Synthetic N-(Alkyl/Aralkyl)-N-(2,3-Dihydro-1,4-Benzodioxin-6-Yl)-4-Methylbenzenesulfonamides as Acetyl cholinesterase Inhibitors-Juniper Publishers

 JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF DRUG DESIGNING & DEVELOPMENT


Abstract

The current research effort involved the reaction of 2,3-dihydro-1,4-benzodioxin-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% Na2CO3 under dynamic pH control to obtain N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methylbenzenesulfonamide (3) which was further coupled with a series of alkyl/aralkyl halides (4a-n) to attain N-alkyl/aralkyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)- 4-methylbenzenesulfonamides (5a-n), using polar aprotic solvent; DMF and catalytic amount of lithium hydride as base. The structural characterization of these newly synthesized compounds was done by IR, 1H-NMR and EIMS spectral data. All these compounds were assessed for their acetyl cholinesterase inhibitory potentials and were found to be moderate inhibitors of this enzyme. Two molecules, 5f and 5n displayed excellent to effective inhibitory potential respectively while the other showed moderate inhibitory potential against acetyl cholinesterase enzyme.

Keywords: 2,3-Dihydro-1; 4-Benzodioxin-6-amine; Sulfonamides; Spectral analysis; Acetyl cholinesterase

Introduction

The basic sulfonamide group SO2NH is found in numerous biological active compounds including antiviral, anticancer, anti-thyroid, antimicrobial, anti-inflammatory and antibiotics drugs along with inhibitors of carbonic anhydrase [1]. Because of their less cost, less toxicity and astonishing activity, these are extensively used as antibacterial agents [2-6]. Furthermore, sulfonamides are also employed as, anti-leprotic, diuretics, antitumor agents, tuberculostatics and oral hypoglycemic drugs [7-8]. Aliphatic sulfonamide derivatives act as antifungal agents [9]. Sulfonamide based antibiotics are utilized as veterinary medicines to treat infections in livestock herds [10]. Compounds bearing benzodioxane ring system exhibits different biological activities such as anti-oxidant [11], anti-hepatotoxic and anti-inflammatory [12,13]. Aryl sulfonamides having benzodioxane moiety have been recognized as inhibitors of ExoU [14]. Because of their non-interaction to defence mechanism of host and broad spectrum activity some effective derivatives of sulfonamides are widely used to treat gastrointestinal and urinary tract infections [15]. Some sulfonamides were also found to be potent carbonic anhydrase, COX-2 and caspase inhibitors [16-18].

Acetyl cholinesterase (AChE, EC 3.1.1.7) belongs to serine hydrolases class of enzymes. This enzyme system is accountable for the termination of acetylcholine at cholinergic synapses. The main function of AChE is to catalyze the hydrolysis of the neurotransmitter acetylcholine and termination of the nerve impulse in cholinergic synapses [19]. The inhibitors of this enzyme are the targets for the treatment of Alzheimer's disease [20]. Biological literature review on sulfonamides displayed that little modification in the structure of sulfonamides can cause remarkable changes in biological activity. These outcomes stimulated us to focus on synthesis of variety of N-alkyl/aralkyl-N-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4- methylbenzenesulfonamides. Recent research work was a successful attempt to synthesize new therapeutic agents for the inhibition of cholinesterase enzyme.

Experimental

Measurements and materials

All of the essential chemicals/solvents were of analytical grade and procured from authorized suppliers, Merck and Alfa Aeser branded. The pre-coated silica gel G-25-UV254 plates were applied for TLC to monitor the completion of reactions using various percentages of n-hexane and ethyl acetate as mobile phase. Open capillary tubes were used in Gallon kamp melting point apparatus to record the melting points. Developed TLC visualized under 254nm UV lamp and UV inactive substances were identified with the spray of ceric sulfate solution. Infrared spectra were noted in KBr pellet on a Jasco-320-A spectrophotometer. 1H-NMR spectra were recorded by Bruker spectrometer in CDCl3 operating at 400MHz at 25 °C. The chemicals shifts (5) were observed in ppm and coupling constants (δ) were noted in Hertz (Hz). The abbreviations used in 1HNMR spectral analysis were; s=singlet, d=doublet, dd=doublet of doublet, t=triplet, br.t=broad triplet, q=quartet, quint=quintet, sex=sextet, sep=septet, m=multiplet. Mass spectra (EIMS) were taken on Finngen Mass Spectrometer.

