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Looking at spectra of exoplanets in the search for signs of life is finally a reality.

https://gizmodo.com/webb-exoplanet-atmosphere-wasp-39b-1849813296

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.

    Results and Discussion

Chemistry

The synthesis of various derivatives, 5a-n, derived by the N-substitution of N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4- methylbenzenesulfonamide (3) has been outlined in Scheme 1 and Table 1. All methods and conditions for this research work are mentioned in experimental section. The synthesis was initiated by the reaction of N-2,3-dihydro-1,4-benzodioxine-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% Na2CO3 at adjusted pH 9 under constant stirring for 2-3 hours at room temperature to yield the parent sulfonamide, N-(2,3- dihydro-1,4-benzodioxin-6-yl)-4-methylbenzenesulfonamide (3). Then, N-alkylation/aralkylation of this parent 3 was carried out with different alkyl/aralkyl halides (4a-n) in DMF as a polar aprotic solvent and LiH as the base to yield the target compounds, 5a-n. We have already reported 5b, 5g, 5h, 5j and 5l along with their structural characterizations [21], however, we are reporting other compounds as new molecules in this investigation. The structures of the studied molecules were deduced through IR, 1H-NMR and EI-MS spectral techniques. For the expediency of the readers, one of the compounds is discussed hereby in detail. The molecule 5f was obtained as brown solid having melting point 124 °C. The molecular formula C20H25NO4S of this molecule was established by its EI-MS showing the molecular ion peak at m/z 375 and by counting the number of protons in its 1H-NMR spectrum. The subsequent fragmentation peaks in its EI-MS spectrum also supported this assignment. The IR spectrum showed absorption bands at 2994, 1660, 1372 and 1144 for the C-H stretching of aromatic ring, C=C stretching of aromatic ring, SO2 and C-O-C stretching respectively. In its 1H-NMR spectrum, the presence of a 4-methylbenzenesulfonyl moiety was assured by two ortho-coupled doublets at 5 7.44 (d, J = 8.5Hz, 2H, H-2', H-6') and 7.30 (d, J = 8.6Hz, 2H, H-3', H-5') along with a singlet at 5 2.34 (s, 3H, CH3-7') for methyl group. The 2,3-dihydro-1,4- benzodioxin-6-yl moiety in this molecule was corroborated by an otho-coupled doublet at 5 6.64 (d, J=8.6Hz, 1H, H-8), a meta-coupled doublet at 5 6.30 (d, J=2.5Hz, 1H, H-5) and corresponding doublet of doublet at 5 6.54 (dd, J=2.6, 8.8Hz, 1H, H-7) along with a broad singlet at 5 4.28 (br.s, 4H, CH2-2 & CH2- 3) for two oxygenated methylenes. The N-substituted 2-pentyl group in this molecule was characterized by its typical signals in aliphatic region at 5 2.84-2.80 (m, 1H, H-2"), 1.51-1.50 (m, 2H, CH2-3"), 1.34 (Sext., J=7.4Hz, 2H, CH2-4"), and 0.90 (t, J=7.5Hz, 3H, CH3-5"). So, on the basis of above collected evidences, the structure of 5f was named as N-(2,3-dihydro-1,4-benzodioxin-6- yl)-4-methyl-N-(2-pentyl) benzenesulfonamide. In an analogous manner, the structures of other derivatives of the series were characterized [22].

Acetylcholinesterase inhibition

The screening of all the derivatives 5a-n, against acetylcholinesterase (AChE) enzyme demonstrated that all the molecules of the series were active, except 5a. These molecules exhibited moderate to weak inhibitory potential and the results are tabulated in Table 2 in the form of % age inhibition and IC50 values. Among these molecules, 5f, was found to be better inhibitor against this enzyme having IC50 value of 71.62±0.09μM, probably due to the substitution of a branched aliphatic group i. e. 2-pentyl group. The molecule, 5n, having substitution of 4-fluorobenzyl group, also showed notable inhibitory potential with IC50 value of 131.78±0.14μM. An extremely potent, eserine molecule was used as reference standard in this assay which has an IC50 value of 0.85±0.0001μM.

    Conclusion

The targeted derivatives, 5a-n, were synthesized in good yields with a facile method and some of them exhibited a notable inhibitory potential against acetyl cholinesterase enzyme, therefore, these molecules might find their utility as possible therapeutic agents for the treatment of Alzheimer's disease.

