Title of Invention

"2-ALKYL 4,5 DISUBSTITUTED 6- METHOXYPRIMAQUINONE ANALOGUES"

Abstract

The present invention relates to design and synthesis of potential antimalarial agents These 8 - aminoquinoline class of compounds resulting from a unique and direct derivitazation at the C-2 position of the quinoline ring are expected to offer improvement over the existing chemotherapeutic approaches to malaria treatment by exerting their biological action on the parasite that may be present in the blood, tissues or blood and tissues of the host

Full Text

The present invention relates to design and synthesis of potential antimalarial agents. The present invention particularly relates to synthesis of 2 - alkyl-4,5-disubstituted -6-methoxyprimaquine analogues having the formula 1 which are expected to offer an improved means for the chemotherapy of malaria. (Formula Removed) Where R represents H, straight chain alkoxy groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups, R1 represents H, CH3, C2H5, R2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyl group containing 3 to 15 carbon atoms, R3 represents various (R) - and (S ) -amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt - forming acid may be organic or inorganic in nature. These 8 - aminoquinoline class of compounds resulting from a unique and direct derivitazation at the C-2 position of the quinoline ring are expected to offer improvement over the existing chemotherapeutic approaches to malaria treatment by exerting their biological action on the parasite that may be present in the blood, tissues or blood and tissues of the host. It is expected that development of these compounds with such broad spectrum of activity as antimalarials will lead to molecules which may provide single drug treatment for the suppression as well as radical cure for all species of human malaria infection. BACKGROUND OF THE INVENTION An infectious disease crisis of global proportion is today threatening health care system of many countries. Malaria, caused by protozoan belonging to the genus Plasmodium, is one of the most severe parasitic diseases. According to the World Health Organization (WHO) estimates, nearly four billion people, mostly in the tropical/impoverished countries, are at the risk of malaria. Each year 2-3 million people, mostly youngsters, in more than one hundred countries die from malaria, and its associated complications. Most malaria deaths occur in sub-Saharan Africa, where malaria accounts for one in five of all childhood deaths. Women are especially vulnerable during pregnancy. They are more likely to die from the disease, suffer miscarriages or give birth to premature, low-weight babies (Kevin, B. J. Drugs, 59, p 719, 2000). In India alone, 2.5-2.8 million clinical cases of malaria are reported annually. Civil conflicts, large-scale human migrations, climatic and environmental changes, inadequate and deteriorating health systems, growing insecticide and drug resistance have all combined to bring about the resurgence of malaria. Hence, malaria remains a major burden to human health in tropical and subtropical areas. The estimated global annual cost (in 1995) for malaria is about US $ 2 billion including that for loss of labor. However, ironically estimated annual expenditure on malaria research, prevention and treatment is approximately US $ 84 million, underlining the need for more efforts to combat this infectious disease. The four identified species of the parasite responsible for causing human malaria are Plasmodium falciparum, P. vivax, P. ovate and P. malariae. However, P. falciparum and P. vivax account for more than 95% of malaria cases in the world, and P. falciparum causes most problems as a result of its prevalence, virulence and drug resistance, and nearly all deaths are attributed to this single parasite species. Malaria infections caused by P. falciparum are prevalent in the major parts of Africa, sub-Saharan Africa and East Asian countries, whereas P. vivax is the causa- oecies primarily of Indian sub-Continent. The disease can be treated in j^i. 48 hours, yet it can cause fatal complications, if the diagnosis and treatment are delayed. Malaria is re-emerging as the biggest infectious killer and is currently the first priority tropical disease of the World Health Organization. Life cycle of malaria parasite has various stages, and each stage has different degree of susceptibility to available antimalarial agents. The currently available antimaiariat agents are conveniently divided into following two