Synthesis of N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4- methylbenzenesulfonamide (3)

2,3-Dihydro-1,4-benzodioxin-6-amine (1.22mL;0.01mol;1) and 4-methylbenzenesulfonyl chloride (0.90g; 0.01mol; 2) were poured into a 250ml round bottom flask having 30ml of distilled water. The pH of the suspension was maintained at 9.0 by introducing 10% Na2CO3 solution at room temperature. The content of reaction was stirred for 2-3 hours and progress of the reaction was examined by TLC time to time till single spot confirm the completion of reaction. The product was obtained by the slow addition of concentrated HCl at pH 2-3 as brown coloured precipitates. These were filtered, washed with distilled water and air-dried to afford pure N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4- methylbenzenesulfonamide (3); Yield: 82%, IR (KBr, cm-1): vmax: 3284 (N-H stretching), 2970 (C-H stretching of aromatic ring], 1650 C=C stretching of aromatic ring), 1410 (SO2 stretching), 1175 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 9.87 (s, -NH, 1H), 7.58 (d, J=8.4Hz, 2H, H-2' & H-6'), 7.32 (d, J=8.0Hz, 2H, H-3' & H-5'), 6.68 (d, J=8.4Hz, 1H, H-8), 6.55 (d, J=2.0Hz, 1H, H-5), 6.50 (dd, J=2.4, 6.5Hz 1H, H-7), 4.14 (s, 4H, H-2 & H-3), 2.33 (s, 3H, H-1''); EI-MS (m/z): 305 (M+; C15H15NO4S), 304 (C15H14NO4S)+, 277 (C13H11NO4S)+, 241 (C15H15NO2)+, 213 (C8H7NO4S)+, 155 (C7H7SO2)+, 150 (C8H8NO2)+,, 135(C8H7O2)+,, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+, 65 (C6H5)+, 51 (C4H3)+.

General procedure for the synthesis of N-substituted derivatives 5a-n

Compound 3 (0.1g; 0.3mmol) solubilised in 10ml of N, N-dimethyl formamide (DMF) aprotic solvent in 100ml round bottom flask. Lithium hydride (0.004g) was mixed in the reaction mixture to activate the reaction followed by stirring for 2-3 hours at room temperature. Then various alkyl/aralkyl halides (4a-n) were introduced and stirring was continued for further 3-4 hours. Completion of reaction was assured by TLC displaying single spot. Then reaction content was quenched with ice cold distilled water along with vigorous shaking to get the precipitates of N-alkyl/aralkyl-N-(2,3-dihydro-1,4-benzodioxin- 6-yl)-4-methylbenzenesulfon-amides (5a-n) which were left for some time undisturbed and collected by the filtration or solvent extraction (using CHCl3) depending upon the nature of the derived compound.

Spectral analysis

The spectral analysis of 5b, 5g, 5h, 5j and 5l has already been reported by our group [21] while that of other compounds is given hereby.

