SYNOPSIS

SYNOPSIS
The thesis entitled Studies on Synthesis and Biological Evaluation of Heterocycles containing Piperazine moiety has been divided into five chapters. !H"P#E$ I% This chapter describes the introduction, natural abundance and biological importance of azoles i.e. benzoxazoles, benzothiazoles, oxadiazole, pyridazinone and piperizine. !H"P#E$ II% This chapter describes the synthesis and biological evaluation of some 4-(aryl/heteroaryl-2ylmethyl -!-phenyl-2-"#-(4-substitutedpiperazine-$-yl propyl%pyridazin-#(2H -one derivatives. !H"P#E$ III% This chapter describes the &ynthesis of piperazinyl benzothiazole/benzoxazole derivatives coupled 'ith $,#,4-oxadiazole-2-thiol( novel hybrid heterocycles as anticancer agents

!H"P#E$ I&% This chapter describes the synthesis and antibacterial and antifungal evaluation of some arylsulfonylpiperazine based benzothiazoles. !H"P#E$ &% This chapter describes the )enzamide derivatives incorporating arylsulfonylpiperazine pharmacophore as potential anti-cancer agents( *esign, synthesis and biological evaluation.

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!H"P#E$ I
+uman health is impacted by a large variety of chemical substances, including those essential to human life, such as vitamins and nutrients and medicines. ,atural substances are intrinsically exhibit superior properties 'ith regard to efficacy and safety in matters related to human health. -s it is difficult to meet the 'orld'ide demand of the re.uirement of the natural products due their lo' abundance in nature, it is essential produce synthetic substances in large .uantities. This can extend to so-called nature identical materials that are natural substances produced synthetically in an identical or 'ith slight modification of the molecular form, in order to increase the biological activity of the molecule. +eterocycles are among the most fre.uently encountered scaffolds in drugs and pharmaceutically relevant substances. The remar/able ability of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely contributed to their uni.ue value as traditional /ey elements of numerous drugs. The development of heterocycles as scaffolds, containing a high degree of diversity has become a leading focus in modern drug discovery. 0n this research program various diverse classes of heterocycles e.g., benzoxazole, benzoxazolone, triazole, piperazine and piperidine derivatives 'ere developed. 1ertain possible modifications on the heterocyclic ring by the addition of diverse substituents may lead to ne' products 'ith better biological profiles. -s a result of the biological activity exhibited by the heterocyclic molecules, the development of ne' chemical entities (,12s is the focus of intense activity in pharmaceutical industry. 3arious types of ne'ly synthesized molecules may be very good at bloc/ing the action or /illing the bacteria 'ithout harming the human cells so as to prevent or cure the disease. The nitrogen, oxygen and sulphur heterocycles are an attractive source of compounds for the identification of ne' biological probes. The main aim is to design and synthesize molecules involving the use of structural motif commonly found in ma4ority of 'ell-established drug molecules. The research 'or/ is mainly concentrated on the above points. Pyridazinone% The pyridazine and pyridazin-#-one family have attracted a great deal of attention due to the 'ide spectrum of their pharmaceutical and agrochemical activities. 5yridazin-#(2+ -ones also possess interesting synthetic versatility and possible binding sites for interaction 'ith various receptors. Therefore, these molecules have been used as positive inotropic agents for the

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treatment of congestive heart failure, potassium channel activators, antiasthmatics, an antihistaminic agent (-zelastine and a phosphodiesterase inhibitor (6ordoverine . Benzo'azoles &ubstituted benzoxazole derivatives and their analogues such as benzimidazoles and benzothiazoles have been the aim of researchers for many years, because they constitute an important class of heterocyclic compounds. )enzoxazole form core of a variety of cytotoxic natural products. )enzoxazole derivatives are biologically significant compounds and /no'n to exhibit various biological activities such as anticancer, antimicrobial, anti +03 and dopamine *4 agonists. ()*)+,#riazoles 0n the last fe' decades, the chemistry of $,2,4-triazoles and their fused heterocyclic derivatives has received considerable attention o'ing to their synthetic and effective biological importance. - large number of $,2,4-triazole-containing ring system have been incorporated into a 'ide variety of therapeutically interesting drug candidates. The mercapto- and thionesubstituted $,2,4-triazoles have been 'ell studied and so far a variety of biological activities have been reported for a large number of their derivatives, such as antitubercular, antimycobacterial, anticancer, antibacterial, antifungal, diuretic, and hypoglycemic properties. Piperazines The piperazine scaffold has been classified as a privileged structure and is fre.uently found in biologically active compounds across a number of different therapeutic areas. This motif is found in drug candidates displaying anti-allergenic, antibacterial, antianxiety, antiemetic and antimigraine activity.

