Author: Metzger, Margaret ; Wan, Baojie ; Nguyen, Duc ; Feiner, Janaya ; Hossain, Akil ; Qader, Mallique ; Nugent, Angela ; Shetye, Gauri ; Franzblau, Scott ; Cuevas, Jake ; Kauffman, John ; Umesiri, Francis E

There is an urgent need to develop new anti-tuberculosis (anti-TB) drugs to tackle drug-resistant strains of Mycobacterium tuberculosis (M.tb). Whereas antimicrobial peptides (AMPs) have received attention because of their antibacterial properties, oligo-N-substituted glycines (peptoids) are now seen as favorable alternatives to AMPs because they are more stable and less vulnerable to protease degradation, less expensive to produce, and better suited to potential pharmaceutical adoption and development. In this work, therefore, we designed, synthesized, and screened 22 new α- and β-peptoids against drug susceptible M. tb strain H37Rv using the Microplate Alamar Blue assay (MABA) to evaluate minimum inhibitory concentration (MIC). Eight compounds (JC5, MM2, MM5, MM9, MM10, MM11, JF11, and JF13) had MICs of less than 10 μg/ml, the most potent of which were JC5 and MM2, with MICs of 1.48 μg/ml and 2.97 μg/ml, respectively. JC5 and MM2 also retained potency against strains mono-resistant to isoniazid and rifampin, and against five of the global M. tb clade representatives. Furthermore, peptoids JC5 and MM2 showed minimum bactericidal concentration (MBC) of 3.02 μg/ml and 5.48 μg/ml respectively. Intracellular activity by luminescence showed a macrophage EC90 of less than 10 μg/ml for both JC5 and MM2. In addition, both compounds showed remarkable narrow spectrum activity. Selectivity with respect to Vero cells was modest but sufficient to consider these classes of alpha and beta-peptoids as good leads for further development of anti-TB drugs.

01 Jan 2004·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Effects of Novel Synthesized Pyridothiazines on Various Guinea Pig Heart Muscle Preparations

Q4 · MEDICINE

Article

Author: Schade, Bettina ; Weber, Manuela ; Studenik, Christian ; Erker, Thomas

Calcium channel blockers have become important tools in the treatment of cardiovascular disorders and other diseases. Hybridization of well established calcium antagonist subclasses was an attempt to optimize their pharmacological profile. The intension of this study was to investigate the electrophysiological properties of MM 10 and MM 11 two newly synthesized compounds structurally closely related to KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-1-oxopropyl]-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate) in various isolated guinea pig heart muscle preparations by means of the conventional intracellular microelectrode tech-nique. MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminopropionyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) exerted very similar effects though the action of MM 11 was more pronounced. Whereas action potential amplitude and maximum upstroke velocity (V(max)) in papillary muscle, left atria and spontaneously beating Purkinje fibers was not affected by the compounds in a concentration range from 3 to 30 micromol/l, action potential duration at 90% time to repolarization was significantly prolonged in a concentration-dependent manner. Action potential duration at 20% time to repolarization was decreased in spontaneously beating Purkinje fibers and remained unchanged in papillary muscles and left atria. In sinoatrial nodes both compounds reduced rate of activity, action potential amplitude, maximum upstroke velocity and slope of slow diastolic depolarization while time to repolarization was prolonged. In 3 out of 6 experiments with spontaneously beating Purkinje fibers, MM 11 (30 micromol/l) led to the occurrence of early afterdepolarizations with a take off potential between -50 and -60 mV. All observed effects were completely reversible during washout with drug-free physiological salt solution. From these results it was concluded that both compounds in addition to their calcium antagonistic properties might depress repolarizing potassium currents. In contrast to the mother compound KT-362 they do not seem to affect the fast sodium inward current. Replacement of the benzothiazepine nucleus by a pyridothiazine structure may weaken or even eliminate sodium channel blocking ability. Shortening of the side chain might result in a general loss in activity.

01 Jan 1999·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Effects of Novel Pyridothiazepines and Pyridothiazines on Contractility of Isolated Guinea-Pig Heart Muscle and Vascular Smooth Muscle Preparations.

Q4 · MEDICINE

Article

Author: Christian Studenik ; Bettina Schade

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl+ ++]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.

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