Insight into the structural requirements of benzothiadiazine scaffold-based derivatives as hepatitis C virus NS5B polymerase inhibitors using 3D-QSAR, molecular docking and molecular dynamics.

Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity.

Anti-tubercular agents. Part 5: synthesis and biological evaluation of benzothiadiazine 1,1-dioxide based congeners.

In an effort to discover new and effective chemotherapeutic agents from this laboratory for the treatment of tuberculosis, here in we describe the synthesis and biological evaluation of a series of novel benzothiadiazine 1,1-dioxide (BTD) based congeners by using rifampicin, streptomycin; ciprofloxacin and amphotericin as positive controls. Further, to understand structural requirements for exploring the structure activity relationship of BTDs, cytotoxicity and in vivo study of recently reported potent molecule 4 (MIC = 1 microg/mL) is also discussed.

Acute hypotensive, hemodynamic effects of long-term treatment with niludipine, a Ca2+-antagonist, in patients with essential hypertension. Niludipine monotherapy and combination with a beta-blocker and a diuretic).

The acute effects of oral administration of niludipine (Bay a 7168), a new dihydropyridine derivative Ca2+-antagonist, on blood pressure (BP), hemodynamics and plasma renin activity (PRA) were investigated in patients with essential hypertension (n = 28) and normotensive volunteers (n = 7). In the hypertensives, BP was acutely lowered by 20 mg of niludipine (from 163/94 to 141/83 nmHg at 2 h, n = 7), 40 mg (163/101 to 140/90), and 60 mg (173/106 to 135/85). Niludipine (60 mg) increased cardiac output (CO; 5.13 to 7.56 l/min), stroke volume (79.0 to 107 ml/beat), and decreased total peripheral resistance (22.3 to 13.6 mmHg/l/min). In the normotensives, BP was not appreciably affected by 60 mg (decrease from 112/73 to 110/68). Heart rate (HR) and PRA were not influenced by the drug in all subjects. Long-term trials were carried out on 21 hypertensives. BP was reduced by niludipine monotherapy (20 mg, 4 times a day) from 167/97 to 140/80 mmHg at the 4th week and remained stable during the entire treatment. Addition of propranolol (10 mg, 4 times a day) did not lower BP any further, but tended to reduce HR. By adding penfluzide (2.5 mg a day) to this regimen, systolic BP was further lowered. Tachycardia, bradycardia, edema, increase in PRA or tachyphylaxis were not observed during the trial. The results indicate that niludipine, either alone or combined with propranolol and penfluzide, is effective in the treatment of patients with essential hypertension.

Antihypertensive, saluretic and hypokalaemic effects of cyclothiazide in comparison with hydrochlorthiazide with amiloride supplement.

The antihypertensive, saluretic and hypokalaemic effects of a small dose of cyclothiazide (2.5 mg daily) were compared with those of a conventional dose of an hydrochlorthiazide-amiloride hydrochloride combination (50 + 5 mg daily). Both preparations were given to 13 patients with mild (WHO I) hypertension in a cross-over manner for six weeks, with an intervening wash-out phase of three weeks. The antihypertensive efficacy of cyclothiazide was well comparable to that of the hydrochlorthiazide-amiloride combination, although cyclothiazide tended to inhibit renal sodium reabsorption less than the combination. Cyclothiazide tended to cause hypokalaemia, apparently due to increased potassium loss, but with the present dosage none of the 13 patients developed marked hypokalaemia (serum potassium less than 3.3 mmol/l). Both drugs led to a comparable increase in serum urate concentration. Neither of the preparations affected creatinine or free-water clearance. The results suggest that even in relatively small doses thiazides effectively decrease blood pressure, and combining thiazides with potassium-sparing diuretics is advantageous only in patients with marked hypokalaemia and its associated risks.