!H"P#E$,II

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This section describes the synthesis and biological evaluation of some 4-(aryl/heteroaryl-2ylmethyl -!-phenyl-2-"#-(4-substitutedpiperazine-$-yl propyl%pyridazin-#(2H -one derivatives. !hemistry% The main idea of synthesizing ne' piperazine containing pyridazin-#( 2H -ones derivatives is to study the cytotoxicity of the products by varying the substituents on pyridazin- #(2+ -one moiety as 'ell as on cyclic amine moiety as these additional groups may enhance the biological activity. 5yridazinone containing piperazine derivatives can be divided from a structural point of vie' in three principal parts that may be responsible for pharmacological activity( (i (ii (iii - pharmacophoric portion constituted by a substituted !-phenyl-pyridazin- #(2H one, - terminal fragment constituted by a cyclic amine moiety, - three carbon lin/er bet'een these t'o substructures.

The title compounds 'ere synthesized from #-aroyl propionic acid via 2( 3H -furanones (2 as /ey intermediate by the follo'ing se.uence of the reactions. The starting material #-aroyl propionic acid (( 'as prepared by condensing benzene 'ith succinic anhydride in presence of anhydrous aluminum chloride by 7riedel-1rafts acylation conditions. The compounds #substituted-8-phenyl-2-yl-methylene-2-(3H -furanones (*a-d 'ere synthesized from ($ by reacting 'ith aromatic aldehydes in the presence of sodium acetate in acetic anhydride. The structures of the furanones (*a-d 'ere confirmed by 09 spectrum 'hich sho' an absorption band at $:!8;$:<: cm-$ for 1=>, characteristic of the lactone carbonyl group. The 2-( 3H furanones (*a-d 'ere reacted 'ith hydrazine hydrate in ethanol at $?;$8 @1 to give the corresponding #-aroyl-2-(substituted-4-yl-methylene -propionic acid hydrazide .a-d. The

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presence of 09 absorption band at #$$?;##4? cm-$ (broad band characteristic of the ,+ group, and bands at $!8?;$!!8 cm-$ and $!:<;$:?? cm-$, characteristic of the amide carbonyl and /etone groups, respectively. The hydrazide derivatives .a-d, after cyclization 'ith $ , +1l in benzene furnished the corresponding 4-al/yl-!-phenyl-#(2H -pyridazinone +a-d as depicted in &cheme $. The structures of the compounds 'ere confirmed by Aass and $+ ,A9 spectral data. The infrared spectra of compounds (+a-d sho'ed a broad absorption band at #$!8;##$? cm -$, 'hich is the characteristic of the ,+ group and an absorption band at $!8?;$!!? cm -$ for 1=>, characteristic of the amide carbonyl group. The $+ ,A9 sho'ed a singlet at d #.B< ppm region, (for example $+ ,A9 signal for +a observes at C = #.B: ppm 'hich is a characteristic pea/ for 9;1+2 protons. 3arious ,-substituted cyclic amines 'ere reacted 'ith $-bromo-#chloropropane and activated zinc under neutral conditions to produce the $-(#-chloropropyl -4substituted cyclic amine derivatives (- (&cheme * .

Scheme (9eagents and conditions( (a 9-1+>, -c2>, ,a>Ae, B?@1, 2 hD (b +ydrazine hydrate, Ae>+, rtD (c $.?, +1l, benzene, rt. D (d E7--l2>#, 1+#1,, reflux, 4 h.