N-(2-Chloroethyl)-N-(2,3-dihydro-1,4-benzodioxin-6- yl)-4-methylbenzenesulfonamide (5a): Off white powder; Yield: 95 %; m.p: 142 °C; Molecular formula: C17H18ClNO4S; Molecular weight: 371g mol-1; IR (KBr, cm-1): vmax: 2976 (C-H stretching of aromatic ring), 1657 (C=C stretching of aromatic ring), 1395 (-SO2 stretching), 1140 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 5 7.50 (d, J=8.5Hz, 2H, H-2' & H-6'), 7.40 (d, J=8.4Hz, 2H, H-3' & H-5'), 6.66 (d, J=7.6Hz, 1H, H-8), 6.50 (dd, J=2.5, 8.2Hz, 1H, H-7), 6.42 (d, J=2.6Hz, 1H, H-5),4.28 (br.s, 4H, CH2-2 & CH2-3), 3.60 (t, J=6.5Hz, 2H, CH2-2"), 3.46 (t, J=7.4Hz, 2H, CH2-1"), 2.34 (s, 3H, CH3-7'); EI-MS (m/z): 371 (M+ C17H18CINO4S), 340 (C15H14ClNO4S)+, 304 (C15H14NO4S)+, 300 (C12H11ClNO4S)+,, 237 (C12H11ClNO2)+, 213 (C10H11ClNO2)+, 155 (C7H7SO2+, 135(C8H7O2)+, 107(C6H3O2)+, 91(C7H7)+, 81(C4HO2)+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-N-(2-Iodoethyl)- 4-methylbenzenesulfonamide (5c): Greyish white solid; Yield: 95%; m.p: 132 °C; Molecular formula: C17H18INO4S; Molecular weight: 459g mol-1; IR (KBr, cm-1): vmax: 2989 (C-H stretching of aromatic ring), 1660 (C=C stretching of aromatic ring), 1379 (-SO2 stretching), 1168 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 5 7.50 (d, J=7.4Hz, 2H, H-2' & H-6'), 7.42 (d, J=8.5Hz, 2H, H-3' & H-5'), 6.68 (d, J=6.68Hz, 1H, H-8), 6.54 (d, J=2.5Hz, 1H, H-5), 6.40 (dd, J=2.5, 8.5Hz, 1H, H-7), 4.26 (br.s, 4H, CH2-2 & CH2-3), 3.72 (t, J=7.5Hz 2H, CH2-1''), 3.36 (t, J=6.8Hz, 2H, CH2-2"), 2.36 (s, 3H, CH3-7'); EI-MS (m/z): 459 [M+ C17H18IO4S], 431 (C15H14INO4S)+, 395 (C17H18INO2)+, 368(C10HuINO4S)+,, 326 (C10H10INO2)+, 304 (C15H14NO4S)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methyl-N-(1-propyl)benzenesulfonamide (5d): Dark brown powder; Yield: 88%; mp: 136 °C; Molecular formula: C18H21NO4S; Molecular weight: 347g mol-1; IR (KBr, cm-1): vmax: 2988 (C-H stretching of aromatic ring), 1662 (C=C stretching of aromatic ring), 1374 (SO2 stretching), 1148 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 5 7.46 (d, J=8.2Hz, 2H, H-2' & H-6'), 7.34 (d, J=8.5Hz, 2H, H-3' & H-5'), 6.68 (d, J=7.5Hz, 1H, H-8),6.40 (d, J=2.5Hz, 1H, H-5), 6.22 (dd, J=2.6, 8.4Hz, 1H, H-7), 4.28 (br.s, 4H, CH2-2 & CH2-3), 3.10 (t, J=7.5Hz, 2H, CH2-1''), 2.34 (s, 3H, CH3-7'), 1.60-1.56 (m, 2H, CH2-2''), 1.05 (t, J=7.4Hz, 3H, CH3-3''); EI-MS (m/z): 347 (M+ C18H21NO4S), 319 (C16H17NO4S)+, 304 (C15H14NO4S)+, 283 (C18H21No2)+, 256 (C11H14NO4S)+, 178 (C11H14NO2)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methyl-N-(1-pentyl)benzenesulfonamide (5e): Brown powder; Yield: 85%; m.p: 114 °C; Molecular formula: C20H25NO4S; Molecular weight: 375g mol-1; IR (KBr, cm-1): vmax: 2984 (C-H stretching of aromatic ring), 1678 (C=C stretching of aromatic ring), 1376 (SO2 stretching), 1142 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400 MHz, δ in ppm): 5 7.40 (d, J=8.4Hz, 2H, H-2' & H-6'), 7.34 (d, J=8.5Hz, 2H, H-3' & H-5'), 6.66, (d, J=7.8Hz, 1H, H-8), 6.44 (dd, J=2.7, 8.5Hz, 1H, H-7), 6.28 (d, J=2.6Hz, 1H, H-5), 4.28 (br.s, 4H, CH2-2 & CH2-3), 3.20 (t, J=7.5Hz, 2H, CH2-1''), 2.34 (s, 3H, CH3-7'), 1.40-134 (m, 6H, CH2-2" to CH2-4"), 0.90 (t, J=7.6Hz, 3H, CH3-5"); EI-MS (m/z): 375 (M + C20H25NO4S), 347 (C18 H21NO4S)+, 311 (C20H25NO2)+, 304 (C15H14NO4S)+, 284 (C13H18NO4S)+, 220 (C13H18NO2)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+, 71 (C5H2+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methyl-N-(2-pentyl)benzenesulfonamide (5f): Brown solid; Yield: 92%; m.p: 124 °C; Molecular formula: C20H25NO4S; Molecular weight: 375g mol-1; IR (KBr, cm-1): vmax: 2994 (C-H stretching of aromatic ring), 1660 (C=C stretching of aromatic ring), 1372 (-SO2 stretching), 1144 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 57.44 (d, J=8.5Hz, 2H, H-2' & H-6'), 7.30 (d, J=8.6Hz, 2H, H-3' & H-5'), 6.64, (d, J=8.6Hz, 1H, H-8), 6.54 (dd, J=2.6, 8.8Hz, 1H, H-7), 6.30 (d, J=2.5Hz, 1H, H-5), 4.28 (br.s, 4H, CH2-2 & CH2-3), 2.84-2.80 (m, 1H, H-2"), 2.34 (s, 3H, CH3-7'), 1.51-1.50 (m, 2H, CH2-3"), 1.34 (Sext., J=7.4Hz, 2H, CH2-4"), 0.90 (t, J=7.5Hz, 3H, CHr5"); EI-MS (m/z): 375 (M+; C20H25NO4S), 347 (C18 H21NO4S)+, 311 (C20H25NO2)+, 304 (C15H14N04S)+, 284(C13H18NO4S)+, 220 (C13H18NO2)+, 155 (C7H7SO2)+, 135 (C8H7O2)+,107 (C6h3O2+, 91 (C7H7)+, 81 (C4HO2)+, 71 (CSHU)+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methyl-N-(2-methybenzyl)benzenesulfonamide (5i): Brown powder; Yield: 88%; m.p: 160 °C; Molecular formula: C23H23NO4S; Molecular weight: 409g mol-1; IR (KBr, cm-1): vmax: 2998 (C-H stretching of aromatic ring), 1680 (C=C stretching of aromatic ring), 1374 (-SO2 stretching), 1162 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400 MHz, δ in ppm): 5 7.44 (d, J=8.4Hz, 2H, H-2' & H-6'), 7.38 (d, J=7.7Hz, 2H, H-3' & H-5'), 7.34-7.28 (m, 4H, H-3'' to H-6''), 6.60, (d, J=7.5Hz, 1H, H-8), 6.50 (dd, J=2.5, 8.5Hz, 1H, H-7), 6.25 (d, J=2.6Hz, 1H, H-5), 4.38 (s, 2H, CH2-7''),4.28 (br.s, 4H, CH2-2 & CH2-3), 2.34 (s, 3H, CH3-7'), 2.26 (s, 3H, CHr8"); EI-MS (m/z): 409 (M+; C23H23N04S), 381 (C21H19NO4S)+, 345 (C23H23NO2)+, 318 (C16H16NO4S)+, 304 (C15H14NO4S)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 105 (C8H9)+, 107 (C6H3O2)+, 91(C7H7)+, 81 (C4HO2)+.

