Appraisal of Pancreatic Lipase Inhibitory Potential of Ziziphus oenoplia (L.)Mill. Leaves by In Vitro and In Silico Approaches.

Pancreatic lipase is one of the crucial lipolytic enzymes of the gut that actively facilitates the digestion and absorption of the dietary triglycerides and cholesteryl esters. Although it has been deemed as one of the most reliable targets for the treatment of obesity and/or dyslipidemia, to date, orlistat is the only known FDA-approved, effective, oral pancreatic lipase inhibitor available for clinical use apart from the centrally acting antiobesity agents. However, it is known to be associated with adverse gastrointestinal and renal complications. In this study, we attempted to assess the antioxidant and porcine pancreatic lipase inhibitory potentials of Ziziphus oenoplia (L.)Mill. leaves through a systematic combination of in vitro and in silico approaches. Among the four different extracts including petroleum ether extract, ethyl acetate extract, ethanolic extract, and aqueous extract obtained through successive solvent extraction, the ethyl acetate extract has outperformed the other extracts and orderly displayed competent peroxide scavenging (IC50 value: 267.30 µg/mL) and porcine pancreatic lipase inhibitory (IC50 value: 444.44 µg/mL) potentials compared to the selected reference compounds: ascorbic acid (IC50 value: 251.50 µg/mL) and orlistat (IC50 value: 502.51 µg/mL) in the selected in vitro assay models. In addition, based on the molecular docking simulations of the six essential phytoconstituents of the leaves of Ziziphus oenoplia (L.)Mill. and their respective chemical analogues against the crystal structure of pancreatic lipase-colipase complex (PDB ID: 1LPB), four best-ranked molecules (PubChem CIDs: 15515703, 132582306, 11260294, and 44440845) have been proposed. Further, among these, the interaction potentials of the two top-ranked molecules (PubChem CIDs: 132582306 and 15515703) were analyzed through molecular dynamics (MD) simulations at a trajectory of 100 ns. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters were theoretically predicted for all of the molecules using Swiss ADME and ADMET lab2.0. In conclusion, Ziziphus oenoplia (L.)Mill. leaves could become a prominent source for various potent bioactive compounds that may serve as prospective leads for the development of clinically cognizable pancreatic lipase inhibitors, provided their pharmacokinetic and in particular toxicity properties are thoroughly optimized.

Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions.

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8-24), 8 (IC50 0.44 µM and IC50 0.62 µM) and 12 (IC50 0.69 µM and IC50 0.54 µM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement.

One pot synthesis, in silico study and evaluation of some novel flavonoids as potent topoisomerase II inhibitors.

A library of novel flavonoid derivatives with diverse heterocyclic groups was designed and efficiently synthesized. Structures of the newly synthesized compounds 4a-i and 8a-l have been characterized by 1H NMR, 13C NMR, MS and elemental analysis. Anticancer activities were evaluated against MCF-7, A549, HepG2 and MCF-10A by MTT based assay. Compared with the positive control Adriamycin, compounds 4a, 4b, 4c, 4d, 8d, 8e and 8j were found to be most active anti-proliferative compounds against human cancer cell line. We found that compounds 4a and 4c exhibited inhibition of enzyme topoisomerase II with IC50 values 10.28 and 12.38 µM, respectively. In silico docking study of synthesized compounds showed that compounds 4a and 4c have good binding affinity toward topoisomerase IIα enzyme and have placed in between DNA base pair at active site of enzyme. In silico ADME prediction results that flavonoid coumarin analogues 4a-i could be exploited as an oral drug candidate.

Computational and Synthetic approach with Biological Evaluation of Substituted Quinoline derivatives as small molecule L858R/T790M/C797S triple mutant EGFR inhibitors targeting resistance in Non-Small Cell Lung Cancer (NSCLC).

New substituted quinoline derivatives were designed and synthesized via a five-step modified Suzuki coupling reaction. A comparative molecular docking study was carried out on two different types of EGFR enzymes which include wild-type (PDB: 4I23) and T790M mutated (PDB: 2JIV) respectively. Compounds were also validated upon T790M/C797S mutated (PDB ID: 5D41) EGFR enzyme at the allosteric binding site. All docking studies confirmed high potency and flexibility towards wild type as well as a mutated enzyme. Anticancer activity of the synthesized derivatives was examined against HCC827, H1975 (L858R/T790M/C797S and L858R/T790M), A549, and HT-29 cell lines by standard MTT assay. Most of the quinoline derivatives revealed a significant cytotoxic effect. The IC50 values of 4-(4-methylquinolin-2-yl)phenyl 4-(chloromethyl)benzoate (5j) were found to be 0.0042 µM, 0.02 µM, 1.91 µM, 3.82 µM and 3.67 µM while IC50 values of osimertinib were 0.0040 µM, 0.02 µM, ND, 0.99 µM and 1.22 µM, respectively. Compound 5j has shownexcellent inhibitory activities against EGFR kinases triple mutant with IC 50 value 1.91 µM. It was observed that, compared to H1975, A549 and A431 cell lines, synthesized compounds significantly inhibited proliferation of the HCC827 cell line. These data suggested that synthesized compounds showed promising selective anticancer activity against tumor cells harboring EGFR Del E746-A750. The potency of compound 5j was compared through molecular dynamic simulations andan insilicoADMET study. QSAR models were generated and the best model was correctly compared with respect to predicted and observed activity of compounds. The built model will assist to design, refine and construct novel substituted quinoline derivatives as potent EGFR inhibitors in near future.

Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach.

The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance. Communicated by Ramaswamy H. Sarma.

Ultrasound assisted synthesis of tetrazole based pyrazolines and isoxazolines as potent anticancer agents via inhibition of tubulin polymerization.

In search of new active molecules against MCF-7, A549 and HepG2, tetrazole based pyrazoline and isoxazoline derivatives under both conventional and ultrasonic irradiation method were designed and efficiently synthesized. Structures of newly synthesized compounds 5a-h and 6a-h were characterized by 1H NMR, 13C NMR, MS and elemental analysis. Several derivatives were found to be excellent cytotoxic against MCF-7, A549 and HepG2 cell lines characterized by lower IC50 values (0.78-3.12 µg/mL). Compounds 5b and 5c demonstrated an antiproliferative effect comparable to that of CA-4. Western blot analysis revealed that, reported compounds accumulate more tubulin in the soluble fraction. Docking studies suggested that, binding of these compounds mimics at the colchicine site of tubulin. In vitro study revealed that the tetrazole based pyrazolines and isoxazolines may possess ideal structural requirements for further development of novel therapeutic agents.

Biosynthesis of silver nanoparticles using dried fruit extract of Ficus carica - Screening for its anticancer activity and toxicity in animal models.

There is an increasing commercial demand for various nanoparticles due to their extensive applicability in various areas such as electronics, catalysis, chemistry, energy and medicine. Metallic nanoparticles are traditionally synthesized by wet chemical techniques, where the chemicals used are quite often toxic and flammable. Fig has been a typical fruit component of the health-promoting Mediterranean diet for a very long time. In the present study, we describe a cost effective and eco-friendly technique for green synthesis of silver nanoparticles from 1 mM AgNO3 solution through the extract of dried fig (Ficus carica L.) fruit as reducing as well as capping agent. Nanoparticles were characterized using UV absorption spectroscopy and SEM. The sizes of the spherical silver particles were found to be in the range of 54-89 nm. The biologically synthesized nanoparticles also exhibited a significant cytotoxic effect on MCF7cell lines and further animal acute toxicity results state that the above AgNPs are toxicologically safe by oral administration.

Use of donkeys and their draught performance in smallholder farming in Zimbabwe.

Animal traction constitutes the most important source of power for agricultural work in smallholder farming in Zimbabwe. Two studies, a survey and a short term on-farm trial were conducted to evaluate the use of donkeys as draught animals. The survey covered 59 households in 2 smallholder farming areas. For the on-farm trial, 12 donkeys and 12 cattle were spanned separately in teams of 4 animals to plough 40 m x 70 m plots of medium textured soil. The survey findings highlighted the drought tolerance of donkeys compared to cattle. Mortality rates of donkeys were lower. Results of the draught performance trial indicated that donkeys ploughed less area per day (P < 0.05) and their walking speed was slower (P < 0.05) than cattle. There was no significant difference (P < 0.05) in draught force between the 2 species. The work rate per hour for ploughing with donkeys was 65% of that of cattle. It was concluded that donkeys play a critical role in providing draught power for smallholder farmers but that their potential is not fully utilised.

Tumoral calcinosis.

Tumoral calcinosis is an interesting clinical entity. It is not uncommon in certain countries. We report our experience with 22 patients with this condition seen over a 7-year period and review in detail the modalities of clinical presentation, theories of etiogenesis, histological appearances, and treatment modalities.

Nutritive value of Leucaena leucocephala for growing bull calves.

Twelve cross-bred (Holstein X Gir) bull calves (11-12 months of age) were divided into two groups and fed over a 90 day period on two levels of leucaena. Animals in Group I were offered leucaena ad lib. whilst those in Group 2 received a restricted amount of leucaena plus a mixture of sorghum straw and molasses (75:25) fed ad lib. Digestibilities of dry matter, crude protein, acid detergent fibre and neutral detergent fibre for leucaena are presented. The live weight gain was significantly (P less than 0.05) higher in animals fed leucaena ad lib. than in those fed a restricted amount of the forage. The animals did not show any symptoms of toxicity during the experimental period.