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Tuberculosis (TB) is an infectious disease and caused by various strains of mycobacteria. In the present study, pharmacophore model was developed using single ligand by ligand-based drug discovery approach. The key features responsible for DprE1 inhibitory activity were taken into consideration for developing pharmacophore. After the virtual screening, top 1000 hits were further subjected to docking study using GLIDE module, Schrödinger. Docking studies have shown promising interaction with amino residues with better glide score. Ligand-based drug design approach yielded a series of 15, 2-(6-nitrobenzo[d]thiazol-2-ylthio)-N-benzyl-N-(6-nitrobenzo[d]thiazol-2-yl)acetamide derivatives. All synthesized derivatives were characterized using NMR, mass, CHN analysis. The synthesized compounds were screened for In vitro antitubercular activity against Mycobacterium tuberculosis (H37Rv). Four compounds, 5g (MIC-1.01 μM); 5i (MIC-0.91 μM); 5k (MIC-0.82 μM); and 5o (MIC-1.04 μM) has shown promising activity compared to MIC of standard isoniazid (INH) and DprE1 enzyme inhibition was compared to BTZ043. Two halogen-substituted compounds have exhibited drastic enzyme inhibition. [ABSTRACT FROM AUTHOR]

The last twenty years have seen noteworthy success in efforts to control HAT (Human African Trypanosomiasis) in Africa. HAT is a neglected tropical disease with major public health and economic effects in sub-Saharan Africa, and its effects on livestock productivity and development are considered major constraints to alleviating poverty in this region. The identification of important chemical features using the existing molecules will be helpful to discover the potent candidate to treat HAT. The development of novel HAT inhibitors is done using pharmacophore based virtual screening and docking study. The 3DQSAR was also performed to determine the predicted biological activity. The best hypothesis from PHASE, gave the five point pharmacophore hypothesis, AAPRR.687 with two hydrogen bond acceptors (A), two aromatic rings (R) and one charged group (P). Amongst them the pharmacophore hypothesis yielded a statistically significant 3D-QSAR model with 0.9521 as coefficient of determination (r2), a Pearson coefficient of 0.8796 and good F value and was considered to be the best pharmacophore hypothesis. The developed pharmacophore based 3D-QSAR model was validated by predicting the activity of test set molecules. The squared predictive correlation coefficient (q2) of 0.7359 was observed between experimental and predicted activity values of test set molecules. The developed pharmacophore was used to screen the chemical database. Subsequently the screened compounds were filtered by molecular docking. Finally five compounds were obtained as novel lead against human African trypanosomiasis. [ABSTRACT FROM AUTHOR]

In recent years, design and synthesis of anticonvulsants effective against multiple seizures has attracted much attention of medicinal chemists. In an attempt to find novel anticonvulsants, herein we have reported structurally optimized sixteen different substituted quinazolinones explored through molecular fragmentation approach. The anticonvulsant activity of synthesized compounds was assessed by using predictable seizure models in mice. Two most promising analogues 8 d (ED50 = 35.1 mg/kg, MES, mice, i. p.; ED50 = 41.5 mg/kg, scPTZ test, mice, i. p.) and 8 l (ED50 = 21.2 mg/kg, MES, mice, i. p.; ED50 = 32.4 mg/kg, scPTZ test, mice, i. p.) exhibited broad spectrum anticonvulsant action in preclinical models of seizures. Compound 8 l was also shown profound activity against pharmaco‐resistant limbic seizures produced in 6 Hz test. Most of the synthesized molecules exhibited moderate to high anticonvulsant activity in all seizure models with no symptoms of neurotoxicity and hepatotoxicity. We have also used in‐silico protocol for prediction of physiochemical and pharmacokinetic properties of synthesized quinazolinones. The promising anticonvulsant activity of synthesized analogues, ex‐vivo toxicity, in‐silico molecular docking, physiochemical and pharmacokinetic predictions make us to anticipate emergence of synthesized quinazolinones as valid leads for the treatment of convulsive disorder. [ABSTRACT FROM AUTHOR]