Identification of novel 2-benzyl-1-indanone analogs as interleukin-5 inhibitors

Boggu, Pulla Reddy,Cho, Jungsuk,Kim, Youngsoo,Jung, Sang-Hun Elsevier 2018 European journal of medicinal chemistry Vol.152 No.-

<P><B>Abstract</B></P> <P>A novel series of 2-benzyl-1-indanone analogs were investigated as IL-5 inhibitory activity. Among the synthesized compounds, 7-(cyclohexylmethoxy)-2-(4-hydroxybenzyl)-2,3-dihydro-1<I>H</I>-inden-1-one (<B>7s</B>, 100.0% inhibition at 30 μM, IC<SUB>50</SUB> = 4.0 μM), and 7-(cyclohexylmethoxy)-2-(3-hydroxybenzyl)-2,3-dihydro-1<I>H</I>-inden-1-one (<B>7t</B>, 95.0% inhibition at 30 μM, IC<SUB>50</SUB> = 6.0 μM) showed the best inhibitory activity against IL-5. The 2-benzyl-1-indanone analogs showed moderate to strong IL-5 inhibitory activity. Especially, hydroxyl (HBD/HBA) substituent at position 3 or 4 on phenyl ring B showed potent IL-5 inhibition. Additionally, the bulky hydrophobic cyclohexylmethoxy group at position 7 of the 1-indanone ring is favorable for the inhibitory activity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Novel 2-benzyl-1-indanone scaffold has been discovered as highly active interleukin-5 inhibitor. </LI> <LI> SAR study explored the importance of hydrophobic group at position 7 and 4-hydoxybenzyl group. </LI> <LI> IC<SUB>50</SUB> values of <B>7s</B> and <B>7t</B> shows 4.0 and 6.0 μM, respectively. </LI> <LI> The conformational study indicates that the folded conformation of <B>7s</B> could be the effective conformation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Discovery of novel 3-(hydroxyalkoxy)-2-alkylchromen-4-one analogs as interleukin-5 inhibitors

Boggu, P.R.,Venkateswararao, E.,Manickam, M.,Kim, Y.,Jung, S.H. S.E.C.T. [etc.] ; Elsevier Science Ltd 2017 European journal of medicinal chemistry Vol.139 No.-

A series of novel chromen-4-one analogs 9a-d and 10a-u was designed, synthesized and evaluated for their IL-5 inhibitory activity. Most of the chromen-4-one analogs showed strong inhibitory activity in low micro molar potency. Among them, 5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-2-isopropyl-4H-chromen-4-one (10t, 90.0% inhibition at 30 μM, IC<SUB>50</SUB> = 5.5 μM, CLogP = 4.76887) and 2-cyclohexyl-5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-4H-chromen-4-one (10u, 95.5% inhibition at 30 μM, IC<SUB>50</SUB> = 3.0 μM, CLogP = 5.96187) showed the best inhibition. The structure activity relationship reveals that the hydrophobic cyclohexylmethoxy group at the position 5 of the chromen-4-one ring A is preferable than at position 6 and the dual hydrogen bonding acceptor property on the chromen-4-one ring should be important for the inhibitory activity. In addition, the optimum length of the side chain at position 3 of chromen-4-one ring is critical for the donation of hydrogen to the binding site and the 3-hydroxypropoxy group showed the best activity. Moreover, the conformational restrictor (isopropyl, cyclohexyl group) at position 2 is much more favorable for the formation of effective conformer of side chain with hydrogen bonding donor property of these chromen-4-one analogs.

Exploration of SAR for novel 2-benzylbenzimidazole analogs as inhibitor of transcription factor NF-jB

PullaReddy Boggu,Eeda Venkateswararao,Manoj Manickam,김영수,정상헌 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.4

A novel series of 2-benzylbenzimidazole analogswas designed, synthesized and investigated for theirin vitro activities against LPS induced NF-jB inhibitionin RAW 264.7 cells using the SEAP assay. Amongthem, 4-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6e,[100% inhibition at 30 lM, IC50 =3.0 lM), 4-((5-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6j, 96% inhibition at 30 lM,IC50 = 4.0 lM) and 2-((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol (6k, 95% inhibition at30 lM, IC50 = 5.0 lM) showed strong inhibitory activity. The structure activity relationship confirmed that thesubstitution on benzimidazole ring A with hydrophobiccyclohexylmethoxy group at position 4 or 5 markedlyenhances the activity. In addition, the hydrophilic hydrogenbonding donor group (OH) at position 2 or 4 on phenyl ringB connected with one methylene spacer to the benzimidazolering is favorable for the inhibitory activity. However,hydrophobic (–OCH3 and –Cl) groups on phenyl ringB decrease the activity.

Synthesis and Evaluation of Benzimidazole Analogs as NF-κB Inhibitors

Pulla Reddy Boggu 충남대학교 약학대학 의약품개발연구소 2018 藥學論文集 Vol.33 No.-

The inhibitory in vitro activity against LPS induced NF-KB bioactivaton in RAW 264.7 cell using the SEAP assay of the substituted 2-benzylbenzimidazole analogs were investigated. Among them, (5-methoxy- 1H-benzo[이imidazol-2-yl)(4-methoxyphenyl)methanol (2b, IC50=8.4 μM) showed strong inhibition. The SAR studies 「evealed that the 5-methoxy group at phenyl ring A with additional benzylic hydroxyl group is important f。「the activity of these compounds.

Synthesis and Proton-Deuterium Exchange Studies of Phenylisoxazolyl-Indoline-Sulfonamide Derivatives

Pulla Reddy Boggu,Sang-Hun Jung 충남대학교 약학대학 의약품개발연구소 2020 藥學論文集 Vol.35 No.-

Identification of N-arylsulfonylpyrimidones as anticancer agents

Subramanian, Santhosh,Boggu, Pulla Reddy,Yun, Jieun,Jung, Sang-Hun The Pharmaceutical Society of Korea 2018 Archives of Pharmacal Research Vol.41 No.3

For confirming the role of five membered ring of imidazolidinone moiety of N-arylsulfonylimidazolidinones (7) previously reported with highly potent anticancer agent, a series of N-arylsulfonylpyrimidones (10a-g) and N-arylsulfonyltetrahydropyrimidones (11a-e) were prepared and their anti-proliferating activity was measured against human cancer cell lines (renal ACHN, colon HCT-15, breast MDA-MB-231, lung NCI-H23, stomach NUGC-3, and prostate PC-3) using XTT assay. Among them, 1-(1-acetylindolin-5-ylsulfonyl)-4-phenyltetrahydropyrimidin-2(1H)-one (11d, mean <TEX>$GI_{50}=3.50{\mu}M$</TEX>) and ethyl 5-(2-oxo-4-phenyltetrahydropyrimidin-1(2H)-ylsulfonyl)-indoline-1-carboxylate (11e, mean <TEX>$GI_{50}=0.26{\mu}M$</TEX>) showed best growth inhibitory activity against human cancer cell lines. Considering the activity results, N-arylsulfonyltetrahydropyrimidones (11) exhibited more potent activity compared to N-arylsulfonylpyrimidones (10) and comparable activity to N-arylsulfonylimidazolidinones (7). Especially, tetrahydropyrimidin-2(1H)-one analogs containing acylindolin-5-ylsulfonyl moiety at position 1 demonstrated their strong growth inhibitory activity against human cancer cell lines.

Investigation of chemical reactivity of 2-alkoxy-1,4-naphthoquinones and their anticancer activity

Manickam, Manoj,Boggu, Pulla Reddy,Cho, Jungsuk,Nam, Yeo Jin,Lee, Seung Jin,Jung, Sang-Hun Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.11

<P><B>Abstract</B></P> <P>To establish the structure-activity relationship of 5-hydroxy-1,4-naphthoquinones toward anticancer activity, a series of its derivatives were prepared and tested for the activity (IC<SUB>50</SUB> in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among them <B>2</B> (IC<SUB>50</SUB>: 2.3; 2.0; 1.4 µM), <B>6</B> (IC<SUB>50</SUB>: 1.9; 2.2; 1.3 µM), <B>9</B> (IC<SUB>50</SUB>: 0.7; 1.7; 0.9 µM) and <B>10</B> (IC<SUB>50</SUB>:1.7; 1.0; 1.2 µM) showed moderate to excellent activity. Our perception toward the DNA substitution of alkoxy groups at the C2 position of these naphthoquinones for the anticancer activity led us to investigate their reactivity of substitution toward dimethylamine as a nucleophile. The ease of the substitution of alkoxy groups at the C2 position with dimethylamine is strongly accelerated by hydroxyl group at C5 position and is well correlated with the found anticancer activity results.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SAR of 1,4-naphthoquinones toward anticancer activity was established. </LI> <LI> C2-Alkoxy and C5-hydroxyl is crucial for activity. </LI> <LI> The substitution of alkoxyl at the C2 with amine is accelerated by hydroxyl at C5. </LI> <LI> The chemical reactivity of these analogs is correlated with their anticancer activity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Exploration of diphenylalkyloxadiazoles as novel cardiac myosin activator

Manickam, Manoj,Boggu, Pulla Reddy,Pillaiyar, Thanigaimalai,Sharma, Niti,Jalani, Hitesh B.,Venkateswararao, Eeda,Jung, Sang-Hun Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14

<P><B>Abstract</B></P> <P>To explore novel cardiac myosin activator, a series of diphenylalkyl substituted 1,3,4-oxadiazoles and 1,2,4-oxadiazoles have been prepared and tested for cardiac myosin ATPase activation <I>in vitro</I>. In all cases, three carbon spacer between the oxadiazole core and one of the phenyl ring was considered crucial. In case of 1,3,4-oxadiazole, zero to two carbon spacer between oxadiazole core and other phenyl ring are favorable. Phenyl ring can be replaced by cyclohexyl moiety. In case of 1,2,4-oxadiazole, zero or one carbon spacer between the oxadiazole and other phenyl ring are favorable. Introduction of hydrogen bonding donor (NH) group at the 2<SUP>nd</SUP> position of the 1,3,4-oxadiazole enhances the activity. Substitutions on either of the phenyl rings or change of phenyl ring to other heterocycle are not tolerated for both the oxadiazoles. The prepared oxadiazoles showed selective activation for cardiac muscle over smooth and skeleton muscles.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The diphenylalkyl oxadiazoles were identified as novel cardiac myosin ATPase activator. </LI> <LI> Three carbon spacer between oxadiazole core and one of the phenyl ring is crucial. </LI> <LI> Introduction of NH group at the 2nd position of the 1,3,4-oxadiazole is favored. </LI> <LI> These oxadiazoles are selective activators for cardiac myosin. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

N-acetylindoline과 acetanilide 유도체들의 방향족 환 수소의 chemical shift 변화의 비교 분석 : para-Disubstituted Benzene 수소의 Chemical Shifts 결정과 Acetamido Group의 안정한 3차원 구조의 결정

이상윤,최민성,마노즈 마닉캄,풀라레디 보꾸,김동현,정상헌 충남대학교 약학대학 의약품개발연구소 2016 藥學論文集 Vol.31 No.-

Chemical shift variations of benzene ring hydrogens along with introduction of amino, acetamido, chlorosulfonyl and aminosulfonyl functional groups in aniline and indoline systems were comparatively analyzed and utilized for determination of stable conformations of acetamido group and chemical shifts for para-disubstituted benzene ring hydrogens. Upon N-acetylation of aniline, chemical shifts of ortho, meta, and para hydrogens are shifted by 0.81, 0.56 and 0.26 downfield from those of aniline. These variations should be incurred by the inductive effect of acetamido group, since the variations are sequentially reduced along with distance from the acetamido function. Indolines upon N-acetylation showed unusual chemical shift variation for 4-, 6-, 7-, and 8-hydrogens (△δ: 0.09, 0.14, 1.47 and 0.24 downfield shift from those of indoline). The remarkably pronounced downfield shift for 7-hydrogen and the unusually small downshifts for 4-and 6-hydrogens of N-acetylindoline compared to those of acetanilide imply the existence of different conformation of acetyl group resulting in the strong electrostatic field effect other than the inductive effect of acetamido group. Although computation of molecular energy of N-acetylindoline around rotation of acetyl group showed two minimum energy conformations, this unusual downfield shift confirms that the real existed conformation of N-acetylindoline is the structure of carbonyl oxygen and hydrogen at 7-position very close. Considering strong electrostatic field effect of N-acetylindoline, acetanilide only possesses the inductive effect, thus conformation of acetamido group in acetanilide should be the structure with carbonyl oxygen of acetamido located away from ortho hydrogens. Therefore the conformation of functional groups must be carefully considered for determination of the chemical shift of benzene ring hydrogens. Chlorosulfonyl and aminosulfonyl group showed chemical shift variation along with the their inductive effect, thus chlorosulfonyl group normally influenced chemical shifts of 4- (△δ: 0.69), 6- (△δ: 0.71) and 7-(△δ: 0.35) hydrogens of indolines from those of N-acetylindoline as shown in aniline system. With these data analysis of indoline system, chemical shifts of hydrogens of symmetrically substituted para-acetamidobenzenzenesulfonyl analogs were obviously determined.

Structure Activity Relationship of 4-Phenyl-1-(1-Acylindolin- 5-Ylsulfonyl)Pyrrolidin-2-Ones on Anticancer Activity

Santhosh Subramanian,Pulla Reddy Boggu,윤지은,Sang-Hun Jung 대한화학회 2020 Bulletin of the Korean Chemical Society Vol.41 No.4

Microtubules play a dynamic role during cell division. In our early studies 4-phenyl-1-(1-acylindoline-5-sulfonylimidazolones were thoroughly explored and found that the indoline bicyclic system next to the sulfonyl group is very important for cytotoxicity. In this research, imidazolone motif was replaced with pyrrolidin-2-one and this isosteric replacement led to show some promising activity. Thus, the structure activity relationship of 4-phenyl-1-(1-acylindolin-5-ylsulfonyl)pyrrolidin-2-ones with the various acyl group at the indoline NH was explored. The presence of benzoyl groups with electron donating group was the more favorable for cytotoxicity while less bulky alkanoyl groups led to decrease cytotoxicity.