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\def\makelabel##1{\upshape ##1}}% } {\end{list}\end{raggedright}} \newenvironment{specHead}[2]% {\vspace{20pt}\hrule\vspace{10pt}% \phantomsection\label{#1}\markright{#2}% \pdfbookmark[2]{#2}{#1}% \hspace{-0.75in}{\bfseries\fontsize{16pt}{18pt}\selectfont#2}% }{} \def\TheFullDate{2013-01-15 (revised: 15 January 2013)} \def\TheID{\makeatother } \def\TheDate{2013-01-15} \title{Synthesis and Evaluation of Quinazolinone Derivatives for Cardiovascular Activity} \author{}\makeatletter \makeatletter \newcommand*{\cleartoleftpage}{% \clearpage \if@twoside \ifodd\c@page \hbox{}\newpage \if@twocolumn \hbox{}\newpage \fi \fi \fi } \makeatother \makeatletter \thispagestyle{empty} \markright{\@title}\markboth{\@title}{\@author} \renewcommand\small{\@setfontsize\small{9pt}{11pt}\abovedisplayskip 8.5\p@ plus3\p@ minus4\p@ \belowdisplayskip \abovedisplayskip \abovedisplayshortskip \z@ plus2\p@ \belowdisplayshortskip 4\p@ plus2\p@ minus2\p@ \def\@listi{\leftmargin\leftmargini \topsep 2\p@ plus1\p@ minus1\p@ \parsep 2\p@ plus\p@ minus\p@ \itemsep 1pt} } \makeatother \fvset{frame=single,numberblanklines=false,xleftmargin=5mm,xrightmargin=5mm} \fancyhf{} \setlength{\headheight}{14pt} \fancyhead[LE]{\bfseries\leftmark} \fancyhead[RO]{\bfseries\rightmark} \fancyfoot[RO]{} \fancyfoot[CO]{\thepage} \fancyfoot[LO]{\TheID} \fancyfoot[LE]{} \fancyfoot[CE]{\thepage} \fancyfoot[RE]{\TheID} \hypersetup{citebordercolor=0.75 0.75 0.75,linkbordercolor=0.75 0.75 0.75,urlbordercolor=0.75 0.75 0.75,bookmarksnumbered=true} \fancypagestyle{plain}{\fancyhead{}\renewcommand{\headrulewidth}{0pt}} \date{} \usepackage{authblk} \providecommand{\keywords}[1] { \footnotesize \textbf{\textit{Index terms---}} #1 } \usepackage{graphicx,xcolor} \definecolor{GJBlue}{HTML}{273B81} \definecolor{GJLightBlue}{HTML}{0A9DD9} \definecolor{GJMediumGrey}{HTML}{6D6E70} \definecolor{GJLightGrey}{HTML}{929497} \renewenvironment{abstract}{% \setlength{\parindent}{0pt}\raggedright \textcolor{GJMediumGrey}{\rule{\textwidth}{2pt}} \vskip16pt \textcolor{GJBlue}{\large\bfseries\abstractname\space} }{% \vskip8pt \textcolor{GJMediumGrey}{\rule{\textwidth}{2pt}} \vskip16pt } \usepackage[absolute,overlay]{textpos} \makeatother \usepackage{lineno} \linenumbers \begin{document} \author[1]{Navneet Singh} \affil[1]{ Roorkee College of Engineering, Roorkee, Uttarakhand Technical University, Dehradun, India} \renewcommand\Authands{ and } \date{\small \em Received: 8 December 2012 Accepted: 31 December 2012 Published: 15 January 2013} \maketitle \begin{abstract} Synthesis and evaluation of 3-(p methoxybenzylidene) hydrazinoacetylamino-2-methyl-6-bromoquinazolin-4-(3H)-one and 3-(p-N, N-dimethylbenzylidenylamino)hydrazineacetylamino-2-methyi-quina-zolin-4 (3H)-one for cardiovascular activity.Synthesis and evaluation of 3-(p methoxybenzylidene) hydrazinoacetylamino-2-methyl-6bromoquinazolin-4-(3H)-one and 3-(p-N, N-dimethylbenzylidenylamino)hydrazine-acetylamino-2methyi-quina-zolin-4 (3H)-one for cardiovascular activity methy-lmono substituted quinazolin-4(3H)-onyl)]-5'-(sub-stitu-tedphenyl)-tetrazolinum chloride (compounds 25-34). \end{abstract} \keywords{quinazolinone derivatives, formazan, hydrazinoacetylamino, cardiovascular, antihypertensive activity.} \begin{textblock*}{18cm}(1cm,1cm) % {block width} (coords) \textcolor{GJBlue}{\LARGE Global Journals \LaTeX\ JournalKaleidoscope\texttrademark} \end{textblock*} \begin{textblock*}{18cm}(1.4cm,1.5cm) % {block width} (coords) \textcolor{GJBlue}{\footnotesize \\ Artificial Intelligence formulated this projection for compatibility purposes from the original article published at Global Journals. However, this technology is currently in beta. \emph{Therefore, kindly ignore odd layouts, missed formulae, text, tables, or figures.