categories i.e. blood-schizontocidal antimalarial agents, which exert their biological activity against the erythrocytic asexual (blood) stages of the malaria parasite, and tissue-schizontocidal antimalarial agents, which exert their antimalarial action on the asexual exoerythrocytic (tissue) stages of the human malaria parasite. All of the available antimalarial drugs are losing their power to treat infection and have become inadequate for the treatment of malaria infection. P. falciparum has developed resistance against majority of blood-schizontocides such as chloroquine ana mefloquine. On the other hand, available tissue-schizontocide such as primaquine is relatively ineffective against the blood schizonts. Additionally, the toxicity of primaquine requires it to be given in divided doses over 14 days to achieve radical curative effects in humans. These problems could be alleviated by the development of compounds, which, while retaining the tissue-schizontocidal activity of 8-aminoquinolines, have increased blood-schizontocidal activity comparable to that of chloroquine and mefloquine. This would enable single drug treatment for suppression as well as radical cure of the malaria infection. The logical lead compound for this research is primaquine supported by following observations: (1) 8-aminoquinolines is the only class of compounds proven to be successful for the treatment of relapsing malaria; (2) the 8-aminoquinolines, such as primaquine are easily synthesized and inexpensive to produce; (3) the 8-aminoquinolines, such as primaquine is the only drug available to exhibit activity against all the stages including that of blood- and tissue-stages of the human malaria life cycle; (4) the 8-aminoquinoline, primaquine has been shown to be effective against drug resistant strains of P. falciparum. Cesoite research efforts of more than GO years malaria is still one of the major killer of the world. Majority of people suffering from malaria belong to poorer section of society/countries, and are unable to afford expensive treatment. One of the factors for the development of resistance to the majority of drugs is believed to be the poor patient compliance. Therefore, elimination of expensive multi-drug therapies, with single drug will help in reducing the cost of treatment. This reduction in the cost would lead to more patient compliance. This would give better results in the prevention, spread and treatment of malaria. The main object of the present invention is to provide ring-substituted 8 - minoquinolines with in vivo antimalarial activity in the range of 10- 100 mg/kg against P. berghei infected mice model. The other main object of the present invention is to provide ring-substituted 8- aminoquinolines with in vivo antimalarial activity in the range of 10 - 100 mg/kg against resistant P. yoelii infected mice model. The other main object of the present invention is to provide a process for preparation of ring-substituted 8 - aminoquinoiine. Another object of the present invention is to provide the ring substituted 8- aminoquinoline having LD50 value above 400 mg per body weight value. Yet another object of the present invention is to provide the peptide derivatives of 8 - aminoquinolines with reduced toxicity. Accordingly, the present invention provides design and synthesis of potential antimalarial agent of formula 1(Formula Removed) wherein R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups, Ri represents H, CH3, C2H5, R2 represents straight chain alkyl group containing 1 to 5 carbons, branched aikyl groups, and cycloalkyl group containing 3 to 15 carbon atoms, Ra represents various (R)- and (S)-amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt-forming acid may be organic or inorganic in nature which comprises; a. reacting 8-nitroquinolines with alkyl carboxylic acid in presence of sulphuric acid, silver nitrate and ammonium persulphate in aprotic solvent at reflux temperature for a period in the range of 5 min t olhr, isolating the ring substituted 8 - nitroquinoline from the reaction mixture b. reducing the ring-substituted 8 - nitroquinoline obtained in step (a) with a noble catalyst and hydrogen under pressure to give ring- substitued 8 - aminoquinoline, c. reacting ring substituted 8 - aminoquinoline with 2-(4-bromopentyl)- 1,3-isoindolinedione and triethylamine at a temperature ranging between 100-140 C for a period in the range of 3-8 hrs to provide isoindolinedione derivative, d. reacting the isoindolinedione derivative obtained in step ( c) with hydrazine-hydrate