SYNTHESIS OF HETEROCYCLIC COMPOUNDS OF BIOLOGICAL INTEREST

Abstract

For human beings inflammatory diseases and cancer continue to be serious health problems. A number of anti-inflammatory drugs and a few anticancer drugs are available in the market. At present anti-inflammatory drugs available have serious side effects such as gastric ulcer, kidney damage & heart failure etc. Need for safer anti-inflammatory drugs and more anticancer drugs exist. There is an urgent need to identify new potent anti-inflammatory and anticancer molecules which can be developed as anti-inflammatory and anticancer drugs. Efforts have been made by us in this direction, which is described in this thesis. For the sake of clarity, the work embodied in thesis is divided into five chapters. First Chapter : General introduction: In part Ia of this this chapter recent work on the use of microwave technology in organic synthesis reported in literature is summarized. In part Ib recent work reported in literature on the synthesis, anti-inflammatory and anticancer activities of acridine, bisacridine, pyrazole, oxadiazole, isoindole, pyrrolopyrazine, amidine, azomethine, benzimidazole and piperazine derivatives is summarized. All the new compounds synthesized and reported in the following chapters were charaterized by IR, 1H NMR, 13C NMR, Mass (GC-MS, APCI-MS) spectroscopy and elemantal analysis. Second Chapter: In this chapter synthesis of bisacridine derivatives IIIa-j and Va-j by following reaction Scheme 2.1 & 2.2 is discussed. NNCSRR1H2NR2NH2IVa-eIIa,bVa-j For Compounds Va-jScheme:-2.2 Synthesis of bisacridine derivatives Va-jNHNRR1CSHNR2NHCSHNNRR1 R R1 R2Vf H H Vg CH3 H Vh OCH3 H Vi H CH3 Vj H OCH3NN(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3 R R1 R2Va H H Vb CH3 H Vc OCH3 H Vd H CH3 Ve H OCH3NN(CH2)3(CH2)3NN(CH2)3(CH2)3NN(CH2)3(CH2)3NN(CH2)3(CH2)3THFstirring atRT, 6hNClRR1NHNRR1R2NHNR1RH2NR2NH2RefluxMeOHIa-eIIa,bIIIa-j For Compounds IIIa-j R R1 R2IIIf H H IIIg CH3 H IIIh OCH3 H IIIi H CH3 IIIj H OCH3NN(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3OOOO(CH2)3(CH2)3Scheme:-2.1 Synthesis of bisacridine derivatives IIIa-j R R1 R2IIIa H H IIIb CH3 H IIIc OCH3 H IIId H CH3 IIIe H OCH3NN(CH2)3(CH2)3NN(CH2)3(CH2)3NN(CH2)3(CH2)3NN(CH2)3(CH2)317-18 h ii Compounds IIIa-j and Va-j were screened for anti-inflammatory activity at 50mg/kg p.o. Compound IIIg exhibited 41% anti-inflammatory activity whereas standard drug ibuprofen exhibited 39% activity at 50 mg/kg p.o. Anticancer activity evaluation against five human cancer cell lines i.e. lung (NCI H-522), ovary (PA-1), breast (T47D), colon (HCT-15) and liver (HepG2) at a concentration of 1× 10-5M, indicate that compound IIIh possess good anticancer activity i.e. 76%, 81%, 86% and 67% against first four cancer cell lines whereas compound IIIa exhibited good anticancer activity i.e. 50% against liver (HepG-2) cancer cell line. Third Chapter: In this chapter synthesis of pyrazole derivatives i.e. IIa-j (Scheme 3.1) and oxadiazole derivatives i.e. IVa-f (Scheme 3.2) using microwave irradiation technique is described. Pyrazole and oxadiazole derivatives (IIa-l, IVa-f) were screened for anti-inflammatory activity at 50mg/kg p.o. and for anticancer activity against five human cancer cell lines (mentioned in chapter-2) at a concentration of 1× 10-5M. Compound IIj and IVh exhibited 35% anti-inflammatory activity as compared to ibuprofen which showed 39% activity at 50 mg/kg p.o. Compound IVd exhibited 48% and 39% anticancer activity against lung (NCI H-522) & liver (HepG2) and compound IIj show 41% anticancer activity against breast (T47D) cancer cell lines. Fourth Chapter: It is divided into two parts i.e. 4a and 4b. Part 4a: deals with the synthesis of azomethine (VIax-cz) and amidine (VIIax-cz) derivatives of isoindole (IIIa, b) and pyrrolopyrazine (IIIc) by following reaction Scheme 4a.1. ZYXCOCHCHRZYXNNR1RR1NHNH2H2OMWI, 3 min X Y Z R R1IIa N CH CH H IIb CH N CH HIIc CH CH N HIId N CH CH HIIe CH N CH HIIf CH CH N HIa-f IIa-lOCH3H3CONMe2OCH3H3COOCH3H3CONMe2NMe2Scheme-3.1: Synthesis of pyrazole derivatives X Y Z R R1IIg N CH CH PhIIh CH N CH PhIIi CH CH N Ph IIj N CH CH PhIIk CH N CH PhIIl CH CH N PhOCH3H3CONMe2OCH3H3COOCH3H3CONMe2NMe2YXZNH2NOHYXZNONRMWI, 7 min IIIa-c IVa-fOHOCH3OCH3H3COOCH3H3COOCH3H3COOHOCH3OHOCH3Scheme-3.2: Synthesis of oxadiazole derivatives X Y Z RIVd N CH CHIVe CH N CHIVf N CH N X Y Z RIVa N CH CHIVb CH N CHIVc N CH N X Y Z IIIa N CH CHIIIb CH N CHIIIc N CH NRCHO iii Azomethine derivatives i.e. (VIax-cz) and amidine derivatives (VIIax-cz) were screened for anti-inflammatory activity at 50mg/kg p.o. and for anticancer activity against five human cancer cell lines i.e. breast (T47D), lung (NCI H-522), colon (HCT-15), ovary (PA-1) and liver (HepG2) at a concentration of 1× 10-5M. Compound VIIcx exhibited good anti-inflammatory activity i.e. 35% as compared to standard drug ibuprofen which showed 39% activity at 50 mg/kg p.o.. Compounds VIbz, VIIcx, VIIcz (breast T47D), VIbz, VIcy (lung NCI H-522), VIbx, VIIbz (colon HCT-15), VIbz (ovary PA-1) and VIbx, VIcz (liver HepG-2) exhibited good anticancer activity. Part 4b: deals with the synthesis of isoindole, pyrrolopyrazine, benzimidazoisoindole and benzimidazopyrrolopyrazine derivatives i.e. IIIx-z, IVx-z; VIxa-ze and VIIxa-ze by following reaction Scheme 4b.1. COOHCOOHR1R1NOONH2+Grinding/RTIa-cIIIa-cH2NNH2H2OR1NOONR1NOONCHR2CNH2R3R2CHOR3CNVIax-czVIIax-czMWIIVx-zVx-zMWIIINNScheme 4a.1 Synthesis of azomethine & amidine derivatives of isoindole & pyrrolopyrazine IIIa-c, VIax-cz & VIIax-cz.For compound Ia-c & IIIa-cR1, a=; R1, c=; R1, b= R1 R2 VIax VIay VIaz VIbx VIby R1 R2 VIbz VIcx VIcy VIczOHOCH3OCH3H3CONCH3CH3OHOCH3OCH3H3CONNNNNNNCH3CH3OHOCH3OCH3H3CONCH3CH3 R1 R2 VIIax VIIay VIIaz VIIbx VIIby R1 R2 VIIbz VIIcx VIIcy VIIczNNNNNNNNNNNNNNNNNN30 min6 min6 minH2NH2NCOOHCOOHRRNOOCOOHH2NRNONCOOH+MWIMWIRNOOH2NRNONOHNR1HNOR1Ix-zIIIx-zIVx-zVIxa-zeR1NH2R1NH2Ix = R =NNIy = R =Iz = R =Va-eVa-eCOOHVIIxa-zeGrinding, RTGrinding, RTIIScheme 4b.1 Synthesis of compounds IIIx-z, IVx-z, VIxa-ze, VIIxa-ze. R R1 VIxa, VIIxa VIxb, VIIxb VIxc, VIIxc VIxd, VIIxd VIxe, VIIxe R R1 VIya, VIIya VIyb, VIIyb VIyc, VIIycVIyd, VIIydVIye, VIIyeH2CNH2CNH2CNH2CH2COH2CNH2CNH2CNH2CH2CO R R1 VIza, VIIza VIzb, VIIzb VIzc, VIIzcVIzd, VIIzdVIze, VIIzeH2CNH2CNH2CNH2CH2CONNNNNNNNNN5 min5 min20 min20 min iv Compounds VIyc and VIIzd exhibited good anti-inflammatory activity i.e. 34% and 37% as compared to standard drug ibuprofen which showed 39% activity at 50 mg/kg p.o. Compounds VIzc, VIIzd (lung NCI H-522), VIye, VIIxd, VIIyd, VIIzc, VIIzd (colon HCT-15), VIxc, VIIzc (ovary PA-1), VIxc, VIyb, VIzc (liver Hep G-2) exhibited good anticancer activity. Fifth Chapter: contains microwave assisted synthesis of piperazine-2,6-dione (IIIa-l) and 4-(1H-indole-2 carbonyl)piperazine-2,6-dione (IVa-l) derivatives by following reaction scheme 5.1. It also contain synthesis of bis piperazine-2,6-dione derivatives (VIax-jz) by following reaction scheme 5.2. HNCOOHCOOHH2NR1+HNNR1OONNR1OONHNHCOOHMWIMWI, 7 minCOIVa-lR1 is same for IIa-l, IIIa-l & IVa-lIIa-lIIIa-lINNCH2CH2CH2NH2CNH2CNH2CSH2COH2CH2CNCH2CH2CH2ONCH2CH2ONCH2CH2SCH2CH2Scheme 5.1 Synthesis of piperazine-2,6-dione (IIIa-l) and 4-(1H-indole-2-carbonyl)piperazine-2,6-dione (IVa-l) derivatives. R1 a b c d R1 e f g h R1 i j k l3 minHOOCR2COOHHNNR1OOCR2COONNR1OONNR1OO+MWIScheme 5.2 Synthesis of heterocyclic compounds VIax-VIjzNNSIIIa-jVx-zVx R2= ; Vy R2= ; Vz R2=VIax-jz R1IIIaIIIb IIIc IIId IIIeNH2CNH2CNH2CSH2COH2CH2CN(CH2)3ON(CH2)2IIIf IIIg IIIh IIIi IIIjNNSNN(CH2)3NH2CNH2C R1 R2VIaxVIay VIaz VIbxVIby VIbzVIcxVIcy VIcz VIdxNN(CH2)3NN(CH2)3NNSNH2CNH2CNNSNNH2CSH2COH2CNH2C R1 R2VIdy VIdz VIexVIey VIezVIfxVIfy VIfz VIgxVIgyNNSNNSNNSNNH2CNH2CNH2CSH2CSH2COH2CH2CN(CH2)2OH2C R1 R2VIgz VIhxVIhy VIhzVIixVIiy VIiz VIjxVIjyVIjzNNSNNSNNSNH2CH2CN(CH2)3ON(CH2)2N(CH2)2N(CH2)3ON(CH2)3O11-12 minNN(CH2)3 v Compounds IIIa-l and IVa-l and VIax-jz were screened for anti-inflammatory activity at 50mg/kg p.o. and for anticancer activity against five human cancer cell lines i.e. breast (T47D), lung (NCI H-522), colon (HCT-15), ovary (PA-1) and liver (HepG2) at a concentration of 1× 10-5M. Biological evaluation reveals that compounds VIbx and VIex possess anti-inflammatory activity 43% and 39% respectively, which is comparable or better than ibuprofen (a standard drug) which exhibited 39% activity at 50 mg/kg p.o. Compounds VIax exhibited anticancer activity 28% against breast (T47D); VIay 39% against lung (NCI H-522); IIIj 49% against colon (HCT-15); IVe 42% against ovary (PA-1) and IIIh, IVf 46%, 45% respectively against liver (HepG2) cancer cell lines. All these compounds exhibited moderate to good anticancer activity against the cell lines mentioned above. Conclusion: In this thesis synthesis, characterization, anti-inflammatory and anticancer activity evaluation of more than one hundred forty compounds is reported. Compounds IIIg (Chapter 2), VIbx, VIex, VIcx, VIdx, IVe (Chapter 5) and VIIzd (Chapter 4b) exhibited anti-inflammatory activity comparable or better than standard drug ibuprofen. Compounds IIIh, IIIi (Chapter 2) against lung (NCI H-522); IIIf, IIIh, IIIi, IIIf (Chapter 2) against ovary (PA-1); IIIh (Chapter 2) against breast (T47D); IIIh (Chapter 2) against colon (HCT-15) and IIIa (Chapter 2), VIxc (Chapter 4b), IIIh, IVf (Chapter 5) against liver (HepG2) exhibited good anticancer activity against various cancer cell lines mentioned above. One compound IIIh (Chapter 2) exhibited good anticancer activity against all the cancer cell lines screened except one i.e. liver (HepG2) cancer cell line. Compounds which exhibited good anti-inflammatory and anticancer activities can be candidate for further studies. From the work reported in this thesis three research papers have been published and three are under review in various international journals.