}} \end{textblock*} \let\tabcellsep& \section[{Introduction}]{Introduction}\par uinazolin-4-(3H)-one, a potent pharmacodynamic heterocyclic nucleus has gained prominence in medicinal chemistry because it possess a wide spectrum of biological activities i.e. anticonvulsant \hyperref[b0]{[1]}, antibacterial \hyperref[b1]{[2]}, anti-inflammatory \hyperref[b2]{[3]}, antimicrobial \hyperref[b3]{[4]} as well as antiproliferative \hyperref[b4]{[5]}. Substitution at 2/3-position of quinazolinone ring imparts the cardiovascular activity \hyperref[b5]{[6]}\hyperref[b6]{[7]}, antitubercular activity \hyperref[b7]{[8]}, CNS depressant \hyperref[b8]{[9]}, antifungal \hyperref[b9]{[10]}, anticancer \hyperref[b10]{[11]}, analgesic \hyperref[b11]{[12]} and antihypertensive \hyperref[b12]{[13]}. Considering quinazolinone nucleus as potent pharmacophore for the cardiovascular activity, some newer derivatives of quinazolinone had been synthesized (Scheme I). The purity of the compounds was checked by TLC using silica gel G. The structure of all the compounds was confirmed by analytical and spectral data. All the newly synthesized compounds were screened for the elemental analysis (Table {\ref I}) and their cardiovascular activity (Table {\ref II}). The most active compounds of this series were 6 and 13. The ALD 50 of these compounds were >2000 mg/kg p.o., indicating good safety margin. \section[{II.}]{II.} \section[{Pharmacological Result and Discussion}]{Pharmacological Result and Discussion}\par Compounds 5, 7, 8 and 9 elicited potent immediate fall of varying degree (20-40 mmHg) and delayed fall of varying degree (10-40 mmHg) and duration (45-60 minutes) (Table {\ref II}). Compounds 5 and 7 were associated with inhibition of CO and NA responses. Such a cardiovascular profile is suggestive of peripheral site of action. Compounds 8 and 9 were associated with inhibition of CO without affecting the NA response which might be suggestive of central site of action. In addition these compounds 8 and 9 showed increase in HR (tachycardia) of 1-2 beats per minutes and 3 bpm respectively. Compound 6 i.e. 3-(pmethoxybenzylidene) hydrazinoacetylamino-2-methyl-6bromoquinazolin-4 (3H)-one showed an immediate fall in blood pressure (35 mmHg) followed by potent and gradual fall in blood pressure (70mmHg) as compared to the control value. The blood pressure lowering activity azolin-4(3H)-ones (compounds 1-2) were prepared by the reaction of ethylchloroacetate with 3-amino-2-methylmonosubstituted quinazolin-4(3H)-one in dry acetone in the presence of anhydrous K 2 CO and short duration (20-40 minutes). These compounds did not affect the heart rate and pressor responses (CO and NA). Moreover, the conversion of these compounds into their corresponding 5-member tetrazolinum salts resulted in compounds (25-34) having mild hypotensive activity (5-20 mmHg) of short duration (5-15 minutes). They appear to be acting directly on the smooth muscles of blood vessels (direct vasodilators) because these compounds did not affect the CO and NA responses and had short duration of action.\par III. \section[{Conclusion}]{Conclusion}\par The intensive study of the cardiovascular profile of the synthesized compounds suggested that compounds 6 and 13 i.e. 3-(p-methoxybenzylidene) hydrazinoacetylamino-2-methyl-6-bromoquinazolin-4 (3H)-one and 3-(p-N, N-dimethylbenzylidenylamino)hydrazinoacetylamino-2-methyl-quinazolin-4(3H)-one respectively had excellent cardiovascular activity. Therefore, these compounds should attract the interest of researchers and pharmaceutical companies for clinical studies and other applications in the therapy of cardiovascular diseases. \section[{IV.}]{IV.} \section[{Experimental Protocols a) Chemistry}]{Experimental Protocols a) Chemistry}\par The melting point of the compounds was determined in open glass capillary with the help of themionic melting point apparatus and is uncorrected. Elemental analysis of all the newly synthesized compounds were determined by a Perkin-Elimer 2400 elemental analyzer, and results were found within the KBR on a Perkin-Elmer spectrum RX-I, spectrometer. 