Conventional and microwave-assisted organic synthesis of novel antimycobacterial agents bearing furan and pyridine hybrids.

Drug resistance in tuberculosis poses a serious threat to humanity because currently available antitubercular drugs are ineffective against Mycobacterium tuberculosis (M. tuberculosis). As a result, the approval of Bedaquiline and Delamanid for the treatment of drug-resistant tuberculosis was accelerated. Still, there is an urgent need to search for new antitubercular drugs with novel mechanisms of action (MoA). Due to this, we have designed a synthetic strategy by utilizing microwave-assisted organic synthesis. We have compared our method with the conventional procedure, and the data show that our procedure is more effective in the preparation of title compounds. A unique series of 1-(2-(furan-2-yl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)-prop-2-en-1-ones (5a-o) was synthesized utilizing conventional and microwave-assisted techniques. Synthetic compounds were investigated for antitubercular activity against Mycobacterium TB H37 Ra and Mycobacterium bovis (M. bovis). Compound 5b was reported to be the most effective against M. tuberculosis H37 Ra (97.69 percent inhibition at 30 µg/ml) and M. bovis (97.09 percent inhibition at 30 µg/ml). An in silico binding affinity study of mycobacterial enoyl-acyl carrier protein reductase (InhA) reveals the binding mechanism and thermodynamic interactions that determine these molecule's binding affinity. Compound 5b had a high glide score of -8.991 and low glide energy of -49.893 kcal/mol.

Conventional and Microwave-Assisted Synthesis, Antitubercular Activity, and Molecular Docking Studies of Pyrazole and Oxadiazole Hybrids.

Microwave-assisted organic reaction enhancement (MORE) has become more important in synthetic organic chemistry for efficient resource utilization. In this study, we synthesized bioactive compounds using both traditional and microwave methods. Microwave-assisted synthesis takes less time and produces higher yields and quality than conventional approaches. We reported the synthesis of N'-(1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene) substituted hydrazides (4a-t). We also tested them against two strains: M. tuberculosis H37Ra and M. bovis BCG. Against M. tuberculosis H37Ra, the compounds 4e, 4h, 4k, 4p, and 4s were the most effective. Compounds 4f, 4g, and 4s showed significant activity against M. bovis BCG. The structures of newly synthesized molecules were determined using spectral methods. Furthermore, molecular docking investigations into the active site of mycobacterial InhA yielded well-clustered solutions for these compounds' binding modalities producing a binding affinity in the range of -10.366 to -8.037. Theoretical results were in good accord with the observed experimental values. The docking score of compound 4e was -10.366, and the Glide energy was -66.459 kcal/mol.

Molecular analysis of Bacillus velezensis KB 2216, purification and biochemical characterization of alpha-amylase.

Alpha-amylase producing strain KB 2216 was identified as Bacillus velezensis. The growth pattern showed that 72 h is the optimum incubation period of amylase production, which is a stationary period for the strain. By the purification process, maximum alpha-amylase activity was achieved up to 418.25 U/mL at 72 h of incubation, which was purified with 4.74 folds, 4230.32 U/mg specific activity, with 31.35% yield. The strain was found to produce an oligomeric alpha-amylase, namely Amy3. Amy3 was a trimeric macromolecule of 195 kDa with 62, 64, and 66 kDa subunits, as revealed by zymogram and SDS PAGE analyses. Amy3 was highly active at 55 °C and pH 5.5. It had shown the highest stability at pH 5.0-5.5 and between 0 ̊C and 4 ̊C. It did not require any metal cofactors, but it was inhibited by Ag2+, Hg2+ and Cd2+ divalent cations. Glucose and maltose were shown to be the end products of soluble starch digestion by Amy3. These interesting properties of Amy3 may be useful for many biotechnological applications in the future.

Utility of Breast MRI for Further Evaluation of Equivocal Findings on Digital Breast Tomosynthesis.

OBJECTIVE: The purpose of this study is to evaluate the utility of MRI as a problem-solving tool for equivocal findings on diagnostic digital mammography (DM) and digital breast tomosynthesis (DBT). MATERIALS AND METHODS: Breast MRI examinations performed from March 2011 to November 2014 were retrospectively reviewed to identify those examinations that were performed to further assess equivocal findings on combined DM and DBT (DM/DBT) examinations. All patients underwent diagnostic ultrasound in conjunction with their DM/DBT examination. Imaging reports were retrospectively reviewed for BI-RADS findings and assessments of diagnostic DM/DBT and diagnostic MRI examinations. A review of the electronic medical records provided information on demographic data, cancer diagnoses, and pathologic findings. Differences in the positive predictive values and negative predictive values of DM/DBT and MRI were compared using a generalized estimating equation for correlated binary data. RESULTS: Of 5330 MRI examinations performed during the study, 67 (1%) were performed for evaluation of an equivocal finding, including 27 asymmetries (40%), 16 focal asymmetries (24%), five masses (7%), and 19 architectural distortion (28%). MRI correlates were identified in 22 of 67 examinations (33%). Biopsies yielded a cancer diagnosis for five of 67 patients (7%). For MRI, the positive predictive value and negative predictive value were 19% and 98%, respectively, whereas for DM/DBT they were 6% and 90%, respectively (p = 0.009 and p = 0.059, respectively). The frequency of recommendations for breast MRI to evaluate equivocal findings decreased exponentially in the 3 years after DBT implementation. CONCLUSION: As clinical implementation of DBT becomes increasingly widespread, breast radiologists need an algorithm for addressing the small number of inconclusive findings that remain equivocal despite thorough DM/DBT and ultrasound examinations. Breast MRI is a useful adjunctive tool for these selected cases.

Synthesis, biological evaluation and molecular docking study of some novel indole and pyridine based 1,3,4-oxadiazole derivatives as potential antitubercular agents.

A series of indole and pyridine based 1,3,4-oxadiazole derivatives 5a-t were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG both in active and dormant state. Compounds 5b, 5e, 5g and 5q exhibited very good antitubercular activity. All the newly synthesized compounds 5a-t were further evaluated for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using modified MTT assay and found to be noncytotoxic. On the basis of cytotoxicity and MIC values against Mycobacterium bovis BCG, selectivity index (SI) of most active compounds 5b, 5e, 5g and 5q was calculated (SI=GI50/MIC) in active and dormant state. Compounds 5b, 5e and 5g demonstrated SI values ⩾10 against all three cell lines and were found to safe for advance screening. Compounds 5a-t were further screened for their antibacterial activity against four bacteria strains to assess their selectivity towards MTB. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of enoyl reductase (InhA), which in turn helped to establish a structural basis of inhibition of mycobacteria. The potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for further optimization.

Design, Synthesis, and Biological Evaluation of 1,4-dihydropyridine Derivatives as Potent Antitubercular Agents.

A series of novel 1,4-dihydropyridine-3,5-dicarbamoyl derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, (1) H NMR, (13) C NMR, and mass spectroscopy. The synthesized compounds 3a-p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 µg/mL and SI > 500, making it more potent than first-line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity.