Recommendations from the Global Bioanalysis Consortium Team A8: documentation.

The A8 Global Harmonization Team focused on the documentation needed to support both small and large molecule bioanalysis. Current regulatory requirements were compiled and compared. The scope of the team's discussions included the validation report, the bioanalytical report, study plans, raw data, and bioanalytical summaries for the common technical document (CTD). A common high-level table of contents for method validation and sample analysis reports is proposed. Suggestions have been made as to how the CTD can be standardized to improve usability and review. Additional comments have been made on reports of failure investigations, study plans, and raw data documentation. The recommendation is that no prescriptive guidelines are required in these areas but should be led by good scientific practices subject to particular circumstances.

Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates.

A series of benzothiazole and benzoxazole linked pyrrolobenzodiazepine conjugates attached through different alkane or alkylamide spacers was prepared. Their anticancer activity, DNA thermal denaturation studies, restriction endonuclease digestion assay and flow cytometric analysis in human melanoma cell line (A375) were investigated. One of the compounds of the series 17d showed significant anticancer activity with promising DNA-binding ability and apoptosis caused G0/G1 phase arrest at sub-micromolar concentrations. To ascertain the binding mode and understand the structural requirement of DNA binding interaction, molecular docking studies using GOLD program and more rigorous 2 ns molecular dynamic simulations using Molecular Mechanics-Poisson-Boltzman Surface Area (MM-PBSA) approach including the explicit solvent were carried out. Further, the compound 17d was evaluated for in vivo efficacy studies in human colon cancer HT29 xenograft mice.

Synthesis, DNA-binding ability and evaluation of antitumour activity of triazolo[1,2,4]benzothiadiazine linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates.

A series of triazolobenzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These compounds have exhibited significant cytotoxicity against most of the cell lines examined. Compound 5a displays GI(50) values from 1.83 to 2.38 microM against seven human tumour cell lines, and is identified as a promising lead compound from this series. Their DNA thermal denaturation studies have also been carried out, and one of the compounds 5c elevates the DNA helix melting temperature of the CT-DNA by 2.6 degrees C after incubation for 36 h.

Synthesis, structural characterization and biological evaluation of novel [1,2,4]triazolo [1,5-b][1,2,4]benzothiadiazine-benzothiazole conjugates as potential anticancer agents.

Two series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine 2-methyl/ethyl sulfanyl benzothiazole derivatives (5a-d) and 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b][1,2,4] benzothiadiazine 2-phenoxy benzothiazole derivatives (16a-c) were synthesized and their structures confirmed by NMR, MS, IR and X-ray crystallography. These compounds were evaluated for their cytotoxicity against 60 human tumour cell lines. One of the synthesized compounds (5b) exhibited significant inhibitory activity against most of the cell lines and has been further evaluated for the five-dose screening.

Synthesis, structure analysis, and antibacterial activity of some novel 10-substituted 2-(4-piperidyl/phenyl)-5,5-dioxo[1,2,4]triazolo[1,5-b][1,2,4]benzothiadiazine derivatives.

A new series of 10-substituted 5,5-dioxo-5,10-dihydro[1,2,4]triazolo[1,5-b]-[1,2,4]benzothiadiazine arylsulfonamide derivatives (10a-j and 13a-f) was synthesized. The structures of these compounds were confirmed on the basis of spectral data, elemental analysis, X-ray analysis, and quantum chemical calculations. These compounds were evaluated for their efficacy as antibacterial agents against various Gram-positive and Gram-negative strains of bacteria. Amongst these compounds 10f and 10i were the most active compounds against Escherichia coli and 13e against E. coli as well as Bacillus subtilis. Moreover, other compounds also showed potent inhibitory activity in comparison to the standard drugs.

Anti-tubercular agents. Part IV: Synthesis and antimycobacterial evaluation of nitroheterocyclic-based 1,2,4-benzothiadiazines.

In continuation of our earlier work on benzothiadiazines, we have prepared a series of nitrofuran, nitrothiophene and arylfuran coupled benzothiadiazines and evaluated them for antimycobacterial and antibacterial activities. One of the compounds 2f has shown good in vitro antimycobacterial activity. All the synthesized compounds have shown moderate to good antibacterial activity.

1,2,4-benzothiadiazine linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity.

Benzothiadiazine-pyrrolobenzodiazepine conjugates linked through different alkane spacers have been prepared. These new classes of hybrid molecules exhibit cytotoxicity against many cancer cell lines. Their DNA thermal denaturation studies have been carried out and one of the compounds (4b) elevates the DNA helix melting temperature of the CT-DNA by 6.7 degrees C after incubation for 36 h.

Total synthesis of myxothiazols, novel bis-thiazole beta-methoxyacrylate-based anti-fungal compounds from myxobacteria.

Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig reactions between 27c and the aldehyde 30. The substituted beta-methoxyacrylate aldehyde 30 was produced via an Evans asymmetric aldol protocol or via the 2H-pyran-2-one 31. An E-selective Wittig reaction between the ylide derived from the phosphonium salt 27c and the (+)-aldehyde 30 led to (+)-myxothiazol Z (1b), and a corresponding reaction with the (+/-)-acrylamide aldehyde 44 gave (+/-)-myxothiazol A (1a). Complementary studies led to synthesis of the ester 47b, corresponding to myxothiazol R and myxothiazol S.

Anti-tubercular agents. Part 3. Benzothiadiazine as a novel scaffold for anti-Mycobacterium activity.

In an effort to develop new and more effective therapies to treat tuberculosis, a series of benzothiadiazine 1,1-dioxide derivatives were synthesized and their in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare was evaluated. One of the compounds, 8c, exhibited potent anti-tubercular activity, particularly for the resistant strains and thus prompted us to investigate its in vivo profile. However, the in vivo testing in a mouse model of tuberculosis infection did not show significant anti-tubercular activity, probably because of its poor bioavailability.