in alcoholic solvent to give ring substituted N8-(4- amino-1-methylbutyl)-8-quinolinamine e. reacting N8-(4-amino-1-methylbutyl)-8-quinolinamine obtained in step (d) with N-protected aminoacid and dicyclohexylcarbodimide in chloroalkane solvent at a temperature ranging between 10-50 C , isolating the ring substituted protective aminoacid quinoline derivative followed by deprotection of aminoacid moiety in the molecule to give compound of formula 1. In an embodiment of the present invention the alkyl carboxylic acid is selected from a group consisting of tri-methyl acetic acid . sobutyric acid, cyclo-hexane carboxylic acid , cyclopentane carboxylic acid, 1-adamantanecarboxylic acid. In another embodiment of the present invention 8-nitroquinoime is selected from 6-methoxy-8-nitroquinoline , 5,6-dimethoxy-8-nitroquinoline , 4-ethyl-5-pentoxy-6-methoxy-8-nitroquinoline, 4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline, 4-methyl-5,6-dimethoxy-8-nitroquinoline, In yet another embodiment of the present invention the catalyst used for the reduction step (b) is raney-nickel. In yet another embodiment of the present invention the reauction is carried out at a pressure in the range of 40-50 psi in a Parr hydrogenator. In yet another embodiment of the present invention alcoholic solvent used-is ethyl alcohol. In yet another embodiment of the present invention the cnloro-alkane solvent is selected from dichloro-methane, chloroform, and dichloroethane. In yet another embodiment of the present invention the deorotection of bezyl- esters in aminoacid moiety in the molecule in step (e) is carried out in presence of Pd-C in methanol in presence of hydrogen gas. In yet another embodiment of the present invention the deprotection of t-Boc protected aminoacid is carried out in presence of methanolic HCI. In yet another embodiment of the present invention the preferred compounds of formula 1, wherein the value of R, R1, R2 and R3 are given below: (Table Removed) In yet another embodiment of the present invention the compounds of formula 1 are active in mice against P. berghei infection at a dose ranging between 10-1 OOmg for 4 days. In yet another embodiment of the present invention the compounds of formula 1 are active in mice against P. yoelii infection at a dose ranging between 10-1 OOmg for 4 days. In yet another embodiment of the present invention the LD5o compounds of formula 1 is above 400mg per kg of body weight. DETAILED DESCRIPTION OF THE INVENTION Most of the available antimalarial drugs are incapable and ineffectual for the treatment of malaria infection. Development of resistance by P. falciparum has been documented against majority of blood-schizontocides. Furthermore, available tissue-schizontocides are high : Primaquine. A^-^-amino-l-methylbutyO-G-methoxy-S-quinoiinamine. is highly effective tissue-schizontocidal agent, and has direct and fast gametocytocidal action on ail species of malarial parasite. The drug also has blood-schizontocida! activity but only at dangerously toxic doses for human use. its nigh toxicity profile [methemogiobinemia and hemolysis particularly in individuals who are genetically deficient of glucose-6-phosphate aehydrogenase (G-6PD)] has largely deterred clinician from its safer use. Our attention was drawn to a recent publication (LaMontagne, M P.. Blumbergs, P.. Smith D. C. J. Med. Chem. 32, p 1728, 1989), where placement of a methoxy group at the C-2 position of the quinoline ring in a pnmaquine derivative produced an analogue far superior with exceptional tissue- and blood-schizontocidal activities. There are three earlier reports on the synthesis cf 2-substituted primaquine derivatives [Shetty, R. V., Wetter, W. P., Blanton, C. D. J. Med. Chem. 20. p 1349, 1977, where substitution at C-2 position are various benzyloxy and benzylthio groups], [Shetty, R. V., Blanton, C. D. J. Med. Chem. 21, p 995, 1978, where substitution at C-2 position are CH2C6H5, OCH3, NH2, N(CH3)3, Cl, C2H5. CH=CH2, NHCOCH3] and [Carroll, F I, Berrang, B. D., Linn, C. P. J. Med. Chem. 23, p 581, 1980, where substitution at C-2 position are C2H5, CH=CH2, CH3, CH2CH2Br). However, none of these compounds exhibited superior biological activities. The present invention describes the utilization of a radical homolytic free radical reaction [Scheme 1] to provide novel 2-alkyl-8-aminoquinoline, 5-alkyl-8-aminoquinoline and 2,5-dialkyl-8-aminoquinoline derivatives and the surprisingly strong broad-spectrum antimalarial activities of the analogues belonging to 2-alkyl-8-aminoquinoline