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The target compounds 4-substituted-!-phenyl-2-"#-(4-substituted-piperzin-$-yl -propyl%pyridazin-#(2H -ones /a-t 'ere prepared by treating pyridazinones +a-d 'ith the appropriate chloro al/yl substituted cyclic amines 'ith E7--l2># in acetonitrile solvent as sho'n in &cheme #. The structures of all the synthesized compounds /a-t 'ere confirmed by $+ ,A9, 09, and Aass spectral analysis. 0n the 09 &pectrum of the products, the disappearance of a band at #$!8; ##?? cm-$ confirmed that the piperazine moiety has substituted at ,-2 position of the pyridazinone. 5yridazinone derivatives /a-t can be divided from a structural point of vie' in three principal parts that may be responsible for pharmacological activity( (i - pharmacophoric portion constituted by a substituted !-phenyl-pyridazin-#(2H -one, (ii - terminal fragment constituted by a cyclic amine moiety and (iii - three carbon lin/er bet'een these t'o substructures. Biology The synthesized 4-substituted-!-phenyl-2-"#-(4-substituted-piperzin-$-yl -propyl%-pyridazin#(2H -ones derivatives 'ere evaluated for anticancer, antibacterial, and antifungal activities. "nti0acterial activity -ll the t'enty synthesized compounds ( /a,t 'ere evaluated for antibacterial activity. The minimum inhibitory concentrations (A01 of synthesized compounds 'ere tested against three representative Fram-positive organisms viz. Bacillus subtilis (AT11 44$ , Staphylococcus aureus (AT11 B! , Staphylococcus epidermidis and Fram-negative organisms viz Escherichia coli (AT11 44# , Pseudomonas aeruginosa (AT11 :4$ and klebsiella pneumoniae (AT11 !$< . -mong the synthesized compounds ) /g and /p,t sho'ed good antibacterial activity 'hile other compounds 'ere not sho'ing prominent activity against the tested strains. These compounds, /p /1) /r and /t contains N-(#-1hloropiperazinyl group at the 4th position of

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cyclic amine. These results indicate that larger groups at 4th position of cyclic amine have no significant contribution to the antibacterial activity of these compounds. "ntifungal activity -ll the t'elve synthesized compounds (/a,t 'ere evaluated for antifungal activity. 0n vitro antifungal activity of the synthesized compounds 'as studied against the five fungal strains. -mong the synthesized compounds /a,t) only /e, /s and /t sho'ed better activity at higher concentration over the range of strains, 'hereas other compounds are not active. !H"P#E$,III series of novel 8-substituted-$,#,4-oxadiazole-2-thiol containing piperazinyl piperazinyl benzoxazole/ benzothiazole 2a-t compounds 'ere synthesized by integrating

benzothiazole/benzoxazoles .a-0 'ith 8-substituted-$,#,4-oxadiazole-2-thiol. The synthetic route for the preparation of target compounds is summarized in &chemes $, 2, #. 0nitially, the compounds .a-0 'ere synthesized by the reaction of 2-1hloro benzoxazole/benzothiazole 'ith piperazine, 'hich on subse.uent al/ylation 'ith $,#-dibromopropane to yield .a-0 (&cheme . .

>n the other hand, 8-substituted-$,#,4-oxadiazole-2-thiol (3a-4 'ere prepared starting 'ith the appropriate carboxylic acid 'hich is converted to the corresponding ester /a-4. The compounds /a-4 'ere hydrazinolyzed using hydrazine hydrate in methanol at $?? @1 to get aryl hydrazides 5a-4. The compounds 5a-4 on reaction 'ith carbon disulphide in ethanolic potassium hydroxide solution under reflux condition yielded corresponding 8-substituted-$,#,4-oxadiazole2-thione 3a-4 (&cheme + .

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The compounds 3a-4 'ere then treated 'ith piperazinyl benzothiazole/benzoxazoles .a0 using E7--l2># and acetonitrile as solvent at <? @1 to afford the final target compounds ( 2a-tD &cheme # . The formation of &-al/ylated products 'ere confirmed by the absence of 1=& characteristic pea/ at $:4.# ppm in
$#

1 ,A9 spectrum. 7urther, the structures of final target

compounds 'ere confirmed by $+ ,A9, $#1 ,A9 and Aass spectral analysis. -ll the obtained compounds are in good yield 'ith high purity.

Biology% The synthesized 2-cyclic amine incorporated pyridazin-#(2H -one derivatives 'ere evaluated for anticancer, antibacterial and antifungal activities. In vitro anticancer screening The ne'ly synthesized compounds, 2a-t 'ere tested for in vitro biological screening for their cytotoxicity to'ards cancer cell lines of various origin by ATT assay. The compounds 'ere tested against five human cancer cell lines, namely cervical (+eGa , breast (A17 : , colon