1H NMR spectra were recorded by Bruker AC-300 F instrument using CDCl 3 /DMSO-Cl 6 as solvent and tetra methyl silane (TMS) as internal reference standard. All chemical shift values were recorded as ? (ppm). Mass spectra were determined on a VG-70-S instrument. \section[{b) General procedure for the preparation of compounds i. 6-bromoanthranilic acid (a)}]{b) General procedure for the preparation of compounds i. 6-bromoanthranilic acid (a)}\par This was prepared according to the method of Wheeler and Oats \hyperref[b13]{[14]}. Bromine (0.8 mol) in acetic acid (20 ml) was added drop wise to the solution of anthranilic acid (0.4 mol) in absolute AcOH (50 ml). The solid was separated to give 6-bromoanthranilic acid. The solid product thus crystallized out, was washed with water and dried. It was recrystallized from ethanol/water M.P. 208 o C, Yield 50\%. \section[{ii. Acetanthranils (b)}]{ii. Acetanthranils (b)}\par These were prepared according to the method of Bogert and Soil \hyperref[b14]{[15]}. A mixture of appropriate anthranilic acid (0.01mol) and acetic anhydride (0.02 mol) were refluxed for 2-3 hours with occasional stirring. The excess of acetic anhydride was distilled off. On cooling, a solid separated out, which was filtered, washed with petroleum ether (40-60 o C) and dried in vacuo. The acetanthranils thus synthesized are given below: a) Acetanthranils M.P. 78 o C b) 6-Bromoacetanthranils M.P. 172 o C \section[{iii. 3-amino-2-methyl monosubstitutedquinazolin-4(3H)ones: (c)}]{iii. 3-amino-2-methyl monosubstitutedquinazolin-4(3H)ones: (c)}\par These were prepared according to the method of Kumar et al \hyperref[b15]{[16]}. A mixture of appropriate acetanthranils (0.01 mol) and hydrazine hydrate (99\%, 0.02 mol) in methanol (dry, 50ml) were refluxed for 8 hours. The excess of solvent was distilled off in vacuo. The residue on cooling gave a crystalline solid, which was recrystallized from methanol-water (1:2). \section[{iv. 3-(ethylacetylamino)-2-methylmono substituted quinazolin-4 (3H)-one: (1-2)}]{iv. 3-(ethylacetylamino)-2-methylmono substituted quinazolin-4 (3H)-one: (1-2)}\par A mixture of 3-amino-2-methyl mono substitutedquinazolin-4(3H)-one (0.01 mol), ethylchloroacetate (0.01 mol) and anhydrous K 2 CO 3 (5.0g) in acetone (dry 80ml) were refluxed for 20 hours on water bath. The acetone was distilled off and the resulting solid mass poured into water, filtered and the separated solid recrystallized from methanol/water to give compounds (1-2). \section[{v. 3-(hydrazinoacetylamino) -2 -methylmono substituted-quinazolin -4 (3H) -one : (3-4)}]{v. 3-(hydrazinoacetylamino) -2 -methylmono substituted-quinazolin -4 (3H) -one : (3-4)}\par A mixture of compounds (1-2) (0.01 mol) and hydrazine hydrate (0.02 mol) in methanol (dry, 50ml) were refluxed for 6-8 hours. The excess of solvent was distilled off. On cooling a crystalline solid is obtained which was recrystallized from methanol/water. \section[{vi. 3-(substitutedarylidene)-hydrazinoacetyl-amino-2methylmono substitutedquinazolin-4(3H)-ones: (5-14)}]{vi. 3-(substitutedarylidene)-hydrazinoacetyl-amino-2methylmono substitutedquinazolin-4(3H)-ones: (5-14)}\par To a solution of compounds (3-4) (0.01 mol) in absolute ethanol (50 ml), substitutedbenzaldehyde (0.01 mol) and a few drops of glacial acetic acid were refluxed for 8 hours. The solvent was distilled off and the viscous mass thus obtained was recrystallized from ethanol/water to give compounds \hyperref[b4]{(5)}\hyperref[b5]{(6)}\hyperref[b6]{(7)}\hyperref[b7]{(8)}\hyperref[b8]{(9)}\hyperref[b9]{(10)}\hyperref[b10]{(11)}\hyperref[b11]{(12)}\hyperref[b12]{(13)}\hyperref[b13]{(14)}. \section[{vii. 