series. The requisite 8-nitorquinolines required for the synthesis of ring-substituted-8-nitroquinolines (Scheme 1) are synthesized from appropriate nitroanilines by Skraup synthesis following the procedures reported earlier (Jain, R., Jain, S., Gupta, R. C., Anand, N., Dutta, G. P. and Puri, S. K. Ind. J. Chem. 33B, p 251, 1994). (Figure Removed) Scheme 1. i. R2C02H. AgNO3. (NH4)2S2OS, 10% H2SO4/CH3CN; ii. raney-Ni/H2; iii. 2-(4-bromopentyl)-1 3-isoindolinedione. Et3N; iv. (a) NH2NH2, EtOH, (b) Boc/Z-AA-OH. DCC. (c) MeOH/HCI or Pd-C. H,, RTP 8-Nitroquinolines on silver catalyzed radical oxidative decarboxylation of alkylcarboxylic acids by ammonium persulfate in 10%H2SO4 as solvent based upon the procedures reported by us earlier for ring-substituted bioimidazoles (Jain. R., Cohen, L. A. King, M. M., El-Kadi, N. Tetrahedron, 53, p2365, 1997. Tetrahedron, 53, p4539, 1997) led to a unique homolytic free radical initialed direct ring alkylation, and readily provided mono and dialkylated 8-nitroquinolines in 60-65% yield. /v*-(4-Amino-1-methylbutyl)-2-alkyl-6-methoxy-8-quinolinamine derivatives (1, R3=H), /v*-(4-amino-1-methylbutyl)-5-alkyl-6-methoxy-8-quinolinamine (1, R3=H) and /v*-(4-amino-1-methylbutyl)-2,5-dialkyl-6-methoxy-8-quinolinamine derivatives (1, R3=H) were synthesized from appropriate 2-alkyl/5-alkyl/2,5-dialkyl-6-methoxy-8-nitroquinoline derivatives in three steps following the procedures reported earlier (Jain, R., Jain. S., Gupta, R. C., Anand, N., Dutta, G. P. and Puri, S. K. Ind. J. Chem. 33B, p251, 1994). Primaquine is known to have poor pharmacokinetic properties. Furthermore, the drug has a short half-life (4-6 h), low therapeutic index and high toxicity, which are the limiting factors in its use as an ideal drug. These limitations can be modified by a prodrug approach, which involves appropriate chemical modification of the drug. A prodrug is a pharmacologically inactive derivative of a parent drug molecule that r ss spontaneous or enzymatic transformation within the body in order 10 release the active drug that may also have improved biological properties over the parent drug molecule. It has, in fact, been shown that linking the primaquine to small peptides resulted in the formation of compounds, which possess reduced toxicity and a longer naif-life compared to primaquine. Furthermore, we have earlier demonstrated that linking arnino acids to the side chain at C-8 position of the quinoiine ring is found to increase the biological activity with reduced toxicity (Hofsteenge, j.. Capuano, A., Altszuler, R.; Moore, S. J. Med. Chem. 29. p 1765. 1986, Philip, A., Kepler, J. A., Johnson, B. H., Carroll, F. I. J. Med. Chem. 31. p 870, 1988). Therefore, a variety of amino acid derivatives of ring-substituted primaquine derivatives as their prodrugs were also synthesized. Thus. 8-aminoqumolines compounds (1, R3= H) on reaction with Z- or Boc-protected amino acids in the presence of 1,3-dicyclohexylcarbodiimide (DCC) in anhydrous dichloromethane afforded the protected compounds in quantitative yield. Removal of protective group either by catalytic hydrogenation in the presence of 10% Pd-C or acid hydrolysis as in the case of Boc-group provided the ring-substituted A/1-[4-(6-methoxy/5-alkoxy-6-methoxy/-4-alkyi-8-qumolylamino)pentyl]-2-amino-2-substituted acetamides [1, R3= various (R)-and (S)-amino acids, L-unnatural amino acids] in quantitative yield. The process of preparation of 8-aminoquinoline analogues is claimed and disclosed in our co-pending application nf-429-02. The following examples are given by way of illustration and should not construed the scope of the invention. EXPERIMENTAL Example 1 Synthesis of 2-fert-Butyl-6-methoxy-8-nitroquinoline 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH3CN (5 ml) while reaction mixture was warmed to 70 °C. Silver nitrate (0.6 mmol), trimethylacetic acid (2.5 mmol), and 10% H2SO4 (10 mL) was then added to the reaction mixture. A freshly prepared solution of ammonium persulfate (3 mmol) in water (10 mL) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH4OH. Extracted with ethyl acetate (4x50 ml), and combined extracts were washed with NaCI solution (2x10 ml). Dried over Na2SCU and solvent removed in vacua to afford oil. which on flash column chromatography over silica gel (230-400 mesh) gave 2-te/t-Buty!-6-methoxy- 8-nitroquinoline in good yield. Yield: 62%; IR (KBr): 1529 and 1362 cm'1 (NO2); 1H NMR (CDCI3): 6 8.03 (d, 1H, 4-Ar-H, J = 8.7 Hz), 7.62 (d, 1H, 3-Ar-H, J- 2.7 Hz) 7.58 (d, 1H, 7-Ar-H, J- 8.8 Hz), 7.23 (d, 1H, 5-Ar-H, J= 2.5 Hz), 3.96 (s, 3H, OCH3), 1.41 (s, 9H, 3 x CH3) 13C NMR (CDCI3): 5 155.5. 