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(+1T$$! , s/in (-#:8 , lung (-84B and liver (+epF2 cell lines. &ome of the test compounds sho'ed potent activity, especially compounds 24 (-4#$ and 2t ",-phenylacetamide% (A17: . 1ompound 24 displayed the highest activity in -4#$, 'hereas the compounds 20 and 2p also sho'ed a comparable activity against -4#$ cell line, 'hile most of the compounds sho'ed moderate activity. 1ompound 2t sho'ed most potent activity among the synthesized compounds in A17-: cell line. 1ompounds 2a, 2e and 24 are also found to have almost similar activity 'ith that of 2t. &o, to conclude, the compounds 'ere more cytotoxic to'ards -4#$ follo'ed by A17:, -84B, +epF2 and +eGa. The reason behind this variation in sensitivity of the cancer cells to'ards the compounds is yet to be studied. 7rom these findings, 'e 'ere able to identify a fe' active molecules 'hich are capable of inhibiting the gro'th of human cancer cell lines, in vitro. !H"P#E$,I& Synthesis and anti0acterial and antifungal evaluation of some arylsulfonylpiperazine 0ased 0enzothiazoles6 5rompted by recent literature developments and as a part of our continuous search for biologically active compounds, 'e 'or/ed on 4oining the t'o active moieties 'ith an intention of getting better biological activity. Hith this concept, 'e are reporting the pharmacological activity of ,-(benzo"d%thiazol-2- yl -2-(piperazin-$-yl acetamide/propanamide analogs for their antibacterial and antifungal activities.

!hemistry The benzothiazole coupled 'ith phenylsulfonylpiperazine acetamide/propanamide derivatives 'ere synthesized by a converging synthesis route that re.uires the preparation of both the sulfonamide and ,-(benzo"d%thiazol-2-yl -2-bromo acetamide/,-(benzo"d%thiazol-2-yl #-bromopropanamide precursors independently that can be subse.uently coupled together. The

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,-(benzo"d%thiazol-2-yl -#-bromopropanamide/2-bromoacetamide (* 'as synthesized in good yield by simple al/ylation involving reaction of 2-aminobenzothiazole and #-bromopropanoyl bromide/ 2-bromoacetyl bromide as outlined in &cheme $. >n the other hand, 4substitutedphenylsulfonyl piperazines (+a-e 'ere prepared by starting 'ith the appropriate arylsulfonylchloride (. reacted 'ith simple piperazine in 1+21l2 under catalyst free conditions at ? @1. The unreacted piperazine 'as removed by treating 'ith saturated a.. ,a+1> # solution to afford the re.uired product. The resultant compounds ( +a,e 'ere no' integrated 'ith substituted ,- (benzo"d%thiazol-2-yl -#-bromopropanamide/2-bromoacetamide (* to afford the title compounds /a,o and 5a,o. The detailed general synthesis procedure of the compounds is mentioned in the experimental section. -ll the synthesized compounds 'ere characterized by $+ ,A9, $#1 ,A9, 2&0-A& and 09 spectra. 7urther, the structure of the compound /f 'as also confirmed by I-ray crystallographic analysis (11*1 B#<:2! and the >9T25 diagram is represented belo'.

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&cheme $( 9eagents and conditions( (a 1+21l2, ?@1 (b )r1>1+2)r, T+7, ?@1 (c E21>#, 1+#1,, r.t

Biological "ctivity Acetylcholine esterase inhibitory activity The benzothiazolophenylsulfonylacetamides (/a,o / propanamide (5a,o derivatives 'ere examined for their anticholinesterase activities by 2llmanJs method. The results of the preliminary -1h2 inhibitory activity of compounds /a,o, 5a,o and the calculated logP values (1logP of the tested compounds (calculated using the 1& 1hem >ffice Kltra version $2.?, 1ambridge&oft, 1ambridge, A-, K&- are sho'n in Table (. These results revealed that the compounds sho'ed moderate to less anticholinesterase potency than the reference drug,