3-[(acetylamino-2-methylmonosubstitutedquinazolin-4(3H)-onyl)]-1'-(substitutedphenyl)-3'-}]{vii. 3-[(acetylamino-2-methylmonosubstitutedquinazolin-4(3H)-onyl)]-1'-(substitutedphenyl)-3'-}\par (substitutedaryl)-formazans: (15-24) Substituted phenyl (0.01 mol) was dissolved in 4ml glacial acetic acid and 3ml of concentrated HCl was added to 0-5 o C. A solution of NaNO 2 (1 gm in 5 ml of water) was added drop wise. The diazonium salt solution thus prepared was added with stirring to compounds (5-14) (0.01mol) in 50 ml toluene. During the addition the temperature was maintained below 10 o C. The reaction mixture thus obtained was left at room temperature for several hrs and then poured into 250 ml of cold water, The dark red solid which separated out was washed with water, filtered and recrystallized from methanol/water to give compounds \hyperref[b14]{(15)}\hyperref[b15]{(16)}\hyperref[b16]{(17)} {\ref (18)} {\ref (19)} {\ref (20)} {\ref (21)} {\ref (22)} {\ref (23)} {\ref (24)}. \section[{ii. 3-(hydrazinoacetylamino)-2-methyl-6-bromoquinazolin-4(3H)-one: 3}]{ii. 3-(hydrazinoacetylamino)-2-methyl-6-bromoquinazolin-4(3H)-one: 3}\par C of aromatic ring); \section[{iv. 3-[(acetylamino-2-methyl-6-bromo-quinazolin-4(3H)onyl)]-1'-(o-chloroaniline)-3'-(p-hydroxyphenyl)formazan: 19}]{iv. 3-[(acetylamino-2-methyl-6-bromo-quinazolin-4(3H)onyl)]-1'-(o-chloroaniline)-3'-(p-hydroxyphenyl)formazan: 19}\par C of aromatic ring); \section[{v. 2'-(p-hydroxyphenyl)-4'-[3-acetylamino-2-methyl-6bromo-quinazolin-4(3H)-onyl)]-5'-(o-chloroaniline)tetrazolinum chloride: 29}]{v. 2'-(p-hydroxyphenyl)-4'-[3-acetylamino-2-methyl-6bromo-quinazolin-4(3H)-onyl)]-5'-(o-chloroaniline)tetrazolinum chloride: 29}\par C of aromatic ring), 1425 (N=N), 1260 (C-N); Preliminary cardiovascular activity tests were carried out on albino rats 100-120g of either sex (the pregnancy was excluded) for all the synthesized indole derivatives. The newly synthesized compounds (test drugs) were administered intravenously (from right femoral vein) by dissolving them in propylene glycol and the effect on blood pressure (B.P), heart rate (HR) and pressor responses evoked either by carotid occlusion (CO) or intravenous noradrenalin (NA) 1-2 ?g/Kg injection was observed. Injection of .20 mL of propylene glycol induced a mild and transient decrease of 1-2 mmHg in blood pressure without affecting the CO and NA response. The blood pressure was recorded from the left common carotid artery by means of a mercury manometer from femoral artery on one channel of "Encardiorite" (India) polygraph using stathus P25 (25-34) X + (CH 3 CO) 2 O O C N X O CH 3 O C N X N NH 2 CH 3 NH 2 NH 2 .H 2 O O C N X N NHCH 2 COOC 2 H 5 CH 3 ClCH 2 COOC 2 H 5 Anhydrous K 2 CO 3 O C N X N NHCH 2 CONHNH 2 CH 3 NH 2 NH 2 .H 2 O Glacial acetic acid Absolute ethanol R OHC R' Cl -N + N O C N X N NHCH 2 CONHN CH 3 R HC R N N O C N X N NHCH 2 CONHN C CH 3 R' H 2 O 2 ,\begin{figure}[htbp] \noindent\textbf{}\includegraphics[]{image-2.png} \caption{\label{fig_0}}\end{figure} \begin{figure}[htbp] \noindent\textbf{} \par \begin{longtable}{} \end{longtable} \par \caption{\label{tab_0}}\end{figure} \begin{figure}[htbp] \noindent\textbf{1} \par \begin{longtable}{P{0.018505535055350554\textwidth}P{0.026974169741697418\textwidth}P{0.06178966789667897\textwidth}P{0.030110701107011067\textwidth}P{0.035129151291512915\textwidth}P{0.02415129151291513\textwidth}P{0.14584870848708487\textwidth}P{0.13330258302583026\textwidth}P{0.13894833948339483\textwidth}P{0.10695571955719556\textwidth}P{0.12828413284132842\textwidth}} Co-\tabcellsep X\tabcellsep R\tabcellsep R'\tabcellsep M.P.\tabcellsep Yield\tabcellsep Recrystal\tabcellsep Molecular\tabcellsep Element Analysis (\%)\tabcellsep \tabcellsep \\ md.\tabcellsep \tabcellsep \tabcellsep \tabcellsep ( o C)\tabcellsep (\%)\tabcellsep llisation\tabcellsep Formula\tabcellsep Calcd.