: Novel bi-heterocycles as potential therapeutic agents

Purpose: To evaluate the therapeutic potential of new bi-heterocycles  containing a 1,3-thiazole and 1,3,4-oxadiazole in the skeleton against Alzheimer's disease and diabetes, supported by in-silico study. Methods: The synthesis was initiated by the reaction of 4-methyl- 1,3-thiazol-2-amine (1) with bromoacetyl bromide (2) in aqueous basic medium to obtain an electrophile,2-bromo-N-(4-methyl-1,3- thiazol- 2-yl)acetamide (3). In parallel reactions, a series of carboxylic acids, 4a-r, were converted through a sequence of three steps, into respective 1,3,4-oxadiazole heterocyclic cores, 7a-r, to utilize as nucleophiles. Finally, the designed molecules, 8a-r, were synthesized by coupling 7a-r individually with 3 in an aprotic polar solvent. The structures of these bi-heterocycles were elucidated by infrared (IR), electron ionization-mass spectrometry (EI-MS), proton nuclear magnetic resonance (1H-NMR) and carbon nuclear magnetic resonance (13C-NMR). To evaluate their enzyme inhibitory potential, 8a-r were screened against acetylcholinesterase (AChE), but brine shrimp lethality bioassay.Results: The most active compound against AChE was 8l with half-maximal inhibitory concentration (IC50) of 17.25 ± 0.07 μM. Against BChE, the highest inhibitory effect was shown by 8k (56.23 ± 0.09 μM). Compound 8f (161.26 ± 0.23μM) was recognized as a fairly good inhibitor of urease. In view of its inhibition of α-glucosidase, 8o (57.35 ± 0.17μM) was considered a potential therapeutic agent.Conclusion: The results indicate that some of the synthesized products with low toxicity exhibit notable enzyme inhibitory activity against selected enzymes compared with the reference drug, and therefore, are of potential therapeutic interestKeywords: 4-Methyl-1,3-thiazol-2-amine,1,3,4-Oxadiazole,  Cholinesterases, α-Glucosidase, Urease, Brine shrim

S-Alkylated/aralkylated 2-(1H-indol-3-yl-methyl)-1,3,4- oxadiazole-5-thiol derivatives. 2. Anti-bacterial, enzymeinhibitory and hemolytic activities

Purpose: To evaluate the antibacterial, enzyme-inhibitory and hemolytic activities of Salkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol  derivatives.Methods: Antibacterial activities of the compounds were evaluated using broth dilution method in 96 well plates. Enzyme inhibitory activities assays were investigated against α-glucosidase, butyrylcholinesterase (BchE) and lipoxygenase (LOX) using acarbose, eserine and baicalien as reference standards, respectively. A mixture of enzyme, test compound and the substrate was incubated and variation in absorbance noted before and after incubation. In tests for hemolytic activities, the compounds were incubated with red blood cells and variations in absorbance were used as indices their hemolytic activities.Results: The compounds were potent antibacterial agents. Five of them exhibited very good antibacterial potential similar to ciprofloxacin, and had minimum inhibitory concentrations (MIC) of at least 9.00 ± 4.12 μM against S. aureus, E.coli, and B. subtilis. One of the compounds had strong enzyme inhibitory potential against α-glucosidase, with IC50 of 17.11 ± 0.02 μg/mL which was better than that of standard acarbose (IC50 38.25 ± 0.12 μg/mL). Another compound had 1.5 % hemolytic activity. Conclusion: S-Alkylated/aralkylated 2-(1H-indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol deviratives with valuable antibacterial, anti-enzymatic and hemolytic activities have been successfully synthesized. These compounds may be useful in the development of pharmaceutical products.Keywords: 2-(1H-Indol-3-ylmethyl)-1,3,4-oxadiazole-5-thiol derivatives, Enzyme inhibition, Antibacterial activity, Hemolytic activity, Molecular dockin

Percutaneous Mitral Valve Repair versus Optimal Medical Therapy in Patients with Functional Mitral Regurgitation: A Systematic Review and Meta-Analysis

Objectives. To compare percutaneous mitral valve repair (PMVR) with optimal medical therapy (OMT) in patients with heart failure (HF) and severe functional mitral regurgitation (FMR). Background. Many patients with HF and FMR are not suitable for surgical valve replacement and remain symptomatic despite maximal OMT. PMVR has recently emerged as an alternative solution. Methods. We performed a systematic review and a meta-analysis to address this question. Cochrane CENTRAL, MEDLINE, and Scopus were searched for randomized (RCT) and nonrandomized studies comparing PMVR with OMT in patients with HF and FMR. Primary endpoint was all-cause midterm mortality (at 1 and 2 years). Secondary endpoints were 30-day mortality and cardiovascular mortality and HF hospitalizations, at maximum follow-up. Studies including mixed cohort of degenerative and functional MR were allowed initially but were excluded in a secondary sensitivity analysis for each of the study’s end points. This meta-analysis was performed following the publication of two RCTs (MITRA-FR and COAPT). Results. Eight studies (six observational, two RCTs) comprising 3,009 patients were included in the meta-analysis. In comparison with OMT, PMVR significantly reduced 1-year mortality (RR: 0.70 [0.56, 0.87]; p=0.002; I2=47.6%), 2-year mortality (RR: 0.63 [0.55, 0.73]; p\u3c0.001; I2=0%), and cardiovascular mortality (RR: 0.32 [0.23, 0.44]; p\u3c0.001; I2=0%). No significant difference between PMVR+OMT and OMT was noted in HF hospitalization (HR: 0.69 [0.40, 1.20]; p=0.19; I2=85%) and 30-day mortality (RR: 1.13 [0.68, 1.87]; p=0.16; I2=0%). Conclusions. In comparison with OMT, PMVR significantly reduces 1-year mortality, 2-year mortality, and cardiovascular mortality in patients with HF and severe MR