134.65, 128.10, 120.2, 115.4, 109.1, 56.1, 38.3. 29.8; MS (El): m/z 260 (M+). Examples listed below are prepared using the protocol described above and by reacting 5,6-dimethoxy-8-nitroquinolines with trimethylacetic acid, cyclohexanecarboxylic acid and isobutyric acid respectively. Example 2 2-fert-Butyl-5,6-dimethoxy-8-nitroquinoline Yield: 55%; IR (KBr): 1528 cnV1 and 1349 cm'1 (NO2); 1H NMR (CDCI3): 6 8.05 (d, 1H. 4-Ar-H, J= 9 Hz), 7.89 (s, 1H, 7-Ar-H), 7.60 (d, 1H, 3-Ar-H, J= 9 Hz), 4.07 (s, 3H, 5-OCH3), 4.02 (s, 3H, 6-OCH3), 1.42 (s, 9H, 3xCH3); HRMS (ESI):291.2(M+1). Example 3 2-Cyclohexyl-5,6-dimethoxy-8-nitroquinoline Yield: 57%; IR (KBr): 1540 and 1375 cm'1 (NO2); 1H NMR (CDCI3): 5 7.94 (d, 1H, 4-Ar-H, J= 9 Hz), 7.75 (s, 1H, 7-Ar-H), 6.93 (d, 1H, 3-Ar-H, J= 9.Hz), 3.98 (s, 3H, 5-OCH3), 3.97 (s, 3H, 6-OCH3), 2.92 (m, 1H, CH), 1.25 (s, 10H, 5xCH2);MS(EI):m/z316(M+). Example 4 2-lsopropyl-5,6-dimethoxy-8-nitroquinoline Yield: 55%; IR (KBr): 1565 and 1340 cm'1 (NO2); 1H NMR (CDCI3): 5 7.87 (dd, 1H, 4-Ar-H, J= 8.9 Hz), 7.65 (s, 1H, 7-Ar-H), 6.86 (d, 1H, 3-Ar-H, J= 8.9 Hz), 4.08 (s, 3H, 5-OCH3), 4.02 (s, 3H, 6-OCHO, 3.12 (m, 1H, CH), 1.25 (s, 6H, 2xCH3), MS (El): m/z 276 (M+). Example 5 -fert-Butyl-4-ethyl-5-pentoxy-6-methoxy-8-nitroquinoline This compound was synthesized using above-mentioned procedure and 4- ethyl-5-pentoxy-6-methoxy-8-nitroquinoline as the starting material in the presence of trimethyl acetic acid. Yield: 42%; IR (KBr): 1550, 1345 cm'1 (NO2); 1H NMR (CDCI3): 6 7.47 (s, 1H, 7-Ar-H), 7.18 (s, 1H, 3-Ar-H), 4.03 (t, 2H, OCH2), 3.90 (s, 3H, OCH3), 3.18 (q, 2H, CH2), 1.80 (m, 4H, 2xCH2), 1.33 (m, 2H, CH2), 1.32 (s, 3H, 3xCH3), 0.82 (t, 3H, CH3); MS (APCI): m/z 375 (M+1). Example 6 2-tert-Butyl-4-ethyl-5-octoxy-6-methoxy-8-nitroquinoline This compound was synthesized using above-mentioned procedure and 4- ethyl-5-octoxy-6-methoxy-8-nitroquinoline as the starting material in the presence of trimethylacetic acid. Yield: 35%; IR (KBr): 1522 and 1345 cm'1 (NO2); 1H NMR (CDCI3): 5 7.75 (s, 1H, 7-Ar-H), 7.33 (s, 1H, 3-Ar-H), 4.10 (t, 2H, OCH2), 3.98 (s, 3H, OCH3), 3.25 (q, 2H, CH2), 1.64 (m, 2H, CH2), 1.52 (m, 6H, 3xCH2), 1.31 (s, 9H. 3xCH3), 0.88 (t, 3H, CH3); MS (APCI): m/z 417 (M+1). Example 7 2-tert-Butyl-4-methyl-5,6-dimethoxy-8-nitroquinoline This compound was synthesized using above-mentioned procedure and 4- methyl-5,6-dimethoxy-8-nitroquinoline as the starting material in the presence of trimethylacetic acid. Yield: 45%; IR (KBr): 1525 and 1340 cm 1 (NO2); 1H NMR (CDCI3): 5 7.74 (s, 1H, 7-Ar-H), 7.29 (s, 1H, 3-Ar-H), 4.00 (s, 3H, 5-OCH3), 3.96 (s, 3H, 6-OCH3), 2.87 (s, 3H, CH3), 1.38 (s, 9H, 3xCH3), MS (APCI): m/z 305 (M+1). Example 8 Synthesis of 2-adamantyl-6-methoxy-8-nitroquinoline 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH3CN (5 ml) while reaction mixture was warmed to 70 °C. Silver nitrate (0.6 mmol), 1- adamantanecarboxylic acid (2 mmol), and 10% H2SO4 (10 ml) was then added to the reaction mixture. A freshly prepared solution of ammonium persulfate (3 mmol) in water (10 ml) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH4OH. Extracted with ethyl acetate (4x50 ml), and combined extracts were washed with NaCI solution (2x10 ml). Dried over Na2S04 and solvent removed in vacua to afford oiL which on flash column chromatography over silica gel (230-400 mesh) gave 2-adamantyl-6-methoxy-8-nitroquinoline in good yield. Yield: 70%; IR (KBr): 1527 cm"1 (NO2); 1H NMR (CDCI3): 5 8.04 (d, 1H, 4-Ar-H. J= 8.7 Hz), 7.61 (d, 1H, 7-Ar-H, J= 2.2 Hz), 7.56 (d, 1H, 3-Ar-H. J= 8.7 Hz), 7.23 (d, 1H, 5-Ar-H, J= 2.4 Hz), 3.95 (s, 3H, OCH3), 2.12 (m, 15H. 12xCH2 and CH); 13C NMR (CDCI3): 5 168.92, 155.49, 134.58, 128.19, 119.84, 115.31, 109.04,56.11,41.57,39.97,36.74,28.67; HRMS (ESI): 339 (M+1). Synthesis of 5-Cyciopentyl-6-methoxy-8-nitroquinoiine and 2,5-dicyclopentyl-6-methoxy-8-nitroquinoline 6-Methoxy-8-nitroquinoline (1 mmol) (scheme 1) was dissolved in CH3CN (5 ml_) while reaction mixture was warmed to 70 °C. Silver nitrate (0.6 mmol), cyclcpentanecarboxylic acid (2.5 mmol), and 10% H2SO4(10 ml) was then added to the reaction mixture. A freshly prepared solution of ammonium persulfate (3 mmol) in water (10 ml) was added drop wise to the pre-heated (70 °C) mixture during 10 minutes. The heating source was then removed and reaction proceeded with evolution of carbon dioxide. After 10 minutes, reaction mixture was poured onto ice, and resulting mixture