(Found)\tabcellsep \tabcellsep \\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep Solvent\tabcellsep \tabcellsep C\tabcellsep H\tabcellsep N\\ 1\tabcellsep 6-Br\tabcellsep -\tabcellsep -\tabcellsep 160\tabcellsep 65\tabcellsep Methanol/Water\tabcellsep C13H14N3O3Br\tabcellsep 45.88(45.90)\tabcellsep 4.11(4.14)\tabcellsep 12.35(12.37)\\ 2\tabcellsep H\tabcellsep -\tabcellsep -\tabcellsep 120\tabcellsep 60\tabcellsep Methanol/Water\tabcellsep C13H15N3O3\tabcellsep 59.77(59.72)\tabcellsep 5.74(5.70)\tabcellsep 16.09(16.06)\\ \tabcellsep 6-Br\tabcellsep -\tabcellsep -\tabcellsep 220\tabcellsep 60\tabcellsep Methanol/Water\tabcellsep C11H12N5O2Br\tabcellsep 40.49(40.45)\tabcellsep 3.68(3.65)\tabcellsep 21.47(21.45)\\ 3\tabcellsep H\tabcellsep -\tabcellsep -\tabcellsep 180\tabcellsep 55\tabcellsep Methanol/Water\tabcellsep C11H13N5O2\tabcellsep 53.44(53.40)\tabcellsep 5.26(5.30)\tabcellsep 28.34(28.30)\\ \tabcellsep 6-Br\tabcellsep H\tabcellsep -\tabcellsep 170\tabcellsep 42\tabcellsep Methanol/Water\tabcellsep C18H16N5O2Br\tabcellsep 52.17(52.14)\tabcellsep 3.86(3.83)\tabcellsep 16.90(16.92)\\ 5\tabcellsep 6-Br\tabcellsep 4-OCH3\tabcellsep -\tabcellsep 182\tabcellsep 45\tabcellsep Acetic acid/Water\tabcellsep C19H18N5O4Br\tabcellsep 49.56(49.52)\tabcellsep 3.91(3.88)\tabcellsep 15.21(15.23)\\ 7\tabcellsep 6-Br\tabcellsep 3-OCH3, 4-OH\tabcellsep -\tabcellsep 240\tabcellsep 40\tabcellsep Benzene/Hexane\tabcellsep C19H18N5O4Br\tabcellsep 49.56(49.52)\tabcellsep 3.91(3.88)\tabcellsep 15.21(15.23)\\ 8\tabcellsep 6-Br\tabcellsep 4-N(CH3)2\tabcellsep -\tabcellsep 186\tabcellsep 42\tabcellsep THF\tabcellsep C20H21N6O2Br\tabcellsep 52.51(52.54)\tabcellsep 4.59(4.63)\tabcellsep 18.38(18.35)\\ 9\tabcellsep 6-Br\tabcellsep 4-OH\tabcellsep -\tabcellsep 198\tabcellsep 45\tabcellsep Ethanol/Water\tabcellsep C18H16N5O3Br\tabcellsep 50.23(50.20)\tabcellsep 3.72(3.70)\tabcellsep 16.27(16.30)\\ 10\tabcellsep H\tabcellsep H\tabcellsep -\tabcellsep 170\tabcellsep 48\tabcellsep Petroleum/Ether\tabcellsep C18H17N5O2\tabcellsep 64.47(64.45)\tabcellsep 5.07(5.04)\tabcellsep 20.89(20.92)\\ 11\tabcellsep H\tabcellsep 4-OCH3\tabcellsep -\tabcellsep 194\tabcellsep 46\tabcellsep Ethanol\tabcellsep C19H19N5O3\tabcellsep 62.46(62.44)\tabcellsep 5.20(5.24)\tabcellsep 19.17(19.20)\\ 12\tabcellsep H\tabcellsep 3-OCH3, 4-OH\tabcellsep -\tabcellsep 200\tabcellsep 42\tabcellsep Benzene\tabcellsep C19H19N5O4\tabcellsep 59.84(59.80)\tabcellsep 4.98(4.94)\tabcellsep 18.37(18.40)\\ 13\tabcellsep H\tabcellsep 4-N(CH3)2\tabcellsep -\tabcellsep 160\tabcellsep 45\tabcellsep Benzene\tabcellsep C20H22N6O2\tabcellsep 63.49(63.52)\tabcellsep 5.82(5.80)\tabcellsep 22.22(22.25)\\ 14\tabcellsep H\tabcellsep 4-OH\tabcellsep -\tabcellsep 170\tabcellsep 45\tabcellsep Acetone\tabcellsep C18H17N5O3\tabcellsep 61.53(61.57)\tabcellsep 4.84(4.82)\tabcellsep 19.94(19.90)\\ 15\tabcellsep 6-Br\tabcellsep H\tabcellsep m-Cl\tabcellsep 142\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C24H19N7O2ClBr\tabcellsep 52.12(52.10)\tabcellsep 3.43(3.46)\tabcellsep 17.73(17.70)\\ 16\tabcellsep 6-Br\tabcellsep 4-OCH3\tabcellsep H\tabcellsep 195\tabcellsep 42\tabcellsep Methanol/Water\tabcellsep C25H22N7O3Br\tabcellsep 54.74(54.78)\tabcellsep 4.01(4.05)\tabcellsep 17.88(17.04)\\ 17\tabcellsep 6-Br\tabcellsep 3-OCH3, 4-OH\tabcellsep o-Cl\tabcellsep 238\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C25H21N7O4BrCl\tabcellsep 50.12(50.16)\tabcellsep 3.50(3.54)\tabcellsep 16.37(16.35)\\ 18\tabcellsep 6-Br\tabcellsep 4-N(CH3)2\tabcellsep p-OCH3\tabcellsep 210\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C27H27N8O3Br\tabcellsep 54.82(54.80)\tabcellsep 4.56(4.52)\tabcellsep 18.95(18.98)\\ \tabcellsep 6-Br\tabcellsep 4-OH\tabcellsep o-Cl\tabcellsep 230\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C24H19N7O3ClBr\tabcellsep 