Whole exome sequence of Pakistani acute lymphocytic leukemia patient from Pakhtuns ancestry reveal the novel genetic variant characterization in the GLDC gene

Background: Acute Lymphoblastic Leukemia (ALL) is the most common malignant disease in children and often involves numerical chromosomal abnormalities, fusion genes, or minor localized deletions that are significant in the development of leukemia. Glycine Decarboxylase (GLDC) gene overexpression and mutation is associated with oncogenic activity in various cancers. However, the pathophysiological roles and structural consequences of GLDC in acute lymphocytic leukemia have not been investigated. Objective: We aimed to identify novel variant in acute lymphocytic leukemia through whole exome sequencing. Methods: This study employs whole exome sequencing to examine seven pediatric patients with Acute Lymphoblastic Leukemia (ALL) in Pakistan. The patients under investigation are of Pakistani origin. The deleterious effect was predicted by SIFT, PolyPhen2, CADD, FATHMM, HOPE, and Mutation Assessors. Structure stability assessment was performed using the I-Mutant-3.0server. The atomic structure of the Single Nucleotide Polymorphism (SNP) was analyzed utilizing the Molecular Dynamics (MD) with WEBGRO server. Results: The present study identified a novel pathogenic heterozygous variant NM_000170.2:p.Ser551Cys/c.1651A>T in GLDC gene of early stage diagnose ALL patient the variant was not present in the dbSNP & 1000Genome Project databases. Structural instability, disrupted function, and altered 3D structure were observed in the mutant GLDC protein model compared to the wild-type structure. Conclusion: The novel SNP was found in a highly conserved region of the GLDC protein and is predicted to be a high-risk candidate for leukemia. This variant greatly affects the stability of the protein

Synthesis, Characterization and Urease Inhibiting Derivatives of 5-(3,4-Methylenedioxyphenyl)-1,3,4-Oxadiazol-2-thiol

In the present work, the urease inhibition activity of 1,3,4-oxadiazole bearing molecules was evaluated and were found to be potential inhibitors. 3,4-(Methylenedioxy)benzoic acid (1) was employed to synthesize 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-thiol (4) via a series of steps. It was further stepped to yield S-substituted-5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazole derivatives (6a-h) on reaction with alkyl/aralkyl halides (5a-h) in DMF using LiH as an activator. All the synthesized compounds were well supported by IR, 1H NMR and EIMS spectral analysis. The enzyme inhibition activity against urease enzyme showed these molecules as potent inhibitors of this enzyme. - See more at: http://www.asianjournalofchemistry.co.in/(X(1))/user/journal/viewarticle.aspx?ArticleID=26_16_15#sthash.Y6WNhFR2.dpu

Synthesis Pharmacological Evaluation, Molecular Docking And Cytotoxicty Studies On Some N-Substituted 5-[(4-Chlorophenoxy)Methyl]-1,3,4-Oxadiazole-2yl-2-Sulfanyl Acetamides

The framework of our systematic efforts focuses on the synthesis of N-substituted 5-[(4-chlorophenoxy) methyl]-1,3,4-oxadiazole-2yl-2-sulfanyl acetamides. 4-Chlorophenoxyacetic acid (1) was utilized as a precursor for the synthesis of parent 1,3,4-oxadiazole moiety. Esterification of 1in the presence of catalytic amount of concentrated sulfuric acid and absolute alcohol generated ethyl 2-(4-chlorophenoxy)acetate (2) which was treated with hydrazine hydrate to yield 2-(4-chlorophenoxy)acetohydrazide (3). Ring closure reaction of 3 with carbon disulfide and alcoholic potassium hydroxide afforded [5-(4-chlorophenoxy)methyl)]-1,3,4-oxadiazole-2-thiol (4). Finally, substitution at thiol position of 4 with electrophiles, N-substituted-2-bromoacetamides (6a-p) in polar aprotic solvent and LiH yielded various N-substituted 5-[(4-chlorophenoxy) methyl]-1,3,4-oxadiazole-2yl-2-sulfanyl acetamides (7a-p). IR, 1H-NMR and EI-MS spectral analysis data unequivocally confirmed all the substitutions on 1,3,4-oxadiazole-2-thiol core. It was recognized that the synthesized derivatives are potential anti-bacterial agents against both gram negative and gram positive bacteria and moderate inhibitors of α-chymotrypsin enzyme. In vitro screening against various bacterial strains unleashed their anti-bacterial potential, especially 5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazol-2yl-N-(3,4-dimethylphenyl)-2-sulfanyl acetamide (7o) exhibited marvelous activity when compared with standard ciprofloxacin against S.typhi (-), K.pneumonae (-) and S. aureus (+).Compounds were computationally docked with the α-chymotrypsin enzyme protein to unravel the active binding sites which displayed significant correlation with the bioactivity data. It can be envisioned that the amalgamation of 5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole-2-thiol with N-substituted-2-bromoacetamides generated N-substituted 5-[(4-chlorophenoxy)methyl]-1,3,4-oxadiazole-2yl-2-sulfanyl acetamides having tremendous antibacterial activity and moderate anti-enzymatic potential. Moreover, substitutions on the oxadiazole moiety lead to the discovery of less cytotoxic compounds as evident from the cytotoxicity data