Convergent synthesis and antibacterial activity of pyrazole and pyrazoline derivatives of diazepam.

Polysubstituted pyrazoles (5)(a-l), pyrazolines (7)(a-c), (8)(a-c) and pyrazolotriazine (10) derivatives of diazepam were synthesized. The structures of hitherto unknown compounds were established by analytical and spectral methods. Some of these compounds were screened to test their antibacterial activity against gram-positive (B. subtilis) and gram-negative (P. aeruginosa). All compounds showed potent activity against these bacteria.     

Cytotoxic activity screening of Bangladeshi medicinal plant extracts

The cytotoxic activity of 23 crude methanol extracts from 19 Bangladeshi medicinal plants was investigated against healthy mouse fibroblasts (NIH3T3), healthy monkey kidney (VERO) and four human cancer cell lines (gastric, AGS; colon, HT-29; and breast, MCF-7 and MDA-MB-231) using MTT assay. High cytotoxicity across all cell lines tested was exhibited by Aegiceras corniculatum (fruit) and Hymenodictyon excelsum (bark) extracts (IC₅₀ values ranging from 0.0005 to 0.9980 and 0.08 to 0.44 mg/mL, respectively). Fourteen extracts from 11 plant species, namely Clitoria ternatea (flower and leaf), Dillenia indica (leaf), Diospyros peregrina (leaf), Dipterocarpus turbinatus (bark and leaf), Ecbolium viride (leaf), Glinus oppositifolius (whole plant), Gnaphalium luteoalbum (leaf), Jasminum sambac (leaf), Lannea coromandelica (bark and leaf), Mussaenda glabrata (leaf) and Saraca asoca (leaf), were also significantly cytotoxic (IC₅₀ < 1.0 mg/mL) against at least one of the cancer cell lines tested. More selectively, Avicennia alba (leaf), C. ternatea (flower and leaf), Caesalpinia pulcherrima (leaf), E. viride (leaf) and G. oppositifolius (whole plant) showed cytotoxicity only against both of the breast cancer cell lines (MCF-7 and MDA-MB-231). In contrast, C. ternatea (flower and leaf) exhibited high cytotoxic activity against MDA-MB-231 (IC₅₀ values of 0.11 and 0.49 mg/mL, respectively), whereas E. viride and G. oppositifolius whole plant extracts exhibited high activity against MCF-7 cells (IC₅₀ values of 0.06 and 0.15 mg/mL, respectively). The cytotoxic activity test results for 9 of the plant species correlate with their traditional use as anticancer agents, thus making them interesting sources for further drug development.     

Transfer of 4‐hydroxynonenal from parasitized to non‐parasitized erythrocytes in rosettes. Proposed role in severe malaria anemia

Severe anaemia is a life‐threatening complication of falciparum malaria associated with loss of predominantly non‐parasitized red blood cells (npRBCs). This poorly elucidated process might be influenced by (i) rosettes, i.e. npRBCs cytoadherent to haemozoin‐containing parasitized RBCs (pRBCs) and (ii) generation in pRBCs of 4‐hydroxynonenal (4‐HNE) through haemozoin‐catalysed lipid peroxidation. We explored whether close proximity in rosettes may facilitate 4‐HNE transfer to npRBCs, which is likely to enhance their phagocytosis and contribute to malaria anaemia. Fluorescence microscopy and flow cytometry data indicated 4‐HNE transfer to npRBCs in rosettes. Rosettes were formed by 64·8 ± 1·8% varO‐expressing pRBCs, and 8·7 ± 1·1% npRBCs were positive for 4‐HNE‐protein‐conjugates, while low‐rosetting parasites generated only 2·4 ± 1·1% 4‐HNE‐conjugate‐positive npRBCs. 4‐HNE transfer decreased after blocking rosetting by monoclonal antibodies. A positive linear relationship between rosette frequency and 4‐HNE‐conjugates in npRBCs was found in 40 malaria patients, a first indication for a role of rosetting in npRBCs modifications in vivo. Children with severe malaria anaemia had significantly higher percentages of 4‐HNE‐conjugate‐positive npRBCs compared to children with uncomplicated malaria. In conclusion, 4‐HNE transfer from pRBCs to npRBCs in rosettes is suggested to play a role in the phagocytic removal of large numbers of npRBCs, the hallmark of severe malaria anaemia.