N-(3-Chlorobenzyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methylbenzenesulfonamide (5k): Grey powder; Yield: 96%, m.p: 152 °C; Molecular formula: C22H20ClNO4S; Molecular weight: 429gmol 1; IR (KBr, cm-1): vmax: 3010 (C-H stretching of aromatic ring), 1672 (C=C stretching of aromatic ring), 1382 (-SO2 stretching), 1090 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400 MHz, δ in ppm): 5 7.50 (br.s, 1H, H-2"), 7.42 (d, J=8.8Hz, 2H, H-2' &H-6'), 7.36 (d, J=8.5Hz, 2H, H-3' & H-5'), 7.30-7.25 (m, 3H, H-4" to H-6'"), 6.66, (d, J=6.5Hz, 1H, H-8), 6.52 (dd, J=2.6, 8.5Hz, 1H, H-7), 6.18 (d, J=2.6Hz, 1H, H-5), 4.42 (s, 2H, CH2-7''), 4.28 (br.s, 4H, CH2-2 & CH2-3), 2.36 (s, 3H, CH3- 7'); EI-MS (m/z): 429 (M+; C22H20ClNO4S), 402 (C20H16ClNO4S)+, 365 (C22H20ClNO2)+, 338 (C15H13ClNO2)+, 304 (C15H14N04S)+, 274 (C15H13ClNO2)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 171 (C7H6Cl)+, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+.