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Falanthamine. -mong the tested compounds, /4) /7) /l and 5i sho'ed better -1h2 inhibitory activity 'ith 018? values ranging from $:.<B ; <:.<? LA. -mong them /l sho'ed potent activity. The structure activity relationship sho'ed that these compounds (/4) /7, /l and 5i have electron'ithdra'ing substituents li/e ;7, ;>17# and electron donating groups li/e ;1+#, ;>1+# present on either benzothiazole or phenyl group of piperazinesulfonyl group of the tested compounds might be contributed to the better activity. "ntimicro0ial activity% The benzothiazolophenylsulfonylacetamides /a,o/propanamide 5a,o derivatives 'ere evaluated for their in vitro antimicrobial activities against the representative bacterial strains Micrococcusleteus (AT11 24:? , S aureus (AT11 B! , S aureus AG&-$! (AT11 2B4? , B subtilis (AT11 $2$ , E coli (AT11 :#B , P aeruginosa (AT11248# , and ! planticola (AT11 8#? as 'ell as fungal strain such as 1andida albicans (AT11 #?$: using the t'o-fold serial dilution techni.ue. The minimal inhibitory concentration (A01, Mg/mG 'as recorded as the lo'est concentration that produced complete suppression of visible gro'th by ta/ing 1iprofloxacin and Aiconazole as the reference drugs. The results revealed that the tested compounds sho'ed varying degrees of inhibition against the tested microorganisms. -mong the synthesized compounds, most of the propanamide series (5a,o exhibited moderate to good antibacterial activity against the Fram-positive bacteria, as 'ell as the "andida albicans strain. The compounds 5g) 5h and 5i sho'ed promising antimicrobial activity specifically against Fram-positive bacterial strains (A01 values ranging from 4.!<-$<.:8 Lg/mG . Hhile, the compounds /o and 5a,5m demonstrated selective activity against the Fram-negative bacterial strains (A01 values ranging from 2.#4-#:.8? Lg/mG . +o'ever, the other compounds sho'ed A01 values of N#?? Lg/mG against all the tested microbial strains. 7urther, four compounds, ,-(!-fluorobenzo"d%thiazol-2-yl -2-(4-tosylpiperazin -$-yl acetamide (/g , ,-(!- fluorobenzo"d%thiazol-2-yl -#-(4-tosylpiperazin-$-yl propanamide (5g , ,-(!-fluoro benzo"d%thiazol-2-yl -#-(4-((4-fluorophenyl sulfonyl piperazin-$-yl sulfonyl propanamide (5h and ,-(!-fluorobenzo"d%thiazol-2-yl -#-(4-((4-methoxyphenyl

piperazin-$-yl propanamide (5i exhibited A01 = 4.!< Mg/mG 'ere identified to have more potent antifungal activity against "andida albicans strain, as compared to the standard drug, Aicanazole (A01 = B.#: Mg/mG . Hhile, the compounds /e, /f, 5c and 5d sho'ed promising antifungal activity (A01 values ranging from B.#:-$<.:8 Lg/mG against "andida albicans found

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to be slightly better or e.uipotent to the standard drug, Aiconazole. The bactericidal activity 'as found almost follo' a similar trend as that of the inhibitory activity against the respective bacterial strains. The structure activity relationship study of the compounds /o, 5c, 5d, 5e, 5f) 5h) 5i and 54 revealed that the substituents present on either benzenesulfonyl moiety or benzothiazole moiety are polar groups li/e ;7 or ;>17# or ;>1+# contributed to the promising antimicrobial activity. +o'ever, in case of compounds 50, the methyl group attached to the benzenesulfonyl scaffold is of electron donating nature 'hich may contribute to the improved activity. Hhile, the introduction of electron 'ithdra'ing groups li/e ;7 and electron donating group li/e ;>1+# and ;1+# group into the 4-substituted position of benzenesulfonyl and fluoro group into the !-substituted position of aminobenzothiazole, both of 'hich ma/e the compounds 5g, 5h and 5i as potent antimicrobial agents among all the synthesized derivatives. 7rom the structure activity relationship point of vie', 'e can conclude that both methoxy group and fluorine containing group on either in benzenesulfonyl moiety or benzothiazole moiety improved the biological activity of these compounds against almost all bacterial strains and "andida albicans. 0n conclusion, t'o series of aminobenzothiazole-benzenesulfonylpiperazine based acetamide and propanamide derivatives 'ere synthesized using 2-aminobenzothiazole. -ll these ne' compounds 'ere confirmed by ,A9, Aass and 09 spectra. Their -1h2 inhibitory activity and antimicrobial activities 'ere evaluated. The -1h2 inhibitory activity of the tested compounds sho'ed moderate to less activity. 7urther antimicrobial results sho'ed that most of the synthesized propanamide derivatives (5a,o exhibited good to moderate antimicrobial activities in vitro. 2specially, the compounds 5g, 5h and 5i bearing methyl, fluoro and methoxyphenyl groups respectively sho'ed the broad antibacterial activities against all tested bacterial strains 'ith A01 values ranging from 2.#4 to$<.:8 Mg/mG. The length of the carbon chain and substitution (preferably polar groups in the arylsulfonylpiperazine or benzothiazole moiety played important role in the antimicrobial activities of the title compounds. These findings demonstrated that aminobenzothiazole analogs are of biological significance, 'hich have the perspective to become ne' members of antimicrobial agents. !H"P#E$,& 0n the present chapter, arylsulfonylpiperazine motif 'as coupled 'ith some substituted benzimide using a t'o carbon spacer (1+2-1> to produce t'enty ne' hybrid derivatives .a,4

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and +a,4. These ne'ly synthesized compounds 'ere evaluated for their cell gro'th inhibitory activities (018? to'ards cultures of five different cancer cells using ATT assay. &ome of the compounds 'ere able to induce good inhibitory activities against the proliferation on TB<F cancer cell line, 'hile most compounds sho'ed moderate activity.