50.65(50.62)\tabcellsep 3.34(3.37)\tabcellsep 17.23(17.23)\\ 19\tabcellsep H\tabcellsep H\tabcellsep o-OCH3\tabcellsep 190\tabcellsep 42\tabcellsep Methanol/Water\tabcellsep C25H23N7O3\tabcellsep 63.96(63.98)\tabcellsep 4.90(4.94)\tabcellsep 20.89(20.86)\\ 21\tabcellsep H\tabcellsep 4-OCH3\tabcellsep o-Cl\tabcellsep 185\tabcellsep 45\tabcellsep Methanol/Water\tabcellsep C25H22N7O3Cl\tabcellsep 59.58(59.56)\tabcellsep 4.36(4.34)\tabcellsep 19.46(19.48)\\ 22\tabcellsep H\tabcellsep 3-OCH3, 4-OH\tabcellsep H\tabcellsep 235\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C25H23N7O4\tabcellsep 61.85(61.88)\tabcellsep 4.74(4.72)\tabcellsep 20.20(20.22)\\ 23\tabcellsep H\tabcellsep 4-N(CH3)2\tabcellsep m-Cl\tabcellsep 142\tabcellsep 40\tabcellsep Methanol/Water\tabcellsep C26H25N8O2Cl\tabcellsep 60.40(60.42)\tabcellsep 4.84(4.88)\tabcellsep 21.68(21.70)\\ 24\tabcellsep H\tabcellsep 4-OH\tabcellsep o-OCH3\tabcellsep 195\tabcellsep 45\tabcellsep Methanol/Water\tabcellsep C25H23N7O4\tabcellsep 61.85(61.88)\tabcellsep 4.74(4.78)\tabcellsep 20.20(20.24)\\ 25\tabcellsep 6-Br\tabcellsep H\tabcellsep m-Cl\tabcellsep 165\tabcellsep 30\tabcellsep Methanol/Water\tabcellsep C24H18N7O2Cl2Br\tabcellsep 49.06(49.08)\tabcellsep 3.06(3.02)\tabcellsep 16.69(16.65)\\ 26\tabcellsep 6-Br\tabcellsep 4-OCH3\tabcellsep H\tabcellsep 220\tabcellsep 30\tabcellsep Methanol/Water\tabcellsep C25H21N7O3ClBr\tabcellsep 51.50(51.54)\tabcellsep 3.60(3.58)\tabcellsep 16.82(16.84)\\ 27\tabcellsep 6-Br\tabcellsep 3-OCH3, 4-OH\tabcellsep o-Cl\tabcellsep 250\tabcellsep 35\tabcellsep Methanol/Water\tabcellsep C25H21N7O4Cl2Br\tabcellsep 47.31(47.35)\tabcellsep 3.31(3.35)\tabcellsep 15.45(15.42)\\ 28\tabcellsep 6-Br\tabcellsep 4-N(CH3)2\tabcellsep p-OCH3\tabcellsep 270\tabcellsep 38\tabcellsep Methanol/Water\tabcellsep C27H26N8O3ClBr\tabcellsep 51.79(51.75)\tabcellsep 4.15(4.12)\tabcellsep 17.90(17.94)\\ \tabcellsep 6-Br\tabcellsep 4-OH\tabcellsep o-Cl\tabcellsep 240\tabcellsep 38\tabcellsep Methanol/Water\tabcellsep C24H18N7O3Cl2Br\tabcellsep 47.76(47.72)\tabcellsep 2.98(2.95)\tabcellsep 16.25(16.23)\\ 29\tabcellsep H\tabcellsep H\tabcellsep p-OCH3\tabcellsep 200\tabcellsep 38\tabcellsep Methanol/Water\tabcellsep C25H23N7O3Cl\tabcellsep 59.98(59.55)\tabcellsep 4.36(4.38)\tabcellsep 19.46(19.42)\\ 31\tabcellsep H\tabcellsep 4-OCH3\tabcellsep o-Cl\tabcellsep 225\tabcellsep 38\tabcellsep Methanol/Water\tabcellsep C25H21N7O3Cl2\tabcellsep 55.76(55.72)\tabcellsep 3.90(3.94)\tabcellsep 18.21(18.25)\\ 32\tabcellsep H\tabcellsep 3-OCH3, 4-OH\tabcellsep H\tabcellsep 244\tabcellsep 35\tabcellsep Methanol/Water\tabcellsep C25H22N7O4Cl\tabcellsep 57.74(57.78)\tabcellsep 4.23(4.20)\tabcellsep 18.86(18.82)\\ 33\tabcellsep H\tabcellsep 4-N(CH3)2\tabcellsep m-Cl\tabcellsep 165\tabcellsep 30\tabcellsep Methanol/Water\tabcellsep C26H24N8O2Cl2\tabcellsep 56.62(56.65)\tabcellsep 4.35(4.32)\tabcellsep 20.32(20.30)\\ 34\tabcellsep H\tabcellsep 4-OH\tabcellsep o-OCH3\tabcellsep 240\tabcellsep 35\tabcellsep Methanol/Water\tabcellsep C25H22N7O4Cl\tabcellsep 57.74(57.70)\tabcellsep 4.23(4.27)\tabcellsep 18.86(18.84)\end{longtable} \par \caption{\label{tab_3}Table 1 :}\end{figure} \begin{figure}[htbp] \noindent\textbf{2} \par \begin{longtable}{P{0.002526539278131635\textwidth}P{0.07832271762208068\textwidth}P{0.04367303609341826\textwidth}P{0.036093418259023353\textwidth}P{0.053418259023354564\textwidth}P{0.11983014861995753\textwidth}P{0.07290870488322718\textwidth}P{0.1494267515923567\textwidth}P{0.12019108280254777\textwidth}P{0.030318471337579617\textwidth}P{0.05522292993630573\textwidth}P{0.03392781316348195\textwidth}P{0.05414012738853503\textwidth}} Co-\tabcellsep X\tabcellsep R\tabcellsep R'\tabcellsep \multicolumn{4}{l}{Dose Change in mean blood pressure mmHg}\tabcellsep \tabcellsep Change\tabcellsep \multicolumn{2}{l}{Effect on pressure}\tabcellsep ALD 50\\ mpd.