    Acknowledgement

Special thanks are paid to the Higher Education Commission (HEC) of Pakistan for financial grant to execute this study

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It's been in while since I blogged.  I'm still here in Tainan (Taiwan) trying to *continue* processing my data -- of which are over 1 million datapoints!  I know I've been a recluse these past several weeks.  Honestly, I have even considered for multiple brief moments that I "can't make it" and finish my doctorate.... 有好一陣子我沒有寫blog了。我還仍在台南（台灣）試著*繼續*做我的研究～～這研究需跑1百萬數據點！這過去幾個禮拜我知道我在閉關。其實，有好幾次我認為我完成不了研究並無法完成博士學位。 ลีไม่ได้เขียนblogสามภาษามาพักใหญ่แล้ว ตอนนี้ลี ยังอยู่ที่เมืองไทหนาน (ไต้หวัน) และพยายามที่จะวิเคราะห์ข้อมูลที่มีมากกว่า 1 ล้านข้อมูล! ลีรู้ว่าหลายอาทิตย์ที่ผ่านมา ลีปลีกตัวจากสังคม จริงๆแล้วมีหลายครั้งที่ลีคิดว่าลีจะไม่สามารถวิเคราะห์ข้อมูลได้ ไม่สามารถจะจบปริญญาเอกได้...

But fortunately, something small happened this past weekend that had a huge, wonderful effect on me.  While taking a break from tabulating all these data points on multiple computers in the lab, I decided to take a random trip to Legends Bar for a few rounds of pool and some drinks. 但是這上個週末有小小很幸福事情發生，卻帶給我滿大的影響。在研究室的工作告一段落後，我臨時決定到Legends酒吧去小酌一下和撞球。 แต่เหตุการณ์เล็กๆที่เกิดขึ้นในสัปดาห์ที่ผ่านมา มันมีผลกระทบที่ยิ่งใหญสำหรับลีมาก ระหว่างที่ลีหยุดพักจากการจัดตารางข้อมูล ลีเกิดอยากไป Legends Bar เพื่อไปดื่มและเล่นสนุกเกอร์สองสามรอบ

On a quiet Wednesday night while playing pool and throwing a few darts, I met a new and awesome Taiwanese friend, named EJ.  She apparently works as an editor and is a friend of a friend and happens to read my blog.  She said something to the effect of, "I'm really impressed with your multilingual blog!  Your Chinese is so good! -- and I even work as an editor!" 在一個安靜禮拜三晚上，在撞球跟射飛鏢的時候，我碰到了朋友的朋友是個台灣人叫EJ。她竟然是個編輯，說看我的 blog。她說「我對你很多語言 blog真的印象深刻！～～我是內行的！」 คืนวันพุธที่เงียบสงบ ระหว่างที่ลีเล่นสนุกเกอร์และลูกดอก ลีได้เจอเพื่อนใหม่ชาวไต้หวันที่เจ๋งมาก เธอชื่อ EJ เธอทำงานเป็นบรรณาธิการ เพราะว่าเธอเป็นเพื่อนของเพื่อนลี เธอจึงเคยเห็นblogของลีแล้ว เธอพูดอะไรในทำนองว่า "ฉันประทับใจในblogที่คุณเขียน โดยใช้หลายภาษา! ภาษาจีนคุณดีมาก! -- และฉัน ทำงานเป็นบรรณาธิการด้วย!"

Because she (thankfully) gave me one of the best compliments I've ever heard, I realized I should heed the advice of all my dear and true friends: Just keep trying! （感謝地）這是我聽過最好的讚美，我意識到我真的好好朋友的建議：繼續努力！ ต้องขอบใจเธอด้วย เพราะจากคำชมของเธอเป็นหนึ่งในคำชมที่ดีที่สุดที่ลีเคยได้ยินมา   ลีรู้สึกว่าลีควรจะฟังคำแนะนำจากเพื่อนฝูงที่บอกว่าให้พยายามสู้ๆ!