9ational concept to the synthesis of 4-substituted-,-(2-(4-((4-substitutedphenyl sulfonyl piperazin-$-yl -2oxoethyl benzamide

- series of novel hippuric acid derivatives containing arylsulfonylpiperazine compounds 'ere synthesized by integrating arylsulfonylpiperazine (*a-48 'ith hippuric acid using 2*10. The synthetic route for the preparation of target compounds (#a;4, 4a-4 is summarized in &cheme $. 0nitially, the compound (a-0 'as synthesized by the reaction of 4fluorobenzoyl/benzoyl chloride 'ith glycine to yield (a-0 (&cheme $ . >n the other hand, 4substitutedphenylsulfonylpiperazines 9*a-48 'ere prepared by starting 'ith the appropriate arylsulfonylchloride reacted 'ith simple piperazine in 1+ 21l2 under catalyst free conditions at ? @1. The unreacted piperazine 'as removed by treating 'ith saturated a.. ,a+1> # solution to afford re.uired product. The resultant compounds 'ere no' integrated 'ith substituted hippuric acid in presence of 2*10 to afford the title compounds. 7urther, the structures of final target compounds 'ere confirmed by $+ ,A9, $#1 ,A9 and Aass spectral analysis. -ll the obtained compounds are in good yield 'ith high purity.

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Biology In vitro anticancer screening The ne'ly synthesized compounds, .a-4 and +a,4 'ere tested for in vitro biological screening for their cytotoxicity to'ards cancer cell lines of various origins by ATT assay. The compounds

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'ere tested against five human cancer cell lines, namely +eGa (1ervical , -84B (Gung , -#:8 (&/in , A*--A)-2#$(breast and TB<F (brain cell lines. The relationship bet'een fraction of surviving cells for different cell lines and drug concentration 'as plotted and the response parameter 018?, 'hich is the concentration re.uired for 8? O inhibition of cell viability, 'as calculated. The obtained data revealed that most of the synthesized compounds sho'ed potent anticancer activity against TB<F cell line. Aost of the compounds sho'ed 01 8? values less than $?? in TB<F cell line, out of 'hich, .0) .d and .g are more cytotoxic compared to others. 7or these compounds, 018? values are in the range of 24.?;#4.#MA, 'hereas some of the compounds sho'ed 018? values less than $2? MA, 'hich indicates that these compounds are also important lead compounds. &imilarly, in -#:8 cell, the 018? value for +e is found to be #<.2MA, The present study revealed that among all the tested compounds most of the compounds sho'ed good results in TB<F cell line compared to other cell lines. The ATT dose-dependent study data also confirmed that, out of all the synthesized compounds, there 'as substantial increase in cytotoxicity of the compounds .0) .d and .g over TB<F 'ith increasing exposure to drug concentration. 0n conclusion, synthesis of novel substituted phenyllsulfonylpiperazines containing benzimide derivative has been described in presence of 2*10 and +>)t. The present study describes the effect of substitution at position 4 of phenyl group of sulfonylpiperazines on the antiproliferative activity. -mong the tested compounds, .0, .d and .g sho'ed potent cytotoxic activity against glioblastoma cell line. 1ompound .d displayed the highest cytotoxicity follo'ed by .0 and .g6 1ompounds +c and +e 'ere sho'ed notable cytotoxic effect to'ards +eGa and -#:8 cell lines respectively. 0n general glioblastoma is the most sensitive to'ards the set of synthesized compounds. &ome of the derivatives also inhibit +eGa and -#:8 cell lines. The results demonstrated that the presence of 4-oxymethyl, methyl and their flouro derivative groups ma/e the target compounds to have good cytotoxic activity. The findings from this study might be beneficial as lead compounds for designing ne' compounds 'ith potential antitumor activity. further activity profile about the synthesized compounds is under progress.

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