\tabcellsep \tabcellsep \tabcellsep \tabcellsep \multicolumn{2}{l}{Mg/kg Control}\tabcellsep Immediate\tabcellsep Delayed\tabcellsep Duration\tabcellsep in resting\tabcellsep responses\tabcellsep \tabcellsep mg/kg\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep i.v.\tabcellsep Mean± SE\tabcellsep Mean± SE\tabcellsep Mean± SE\tabcellsep in minutes\tabcellsep HR bpm\tabcellsep CO\tabcellsep NA\tabcellsep p.o.\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep Mean± SE\tabcellsep \tabcellsep \tabcellsep \\ \tabcellsep \multicolumn{2}{l}{6-Br H}\tabcellsep -\tabcellsep 2.5\tabcellsep 138±11.51\tabcellsep 118.6±12.42*\tabcellsep 127±12.02\tabcellsep 49.6±1.67\tabcellsep -\tabcellsep Inhibited\tabcellsep \multicolumn{2}{l}{Inhibited >1000}\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OCH 3}\tabcellsep -\tabcellsep 1.25\tabcellsep 151±5.94\tabcellsep 136±4.18***\tabcellsep 106±4.04***\tabcellsep 72.4±6.38\tabcellsep -\tabcellsep Inhibited\tabcellsep Inhibited\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep 2.5\tabcellsep 154.4±4.98\tabcellsep 119±5.76***\tabcellsep 83.8±4.52***\tabcellsep 95±5.00\tabcellsep -\tabcellsep Inhibited\tabcellsep \multicolumn{2}{l}{Inhibited >2000}\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep 5.0\tabcellsep 158.4±5.87\tabcellsep 108.4±6.68***\tabcellsep 58.4±5.20***\tabcellsep \multicolumn{2}{l}{134.8±7.59 -}\tabcellsep Inhibited\tabcellsep Inhibited\\ \tabcellsep \multicolumn{3}{l}{6-Br 3-OCH 3 , 4-OH -}\tabcellsep 2.5\tabcellsep 138.4±8.96\tabcellsep 114±7.48**\tabcellsep 98.4±9.00***\tabcellsep 45.2±2.16\tabcellsep -\tabcellsep Inhibited\tabcellsep \multicolumn{2}{l}{Inhibited >1000}\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-N(CH 3 ) 2}\tabcellsep -\tabcellsep 2.5\tabcellsep 138.2±11.54\tabcellsep 104.6±11.61**\tabcellsep \multicolumn{2}{l}{106.2±12.77*** 60.8±1.09}\tabcellsep \multicolumn{2}{l}{Potentiated Inhibited}\tabcellsep -\tabcellsep >1000\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep 1-2 bpm\tabcellsep \tabcellsep \\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OH}\tabcellsep -\tabcellsep 2.5\tabcellsep 146±7.41\tabcellsep 106.8±6.18**\tabcellsep 126.2±5.93**\tabcellsep \multicolumn{3}{l}{56.67±2.81 Potentiated Inhibited}\tabcellsep -\tabcellsep >1000\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep \tabcellsep 3 bpm\tabcellsep \tabcellsep \\ \tabcellsep H\tabcellsep H\tabcellsep -\tabcellsep 2.5\tabcellsep 145.5±7.46\tabcellsep 116.6±5.77***\tabcellsep 96.6±5.60***\tabcellsep 74.4±3.08\tabcellsep -\tabcellsep Inhibited\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-OCH 3\tabcellsep -\tabcellsep 2.5\tabcellsep 145.6±6.50\tabcellsep 126.2±4.32\tabcellsep 105±4.04***\tabcellsep 59.8±2.86\tabcellsep -\tabcellsep Blocked\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep \multicolumn{2}{l}{3-OCH 3 , 4-OH -}\tabcellsep 2.5\tabcellsep 141±13.87\tabcellsep 91.6±13.84***\tabcellsep 118.4±16.19\tabcellsep 59±2.64\tabcellsep -\tabcellsep Inhibited\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-N(CH 3 ) 2\tabcellsep -\tabcellsep 1.25\tabcellsep 159.6±7.30\tabcellsep 124.6±8.73***\tabcellsep 89.6±9.81***\tabcellsep 99.6±2.96\tabcellsep -\tabcellsep Inhibited\tabcellsep -\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep 2.5\tabcellsep 156.4±6.98\tabcellsep 104.2±7.38***\tabcellsep 55.8±6.79***\tabcellsep \multicolumn{2}{l}{128.2±2.86 -}\tabcellsep Inhibited\tabcellsep -\tabcellsep >2000\\ \tabcellsep \tabcellsep \tabcellsep \tabcellsep 5.0\tabcellsep 169.2±7.80\tabcellsep 90.8±9.09\tabcellsep 38.8±7.67***\tabcellsep 195±4.12\tabcellsep -\tabcellsep Inhibited\tabcellsep -\\ \tabcellsep H\tabcellsep 4-OH\tabcellsep -\tabcellsep 2.5\tabcellsep 143.2±8.16\tabcellsep 93.2±5.54***\tabcellsep 133.2±6.45***\tabcellsep 60.2±1.67\tabcellsep -\tabcellsep Blocked\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br