So shortly after final exams, I was able to get away for a bit and took up my friend’s invitation.  During our Chinese-English language exchanges, JueLing 玨玲, a fellow PhD student commuter who lives in Taichung, was always telling me about the many natural wonders there.   期末考不久之後，我有機會可以離開壓力然後赴朋友的約。我們在中英語言交換時，我一個住在台中的博士生朋友玨玲，告訴我台中有很多自然景觀。 หลังจากสอบเสร็จ ฉันได้มีโอกาสไปเที่ยวไทจง(Taichung)ตามคำเชิญของJueLing เพื่อนนักเรียนปริญญาเอก ที่อาศัยอยู่ที่ไทจง เราได้คุยแลกเปลี่ยนภาษาและวัฒนธรรม JueLing มักจะเล่าให้ฉันฟังว่าไทจงนั้นสวยงามอย่างไร

Located along wider coastal floodplains than compared to other major cities within Taiwan, Taichung’s urbanization is much more spread out.  Even so, there is still a huge network of hiking trails within the DaKeng area of Taichung’s Beitun District. We hiked for several hours along one of the more difficult trails (Trail #4).  However, I think the view from up above was totally worth it!   相對於台灣其它的城市，因為台中位於海岸沖積平原所以它的都市化(urbanization)比較分散。雖然是這樣子，在台中北屯區的大坑還有很多相互連結的爬山步道。我們在比較難的步道（四號步道）爬了很多鐘頭。但是，我覺得從上面俯瞰風景真的值得！ เมืองไทจงมีบริเวณชายฝั่งที่กว้างกว่าเมืองใหญ่อื่นๆ  ความเจริญ(urbanization)ของเมืองไทจงนั้นถือว่ากระจายออกเป็นวงกว้างมากกว่าเมืองใหญ่อื่นๆ  แม้ว่าเมืองไทจงจะมีความเจริญมาก แต่ก็ยังมีเส้นทางเดินป่าอยู่มากในบริเวณต้าเคิง(DaKeng) ตำบลเบ๋ตุ่น (Beitun) ของเมืองไทจง   เราไปเดินป่า (hiking) กันอยู่หลายชั่วโมง  ซึ่งเส้นทางนี้เป็นหนึ่งในเส้นทางที่ยากที่สุด (เส้นทางที่สี่) แต่พอไปถึงยอดเขาแล้วมองลงมา เห็นวิวที่สวยงาม ฉันคิดว่ามันคุ้มมากที่เดินมาหลายชั่วโมงนี้!

In the meantime, I have been trying to stay on top of things while still juggling a LOT on my plate.  I have recently started a new part-time job translating documents from the Thai Food and Drug Administration into English for my coworkers who are Taiwanese Chinese.  Once I get home from that, I have also been cramming and writing R Script (computer) code for my spectral analyses during the nighttime.   同時間，我嘗試妥善打理每件事雖然我超忙。我最近開始打工為我的台灣同事把泰國食品藥物管理署文件翻譯成英文。晚上我下班到家以後，我把握時間然後寫關於我光譜分析的R Script（電腦）編碼。 ในขณะเดียวกันฉันก็พยายามที่จัดสมดุล ให้กับตารางงานที่ยุ่งเหยิงของฉัน เมื่อเร็วๆนี้ฉันเพิ่งเริ่มทำงานpart-time โดยต้องแปลเอกสารของสำนักงานคณะกรรมการอาหารและยาของประเทศไทยเป็นภาษาอังกฤษ เพื่อที่จะให้เพื่อนร่วมงานคนไต้หวันเข้าใจ  ตอนกลางคืนก็ต้องคร่ำเคร่งกับการเขียนรหัส R Script (เขียนโปรแกรมคอมพิวเตอร์) สำหรับการวิเคราะห์สเปกตรัม

The actual data analysis is not so bad per se, but the sheer amount of text files is so daunting (approximately 135,000 files!).  For a crash course in R programming, I really recommend using YouTube.  In particular, you should check out Mike Marin’s YouTube channel.  Here’s hoping I stay sane during this summer “break”! 其實分析本身不那麼糟糕，可是幾個大的規模text文件真的讓我怯步（13萬5千個文件左右！）。如果你要R編碼速成課，我建議用YouTube。尤其，你應該看看Mike Marin的YouTube頻道。希望在這個「暑假」，我沒瘋掉！ ที่จริงแล้วการวิเคราะห์ข้อมูลนั้นก็ไม่ได้ยากอะไรมาก  แต่จำนวนของไฟล์ข้อมูลมันเยอะมาก (ประมาณ135,000 ไฟล์) ถ้าสนใจหลักสูตรเร่งรัดของการเรียนโปรแกรม R ฉันขอแนะนำช่อง Youtube ของ Mike Martin  หวังว่าระหว่าง “ปิดเทอม” ที่แสนยุ่งเหยิงนี้เราจะไม่บ้าไปก่อน!