N-(2-Bromobenzyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methylbenzenesulfonamide (5m): Brown powder; Yield: 96%; m.p: 168 °C; Molecular formula: C22H20BrNO4S; Molecular weight: 475gmol-1; IR (KBr, cm-1): vmax: 3010 (C-H stretching of aromatic ring), 1670 (C=C stretching of aromatic ring), 1366 (-SO2 stretching), 1156 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 57.50 (br.d, J=6.8Hz, 1H, H-3''), 7.42 (d, J=8.5Hz, 2H, H-2' &H-6'), 7.36 (d, J=8.5Hz, 2H, H-3' & H-5'), 7.28-7.24 (m, 4H, H-4'' to H-6"), 6.62, (d, J=6.8 Hz, 1H, H-8), 6.48 (dd, J=2.5, 8.6Hz, 1H, H-7), 6.20 (d, J=2.8Hz, 1H, H-5),4.41 (s, 2H, H-7"), 4.28 (br.s, 4H, CH2-2 & CH2-3), 2.34 (s, 3H, CH3- 7'); EI-MS (m/z): 475 [M+; C22H20BrNO2], 447 (C20H16BrNO4S)+, 411 (C22H20BrNO2)+, 320 (C15Hl3BrN0l)+, 304 (C15H14NO4S)+, 384 (C15H13BrNO4S)+, 171 (C7H6Br)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 107 (C6H0l)+, 91 (C7H7)+.

N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methyl-N-(4-fluorobenzyl)benzenesulfonamide (5n): Light grey powder; Yield: 90%, m.p: 122 °C; Molecular formula: C22H20FN04S; Molecular weight: 413g mol 1; IR (KBr, cm-1): vmax: 2994 (C-H stretching of aromatic ring), 1686 (C=C stretching of aromatic ring), 1380 (-SO-, stretching), 1195 (C-F stretching), 1086 (C-O-C stretching of ether); 1H-NMR (CDCl3, 400MHz, δ in ppm): 57.44 (d, J = 8.6Hz, 2H, H-2' & H-6'), 7.34 (d, J = 7.5Hz, 2H, H-3' & H-5'), 7.38 (dd, J=5.3, 8.5Hz, 2H, H-2” & H-6”, multiplicity due to coupling of F19), 7.14 (br.t, J=8.6, 2H, H-3” & H-5”, due to coupling of F19), 6.62, (d, J=7.5Hz, 1H, H-8), 6.50 (dd, J=2.5, 7.8Hz, 1H, H-7), 6.20 (d, J=2.5Hz, 1H, H-5), 4.36 (s, 2H, CHr7"),4.28 (br.s, 4H, CH2-2 & CH2-3), 2.32 (s, 3H, CH3-7'); EI-MS (m/z): 413 (M+; C22H20FNO4S), 385 (C20H16FNO4S)+, 349 (C22H20FNO2)+, 322 (C15H13FNO4S)+, 304 (C15H14NO4S)+, 155 (C7H7SO2)+, 135 (C8H7O2)+, 109 (C7H6F)+, 107 (C6H3O2)+, 91 (C7H7)+, 81 (C4HO2)+, 65 (C6H5)+, 51(C4H3)+.