H}\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 136±4.18\tabcellsep -\tabcellsep 76±3.80***\tabcellsep 30.6±1.94\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OCH 3}\tabcellsep H\tabcellsep 2.5\tabcellsep 134±4.18\tabcellsep -\tabcellsep 69±7.21***\tabcellsep 29.2±2.28\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >2000\\ \tabcellsep \multicolumn{3}{l}{6-Br 3-OCH 3 , 4-OH o-Cl}\tabcellsep 2.5\tabcellsep 139±9.61\tabcellsep -\tabcellsep 99.8±9.98***\tabcellsep \multicolumn{2}{l}{42.33±2.51 -}\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-N(CH 3 ) 2}\tabcellsep \multicolumn{2}{l}{p-OCH 3 2.5}\tabcellsep 138.2±11.54\tabcellsep -\tabcellsep 104.6±11.61**\tabcellsep 29±2.64\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OH}\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 137.4±6.06\tabcellsep -\tabcellsep 120±7.21***\tabcellsep 23.8±2.77\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep H\tabcellsep \multicolumn{2}{l}{p-OCH 3 2.5}\tabcellsep 139±9.61\tabcellsep -\tabcellsep 99.8±9.98***\tabcellsep 22.6±3.97\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-OCH 3\tabcellsep o-Cl\tabcellsep 2.5\tabcellsep 134.2±13.04\tabcellsep -\tabcellsep 105±11.57***\tabcellsep 39.2±2.20\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep \multicolumn{2}{l}{3-OCH 3 , 4-OH H}\tabcellsep 2.5\tabcellsep 137.6±11.67\tabcellsep -\tabcellsep 95±12.18***\tabcellsep 21.6±2.70\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-N(CH 3 ) 2\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 138.4±8.97\tabcellsep -\tabcellsep 104.6±9.01***\tabcellsep 29.6±1.67\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-OH\tabcellsep o-CH 3\tabcellsep 2.5\tabcellsep 135±9.61\tabcellsep -\tabcellsep 93.4±9.86***\tabcellsep 30±1.41\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br H}\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 132±8.13\tabcellsep -\tabcellsep 122±8.68\tabcellsep 9.6±1.81\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OCH 3}\tabcellsep H\tabcellsep 2.5\tabcellsep 133.8±8.37\tabcellsep -\tabcellsep 116.4±6.50**\tabcellsep 14±3.08\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >2000\\ \tabcellsep \multicolumn{3}{l}{6-Br 3-OCH 3 , 4-OH o-Cl}\tabcellsep 2.5\tabcellsep 132.2±10.77\tabcellsep -\tabcellsep 120.2±13.40*\tabcellsep 9.6±2.60\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-N(CH 3 ) 2}\tabcellsep \multicolumn{2}{l}{p-OCH 3 2.5}\tabcellsep 132±9.61\tabcellsep -\tabcellsep 115.2±10.18*\tabcellsep 12±1.87\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep \multicolumn{2}{l}{6-Br 4-OH}\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 132.2±10.77\tabcellsep -\tabcellsep 117±9.54*\tabcellsep 14±3.08\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep H\tabcellsep \multicolumn{2}{l}{p-OCH 3 2.5}\tabcellsep 130.6±7.53\tabcellsep -\tabcellsep 120.4±6.73*\tabcellsep 13.6±2.70\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-OCH 3\tabcellsep o-Cl\tabcellsep 2.5\tabcellsep 132.2±6.01\tabcellsep -\tabcellsep 127.2±6.37*\tabcellsep 5.2±1.48\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep \multicolumn{2}{l}{3-OCH 3 , 4-OH H}\tabcellsep 2.5\tabcellsep 132±9.46\tabcellsep -\tabcellsep 123±8.68***\tabcellsep 5.8±1.92\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-N(CH 3 ) 2\tabcellsep m-Cl\tabcellsep 2.5\tabcellsep 133.6±6.10\tabcellsep -\tabcellsep 128.6±5.77*\tabcellsep 8.8±3.11\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\\ \tabcellsep H\tabcellsep 4-OH\tabcellsep o-CH 3\tabcellsep 2.5\tabcellsep 133.8±9.90\tabcellsep -\tabcellsep 121.4±9.60*\tabcellsep 10±1.58\tabcellsep -\tabcellsep -\tabcellsep -\tabcellsep >1000\end{longtable} \par \caption{\label{tab_4}Table 2 :}\end{figure} \footnote{© 2013 Global Journals Inc. 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