was made alkaline with addition of 30% NH4OH. Extracted with ethyl acetate (4x50 ml), and combined extracts were washed with NaCI solution (2x10 ml). Dried over Na2S04 and solvent removed in vacua to afford a mixture of mono and dicyclopentyl derivative that was separated by flash column chromatography over silica gel (230-400 mesh) to provide 5-Cyclopentyl-6-methoxy-8-nitroquinoline and 2,5-dicyclopentyl-6-methoxy-8-nitroquinoline. Example 9 5-Cyclopentyl-6-methoxy-8-nitroquinoline Yield: 52%; IR (KBr): 1535 and 1215 cm"1 (N02); 1H NMR (CDCI3): 5 8.82 (d, 1H, 2-Ar-H, J= 4.1 Hz), 8.06 (d, 1H, 4-Ar-H J= 8.3 Hz), 7.42 (m, 1H, 3-Ar-H), 7.14 (s. 1H, 7-Ar-H), 3.98 (s, 3H, OCH ' 3.15 (m, 1H, CH), 1.64 (m. 8H, 4xCH2) MS (El): m/z 272 (M+). Example 10 2,5-Dicyclopentyl-6-methoxy-8-nitroquinoline Yield: 10%; IR (KBr): 1545, 1388 cm"1 (NO2); 1H NMR (CDCI3): 6 8.09 (d. 1H, 4-Ar-H. J= 8 Hz), 7.47 (d, 1H. 3-Ar-H, J= 8 Hz). 7.17 (s, 1H, 7-Ar-H), 3.98 (s. 3H. OCH3), 2.82 (m, 2H, 2xCH), 1.74(m, 16H, 8xCH2); MS (E!): m/z 340 (M'). Examples listed below are prepared using the protocol described above, and by reacting 6-methoxy-8-nitroquinolines with isobutyric acid and cyclohexanecarboxylic acid respectively. Example 11 5-lsopropyl-6-methoxy-8-nitroquinoline Yield: 47%; IR (KBr): 1540 and 1388 cm"1 (NO2); 1H NMR (CDCI3): 5 8.79 (d, 1H, 2-Ar-H, J= 4.1 Hz), 8.07 (d, 1H, 4-Ar-H, J= 8.2 Hz), 7.4 (dd, 1H, 3-Ar-H, j= 8.2 Hz), 7.14 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3.19 (m, 1H, CH), 1.43 (d, 6H. 2xCH3); 13C NMR (CDCI3): 5 156.97, 149.81, 134.32, 132.13, 128.01, 122.74, 118.86, 106.61,56.27. 30.19,20.69; MS (El): m/z 246 (M+). Example 12 2,5-Diisopropyl-6-methoxy-8-nitroquinoline Yield: 12%; IR (KBr): 1545 and 1395 cm"1 (NO2); 1H NMR (CDCI3): 5 8.09 (d, 1H, 4-Ar-H, J= 8.4 Hz), 7.47 (d, 1H, 3-Ar-H, J= 8 Hz), 7.19 (s, 1H, 7-Ar-H), 3.99 (s, 3H, OCH3), 3.22 (m, 1H, 2xCH), 1.52 (d, 6H, 2xCH3), 1.48 (d, 6H, 2xCH3); MS (El): m/z 288 (M+). Example 13 5-Cyclohexyl-6-methoxy-8-nitroquinoline Yield: 43%; IR (KBr): 1533 and 1386 cm"1 (NO2); 1H NMR (CDCI3): 5 8.79 (d,. 1H, 2-Ar-H, J= 4 Hz), 8.05 (d, 1H, 4-Ar-H, J= 8.3 Hz), 7.43 (dd, 1H, 3-Ar-H, J= 8.2 Hz), 7.13 (s, 1H, 7-Ar-H), 3.99 (s, 3H, OCH3), 2.82 (m, 1H, CH), 1.67 (m, 10H, 5xCH2); 13C NMR (CDCI3): 5 156.37, 128.76, 127.54, 122.29, 106.23, 71.72. 55.87, 40.69, 29.63, 27.65, 26.71, 25. 73, 19.09; MS (El): m/z 286 (M+). Example 14 2,5-Dicyclohexyl-6-methoxy-8-nitroquinoline Yield: 11%; IR (KBr): 1537 and 1382 c'nT1 (NO2); 1H NMR (CDCI3): 5 8.09 (d, 1H, 4-Ar-H, J= 8.2 Hz), 7.49 (d, 1H, 3-Ar-H, J= 8.2 Hz), 7.12 (s, 1H, 7-Ar-H), 3.94 (s, 3H, OCH3), 2.87 (m, 1H, 2xCH), 1.77 (m, 20H, 10xCH2); MS (El): m/z 368 (M+). General procedure for the synthesis of ring-substituted 8- quinolinamines A solution of ring-substituted 8-nitroquinoline (5 mmol) in 95% ethanoi (20 ml) was hydrogenated over raney nickel (Ti grade) for ~6 h at 45 psi in a Parr hydrogenator. Catalyst was removed by filtration, and solvent was removed under reduced pressure to provide of ring-substituted 8-quinolinamines as oil, which were subjected to nest step reaction without any further purification. Example 15 2-tert-Butyl-6-methoxy-8-quinolinamine Yield: 86%; IR (KBr): 3480 and 3375 cm"1 (NH2); 1H NMR (CDCI3): 6 7.84 (d, 1H, 4-Ar-H; J= 8.6 Hz), 741 (d, 1H, 3-Ar-H, J- 8.S Hz), 6.54 (d, 1H, 7-Ar-H, J- 2.5 Hz), 6.43 (d, 1H, 5-Ar-H, J= 2.5 Hz), 4.98 (bs, 1H, NH2), 3.83 (s, 3Hr OCH3), 1.42 (s, 9H, 3xCH3); HRMS (ESI): m/z 231 (M+1). Example 16 2-Adamantyl-6-methoxy-8-quinolinamine Yield: 94%; IR (KBr): 3445-3353 cm "1 (NH2); 1H NMR (CDCI3): 6 7.89 (d, 1H, 4-Ar-H, J- 8.6 Hz), 7.41 (d, 1H, 3-Ar-H, J= 8.6 Hz), 6.55 (d, 1H, 7-Ar-H, J= 2.2 Hz), 6.45 (s, 1H, 5-Ar-H, J= 2.1 Hz), 5.21 (bs, 2H, NH2), 3.75 (s, 1H, OCH3) 2.29-1.75 (m, 15H, 12xCH2 and CH); 13C NMR (CDCI3): 5 163.30, 158.85, 145.86, 134.90, 130.89, 128.82, 118.38, 96.27, 91.65, 55.19, 42.10, 39.30, 37.81, 36.94, 31.94, 29.71, 28.89, 22.71, 14.64, 14.16; HRMS (APCI): m/z 309 (M+1). Example 17 5-Cyclopentyl-6-methoxy-8-quinolinamine Yield: 92%; IR (KBr): 2958 and 2928 cm"1 (NH2); 1H NMR (CDCI3): 5 8.58 (d, 1H, 2-Ar-H), 7.90 (d, 1H, 4-Ar-H), 7.26 (s, 1H, 3-Ar-H), 6.51 (s, 1H, 7-Ar-H), 5.09 (bs, 2H, NH2), 3.89 (s, 3H, OCH3), 3.57 (m, 1H, CH) 1.88 (m, 8H, 4xCH2); MS (El): m/z 242 (M+). Example 18 5-lsopropyl-6-methoxy-8-quinolinamin Yield: 95%; IR (KBr): 3330 cm'1 (NH2); 1H NMR (CDC!3): 5 7.71 (d. 1H. 2-Ar- H), 7.54 (d, 1H, 4-Ar-H), 6.76 (1H, d, 3-Ar-H), 6.53 (s, 1H, 7-Ar-H), 5.13 (bs, 2H. NH2), 4.22 (s, 3H. OCH3), 3.07 (m, 1H, CH), 1.39 (d, 6H. 2/CH3); MS (El): m/z 216 (M+). Example 19 5-Cyclohexyl-6-methoxy-8-quinolinamine Yield: 82%; IR (KBr): 3008 and 2926 cm'1 (NH2); 1H NMR (CDCI3): 6 8.59 (d, 1H. 2-Ar-H, J= A Hz), 7.92 (d, 1H. 4-Ar-H, J= 8.4 Hz), 7.26 (d, 1H, 3-Ar-H. J= 8.2 Hz), 6.50 (s, 1H, 7-Ar-H), 5.1 (bs, 2H, NH2), 3.89 (s, 3H, OCH3) 3.10 (m, 1H, CH), 1.69 (m, 10H, 5xCH2); MS (El): m/z 256 (M+). Example 20 2,5-Dicyclopentyl-6-methoxy-8-quinolinamine Yield: 90%; IR (KBr): 2930 cm'1 (NH2); 1H NMR (CDCI3): 6 7.92 (d, 1H, 4-Ar- H), 7.23 (s, 1H, 3-Ar-H), 6.57 (s, 1H, 7-Ar-H), 5.09 (bs, 2H, NH2), 3.89 (s, 3H, OCH3), 3.29 (m, 1H, 2xCH) 1.94 (m, 16H, 8xCH2); MS (El): m/z 310 (M+). Example 21 2,5-Diisopropyl-6-methoxy-8-quinolinamine Yield: 88%; IR (KBr): 3333 cm'1 (NH2); 1H NMR (CDCI3): 6 7.67 (d, 1H, 4-Ar- H), 6.90 (1H, d, 3-Ar-H), 6.77 (s, 1H, 7-Ar-H), 5.17 (bs, 2H, NH2), 4.15 (s, 3H, OCH3), 3.17 (m, 2H, 2xCH), 1.42 (d, 6H, 2xCH3), 1.37 (d, 6H, 2xCH3); MS (El): m/z 258 (M+). Example 22 2,5-Dicyclohexyl-6-methoxy-8-quinolinarnine Yield: 88%; IR (KBr): 3030 cm"1 (NH2); 1H NMR (CDCI3): 5 7.95 (d, 1H, 4-Ar- H), 7.28 (d, 1H, 3-Ar-H), 6.58 (s, 1H, 7-Ar-H), 5.14 (bs, 2H, NH2), 3.84 (s, 3H, OCH3) 3.23 (m, 2H, 2xCH), 1.77 (m, 20H, 10xCH2); MS (Ei): m/z 338 (M*). Example 23 2-fe/t-Butyl-5,6-dimethoxy-8-quinolinamine Yield: 100%; IR (KBr): 3461 crrT1 (NH2); 1H NMR (CDCI3): 5 8.32 (d, 1H, 4-Ar- H, J= 9 Hz), 7.52 (d, 1H, 3-Ar-H, J= 9 Hz), 6.81 (s, 1H, 7-Ar-H), 5.1 (bs, 2H, NH2), 3.95 (s, 3H, 5-OCH3), 3.88 (s, 3H, 6-OCH3) 1.51 (s, 9H, 3xCH3); HRMS (ESIV 261.2 (M+1). Example 24 2-Cyclohexyl-5,6-dimethoxy-8-quinolinamine Yield: 80%; IR (KBr): 3230 cm'1 (NH2); 1H NMR (CDCI3): 5 8.33 (d. 1H. 4-Ar- H. J= 9.4 Hz), 7.51 (d, 1H. 7-Ar-H. J= 9.5 Hz), 6.81 (s, 1H. 7-Ar-H). 5.17 (bs, 2H. NH2, exchangeable with D20), 3.95 (s, 3H, 5-OCH3), 3.88 (s, 3H. 6- OCH3),3.1 (m, 1H, CH), 1.45 (m, 10H, 5xCH2); MS (El): m/z 286 (MT). Example 25 2-lsopropyl-5,6-dimethoxy-8-quinolinamine Yield: 100%; IR (KBr): 3355 cm'1 (NH2); 1H NMR (CDCI3): 5 7.70 (d, 1H. 4-Ar- H). 7.23 (d, 1H, 3-Ar-H), 6.82 (s, 1H, 7-Ar-H), 5.71 (bs, 2H, NH2), 4.14 (s. 3H, 5- OCH3), 4.12 (s, 3H, 6-OCH3), 3.1 (m, 1H, CH), 1.2 (s, 6H, 2xCH3); MS (El): m/z 246 (M+). Example 26 2-tert-Butyl-4-ethyl-5-pentoxy-6-methoxy-8-quinolinamine Yield: 95%; IR (KBr): 3350 cm'1 (NH2); 1H NMR (CDCI3): 5 7.28 (s, 1H, 3-Ar- H), 6.92 (s, 1H, 7-Ar-H), 4.06 (t, 2H, OCH2), 3.93 (s, 3H, OCH3), 3.27 (q, 2H. CH2), 1.85 (m, 4H, 2xCH2), 1.39 (m, 2H, CH2), 1.40 (s, 3H, 3xCH3), 0.94 (t, 3H, CH3); MS (APCI): m/z 345 (M+1). Example 27 2-fert-Buytl-4-ethyl-5-octoxy-6-methoxy-8-quinolinamine Yield: 93%; %; IR (KBr): 3355 cm'1 (NH2); 1H NMR (CDCI3): 5 7.33 (s, 1H, 3- Ar-H), 6.97 (s, 1H, 7-Ar-H), 4.1 (t, 2H, OCH2), 3.97 (s, 3H, OCH3), 3.29 (q, 2H. CH2), 1.67 (m, 2H, CH2), 1.57 (m, 6H, 3xCH2), 1.41 (s, 9H, 3xCH3), 0.98 (t, 3H, CH3); MS (APCI): m/z 375 (M+1). Example 28 2-rert-Butyl-4-methyl-5,6-dimethoxy-8-quinolinamine Yield: 90%; IR (KBr): 3358 cm'1 (NH2); 1H NMR (CDCI3): 6 7.39 (s, 1H, 3-Ar- H), 6.99 (s, 1H, 7-Ar-H), 4.00 (s, 3H, 5-OCH3), 3.96 (s, 3H, 6-OCH3), 2.89 (s, 3H, CH3), 1.42 (s, 9H, 3xCH3), MS (APCI): m/z 275 (M+1). Typical procedure for the synthesis of ring-substituted 2-[4-(6-methoxy- 8-quinolinamino)pentyl]-1,3-isoindolined!ones A mixture of ring-substituted 8-quinolinarr .•'? (Q mmol), 2-(4-bromopentyl)-1,3- isoindolinedione (6.0 mmol) and triethylamine (6 mmol) was heated at 120 °C with stirring for 3 h. An additional quantity of 2-(4-bromopentyl)-1.3-soindoiinedione (6 mmol) and triethylamme (6 mmoi) was added and stirring .vas continued with heating for 4 h. A third equivalent of 2-(4-bromopentyl)-' 3-isomaolinedione (6 mmoi) and triethylamine (6 mmoi) was added, ana the -eaction mixture was neated at 120 °C for 16 h. The reaction mixture was then diluted with ethyl acetate (100 ml) and filtered. The filtrate was basified with 2N NaOH solution and extracted with ethyl acetate (3x50 ml). The combined extracts were washed with water (2x10 ml), dried over Na2SOd and concentrated under reduced pressure to yield a dark residue that was purified by flash column chromatography on silica gel (230-400 mesh) using ethyl acetate/hexane as eluant to provide ring-substituted 2-[4-(6-methoxy-8-quinolinamino)pentyl]-1,3-isoindoline-diones as oil. Example 29 2-[4-(2-fert-Butyl-6-methoxy-8-quinoiinamino)pentyl]-1,3-isoindolinedione Yield: 83%; IR (KBr): 3387 cm 1 (NH2), 1713 (C=0); 1H NMR (CDCI3): 6 7.83 'd, 1H. 4-Ar-H; J- 8.5 Hz), 7.80 (m. 4H. Ar-H), 7.41 (d, 1H, 3-Ar-H, J= 8.5 Hz), 5.27 (d, 1H, 7-Ar-H, J= 2.43 Hz), 