Acetylcholinesterase inhibition assay

The inhibition activity of acetylcholinesterase was performed by according to a reported method [22] with little modifications. Total volume of the reaction mixture was 100μL and it also contained 60μL Na2HPO4, which acts as buffer having 50mm concentration (pH 7.7). Ten μL test compound 0. 5mm well-1, followed by the addition of 10μl (0.5 unit well-1) enzyme. The reaction contents was agitated well and read prior at the wavelength 405nm. Then mixture was pre-incubated at 37 °C for 10 minute. The reaction was started by adding 10μl of 0.5mm well-1 substrate (acetylthiocholine iodide) followed by the addition of 10μl DTNB (0.5mm well-1). After 15 min of incubation at 37 °C, absorbance was recorded at 405nm using 96-well plate reader Synergy HT (BioTek, USA). Each and every experiment was carried out with their particular controls in triplicate. Eserine (0.5mm well-1) was act as positive control. The equation that was used to calculate % inhibition was:

Inhibition (%)=(Control-Test)/Controlx100

IC50 values (concentration at which there is 50% enzyme inhibition) of compounds were calculated using EZ-Fit Enzyme kinetics software (Perella Scientific Inc. Amherst, USA).

Statistical analysis

All the measurements were done in triplicate and statistical analysis was performed by Microsoft Excel 2010. Results are presented as mean ± SEM.

For more Open Access Journals in Juniper Publishers please click on: https://www.crunchbase.com/organization/juniper-publishers

For more articles in Open Access Novel Approaches in Drug Designing & Development please click on: https://juniperpublishers.com/napdd/index.php

For more Open Access Journals please click on: https://juniperpublishers.com

To know more about Juniper Publishers please click on: https://juniperpublishers.business.site/


Comments

Post a Comment

Popular posts from this blog

Erythrocyte as a Therapeutic Target-Juniper Publishers

Image
  JUNIPER PUBLISHERS - OPEN ACCESS JOURNAL OF DRUG DESIGNING & DEVELOPMENT Abstract Erythrocytes are powerful components of blood flow designed to scavenger or deliver nitic oxide (NO) and oxygen to all cells in the body and transport carbon dioxide from them to the lungs. Blood components started to be quantified and erythrocyte blood shapes used as diagnostic and prognostic tools in clinical practice. Erythrocytes have hemorheological, hemostatic and pro or anti-inflammatory properties enlarging their physiological implications in health and disease. As blood component the erythrocytes establish interaction with others white blood cells, platelets, plasma lipoproteins and vascular endothelial cells. The aim of this mini review is highlight the signaling pathway of nitric oxide in which some steps explain the efficacy of some therapeutic drugs already used and could point new targets for further application in inflammatory vascular diseases Keywords: Eryth...
Read more

Considering Drug Metabolism and Molecular Complexity in Drug Design-Juniper Publishers

Image
  JUNIPER PUBLISHERS - OPEN ACCESS JOURNAL OF DRUG DESIGNING & DEVELOPMENT Abstract Drugs aesign is usually focusea on affinity to binaing sites. However, such an approach, which is meaningful ana promising, shoula not neglect the contribution of metabolism to the efficacy ana tolerability of a arug. Metabolism is often primarily regaraea as a source of arug elimination. On the other hand, metabolites can have their own pharmacological properties, which may be highly undesired, but, in other cases, can be favorable. In this short review, examples are given for oxiaotoxicity of metabolites, incluaing the possibility of organic reaox cycling, for non-enzymatic formation of metabolites with unaesirea properties, for unexpectea changes in lipophilicity, ana for presumably favorable properties of certain metabolites. The relationship of molecular complexity of a arug to the number of metabolites is aaaressea. The necessity for not neglecting the possible toxicity of...
Read more

Avasimibe and Sirt 1 Activators Reverse NAFLD and Obesity-Juniper Publishers

Image
  JUNIPER PUBLISHERS - OPEN ACCESS JOURNAL OF DRUG DESIGNING & DEVELOPMENT Opinion In epidemiological studies human obesity is clearly associated with the increased risk for atherosclerosis contributing to the early onset of coronary artery disease and diabetes. Visceral obesity in particular increases the risk of atherosclerosis owing to both insulin resistance and dyslipoproteinemia. Risk factors for atherosclerosis that could be exacerbated by obesity include hypertension and hyper lipidemia particularly hyper triglyceridemia which are risk factors for Alzheimer’s disease. The susceptibility of humans to obesity is far higher compared with other species and in man favours the deposition of fat [1]. Amongst mammals humans have been reported to have the highest level of fatness than any other species and genes and environmental factors predispose humans to obesity [2]. Novel research provides information for anti-aging genes with connections between appeti...
Read more