Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents.

A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC50 9.10 µM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme.

N-terminally modified linear and branched spermine backbone dipeptidomimetics against planktonic and sessile methicillin-resistant Staphylococcus aureus.

Toward the discovery of useful therapeutic molecules, we report the design and synthesis of a focused library of new ultrashort N-terminally modified dipeptidomimetics, with or without modifications in the spermine backbone leading to linear (series 1) or branched (series 2) tryptophans, as antimicrobial agents. Eight peptidomimetics in the library showed good antibacterial activity (MICs of 1.77 to 14.2 µg/ml) against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis bacterial strains. Tryptophan fluorescence measurements on artificial bacterial or mammalian mimic membranes and assessment of the MRSA potential depolarization ability of the designed compounds revealed membrane interactions dependent on tryptophan positioning and N-terminal tagging. Among active peptidomimetics, compounds 1c and 1d were found to be nonhemolytic, displaying rapid bactericidal activity (at 4× MIC) against exponentially growing MRSA. Further, scanning electron microscopy of peptidomimetic 1c- and 1d-treated MRSA showed morphological changes with damage to cell walls, defining a membrane-active mode of action. Moreover, peptidomimetics 1c and 1d did not induce significant drug resistance in MRSA even after 17 passages. We also investigated the activity of these molecules against MRSA biofilms. At sub-MIC levels (∼2 to 4 µg/ml), both peptidomimetics inhibited biofilm formation. At concentrations higher than the MIC (35 to 140 µg/ml), peptidomimetics 1c and 1d significantly reduced the metabolic activity and biomass of mature (24-h) MRSA biofilms. These results were corroborated by confocal laser scanning microscopy (live/dead assay). The in vitro protease stability and lower cytotoxicity of peptidomimetics against peripheral blood mononuclear cells (PBMCs) support them being novel staphylocidal peptidomimetics. In conclusion, this study provides two peptidomimetics as potential leads for treatment of staphylococcal infections under planktonic and sessile conditions.

Pharmacological significance of triazole scaffold.

The triazole nucleus is one of the most important and well known heterocycles which is a common and integral feature of a variety of natural products and medicinal agents. Triazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, antihypertensive, antimalarial, local anaesthetic, antianxiety, antidepressant, antihistaminic, antioxidant, antitubercular, anti-Parkinson's, antidiabetic, antiobesity and immunomodulatory agents, etc. The broad and potent activity of triazole and their derivatives has established them as pharmacologically significant scaffolds. The basic heterocyclic rings present in the various medicinal agents are 1,2,3-triazole and 1,2,4-triazole. A large volume of research has been carried out on triazole and their derivatives, which has proved the pharmacological importance of this heterocyclic nucleus. The present paper is an attempt to review the pharmacological activities reported for triazole derivatives in the current literature with an update of recent research findings on this nuclei.

2(3H)-furanones and 2(3H)-pyrrolones: synthesis and antimycobacterial evaluation.

A series of 3-arylidene-5-(substituted phenyl)-2(3H)-furanones (3-10) and their nitrogen analogues, 3-arylidene-5-(substituted phenyl)-1-benzyl-2(3H)-pyrrolone (11-14), and 3-arylidene-5-(substituted phenyl)-2(3H)-pyrrolones (15-21) were synthesized. All the compounds were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) in BACTEC medium using the Microplate Alamar Blue Assay (MABA). Among the synthesized compounds, compound 19, 3-(4-chlorobenzylidene)-5-(4-methylphenyl)-2(3H)-pyrrolone, emerged as a lead compound having the highest activity against Mycobacterium tuberculosis. The antimycobacterial activity was found to improve upon replacement of oxygen of furanone ring with nitrogen atom (pyrrolones), however, substitution with benzylamine moiety (1-benzylpyrrolones) markedly decreases the activity.