6.24 (d, 1H, 5-Ar-H, J= 2.4 Hz), 6.13 (bs, 1H, NH), 3.75 (t, 2H, N-CH2), 3.62 (bs, 1H, N-CH), 1.86-1.61 (m, 4H, 2xCH2), 1.41 (s, 9H, 3 xCH3), 1.29 (d, 3H, CH3); 13C NMR (CDCI3): 6 168.39, 163.33, 158.81, 144.71, 134.97, 133.98, 133.50, 132.11, 132.07, 127.27, 123.16, 118.77, 96.75, 91.64, 55.18, 50.53, 47.99, 38.07, 37.97, 37.68, 37.17, 33.98, 30.25, 27.02, 26.46, 25.31, 20.59; MS (El): m/z445 (M+). Example 30 2-[4-(5-Cyclopentyl-6-methoxy-8-quinylamino)pentyl]-1,3-isoindolinedione Yield: 44%; IR (KBr): 1712 cm'1 (C=O); 1H NMR (CDCI3): 5 8.56 (d, 1H, 2-Ar-H, J= 2.8 Hz), 7.81 (m, 4H, Ar-H), 7.91 (d, 1H, 4-Ar-H, J= 7.8 Hz), 7.21 (m, 1H, 3-Ar-H), 6.65 (s, 1H, 7-Ar-H), 5.12 (bs, 1H, NH), 3.89 (s, 3H, OCH3), 3.69 (m, 3H, N-CH and N-CH2) 3.46 (m, 1H, CH), 2.02 (m, 4H. 2xCH2), 1.69 (m, 8H, 4xCH2), 1.22 (d, 3H, CH3); MS (El): m/z 457 (M+). Example 31 2-[4-(2-Adamantyl-6-methoxy-8-quinolylamino)pentyl]-1,3-isoindolinedione Yield: 56%; IR (KBr): 3363 cm'1 (NH), 1711 cm"1 (C=0); 1H NMR (CDCI3): 6 7.86 (d. 1H, 4-Ar-H), 7.81 (m. 4H. Ar-H), 7.38 (d, 1H. 3-Ar-H. J= 8.4 Hz). 6.27 id. 1H. 7-Ar-H), 6.25 (d. 1H, 5-Ar-H), 3.85 (s, 3H. OCH3), 3.69 (m. 3H. N-CH and N-CH2) 1.91 (m, 15H, 12xCH2 and CH), 1.6 (m, 4H, 2xCH2), 1.31 (d. 3H. CH3); 13C NMR (CDCI3): 6 168.39, 163.18, 158.78. 144.97. 134.85. 133.91, 127.58, 123.16, 118.39, 96.51, 91.54, 69.48, 55.17. 47.89. 42.05. 39.29, 38.79, 38.01, 37.82, 36.94, 34.001, 33.17, 28.88, 27.98, 25. 31, 24.60. 20.66, 19.93; HRMS (APCI): 524 (M+1). Example 32 2-[4-(5-lsopropyl-6-methoxy-8-quinolylamino)pentyl]-1,3-isoindolinedione Yield: 53%; IR (KBr): 3433 cm'1 (NH), 1709 cm'1 (C=O); 1H NMR (CDCI3): 5 8.57 (d, 1H, 2-Ar-H. J= 3.0 Hz), 8.10 (d, 1H, 4-Ar-H, J- 7.9 Hz), 7.83 (m, 4H, Ar-H), 7.37 (dd, 1H, 3-Ar-H. J= 8.0 Hz), 6.84 (s, 1H, 7-Ar-H), 4.81 (bs, 1H, NH), 3.86 (s, 3H, OCH3) 3.52 (m, 3H, N-CH and N-CH2), 1.70 (m, 2H, CH2), 1.46 (m, 2H, CH2), 1.32 (d, 6H, 2xCH3), 0.98 (d, 3H, CH3); 13C NMR (CDCI3): 167.76, 158.49, 145.49, 143.41, 138.41, 138.43, 134.47, 134.21, 131.26, 127.27, 127.05, 122.87, 121.08, 98.27, 54.41, 37.06, 34.06, 34.51, 27.86, 23.90, 20.55; MS (El): m/z431(M+). Example 33 2-[4-(5-Cyclohexyl-6-methoxy-8-quinylamino)pentyl]-1,3-isoindolinedione Yield: 63%; IR (KBr): 3387 cm'1 (NH), 1713 cm'1 (C=O); 1H NMR (CDCI3): 5 8.57 (d, 1H, 2-Ar-H), 7.84 (m, 4H, Ar-H), 7.81 (d, 1H, 4-Ar-H, J= 6 Hz), 7.26 (d, 1H, 3-Ar-H, J= 6 Hz), 6.64 (s, 1H, 7-Ar-H), 3.89 (s, 3H, OCH3), 3.68 (t, 2H, N-CH2) 3.32 (m, 1H, N-CH), 3.18 (m, 1H, CH), 2.22 (m, 4H, 2xCH2), 1.5 (m, 10H. 5xCH2), 1.1 (d, 3H, CH3); MS (El): m/z 501 (M+). Example 34 2-[4-(2,5-Diyclopentyl-6-methoxy-8-quinviamino)pentyl]-1,3-isoindolinedione Yield: 89%; IR (KBr): 1715 cm' (C=O); 1H NMR (CDCI3): 2-[4-(2,5-Diisopropyl-6-methoxy-8-quinolylamino)pentyi]-1.3-isoindolinedione Yield: 77%; IR (KBr): 3400 cm'1 (NH), 1715 cm'1 (C=O); 1H NMR (CDCI3): 6 8.12 (d. 1H, 4-Ar-H). 7.80 (m. 4H. Ar-H), 7.35 (d, 1H, 3-Ar-H), 6.87 (s, 1H, 7-Ar-H), 4.82 (bs, 1H. NH), 3.87 (s, 3H, OCH3) 3.53 (m, 3H, N-CH and N-CHZ), 3.10 (m, 2H, 2xCH), 1.73 (m, 2H, CH2), 1.49 (m, 2H, CH2), 1.39 (d, 6H, 2xCH3), 1.32 (d, 6H, 2xCH3), 0.98 (d. 3H. CH3); MS (El): m/z 473 (MT). Example 36 2-[4-(2,5-Dicyclohexyl-6-methoxy-8-quinylamino)pentyl]-1,3-isoindolinedione Yield: 88%; IR (KBr): 3360 cm'1 (NH), 1713 cm'1 (C=O); 1H NMR (CDCI3): 6 7.88 (d, 1H, 4-Ar-H), 7.23 (d, 1H, 3-Ar-H), 6.67 (s, 1H, 7-Ar-H), 3.88 (s, 3H, OCH3), 3.65 (t, 2H, N-CH2) 3.33 (m, 1H, N-CH), 3.15 (m, 2H, 2xCH), 2.22 (m, 4H, 2xCH2), 1.65 (m, 20H, 10xCH2), 1.17 (d, 3H, CH3); MS (El): m/z 553 (M+). Example 37 2-[4-(2-tert-Butyl-5,6-dimethoxy-8-quinolylamino)pentyl]-1,3-isoindolinedione Yield: 56.4%; IR (KBr): 3382 cm'1 (NH), 1712 cm'1 (C=O); 1H NMR (CDCI3): 5 8.20 (d, 1H, 4-Ar-H, J= 9 Hz), 7.82 (m, 4H, Ar-H), 7.46 (d, 1H, 3-Ar-H, J- 9 Hz), 6.38 (s, 1H, 7-Ar-H), 6.02 (bs, 1H, NH), 3.96 (s, 3H, 5-OCH3), 3.84 (s, 3H, 6-OCH3) 3.69 (t, 2H, N-CH2), 3.64 (m, 1H, N-CH), 1.73 (m, 4H, 2xCH2) 1.41 (s, 9H, 3xCH3), 1.31 (d, 3H, CH3); HRMS (ESI): 476.2 (M+1). Example 38 2-[4-{2-Cyclohexyl-5,6-dimethoxy-8-quinylamino)pentyl]-1,3-isoindolinedione Yield; 70%; IR (KBr): 3350 cm'1 (NH,' 1720 cm'1 (C=O); 1H NMR (CDC,:,: 5 8.22 (d, 1H, 4-Ar-H, J= 9.2 Hz), 7.75 (m, 4H, Ar-H), 7.46 (d, 1H, 3-Ar-H, J= 9.2 Hz). 6.39 (s, 1H. 7-Ar-H), 6.0 fbs. 1H, NH), 3.96 (s, 3H, 5-OCH3), 3.84 (s, 3H, 6-OCH3) 3.69 (t, 2H, N-CH2), 3.64 (m, 1H, CH). 1.75 (m, 4H. 2 CH2) 1.41 (m. 10H. 5xCH2), 1.35 (d. 3H, CH3); MS (El): m/z 501 (MT) 469. Example 39 2-[4-(2-lsopropyl-5,6-dimethoxy-8-quinolylamino)pentyi]-1,3- isoindolinedione Yield: 49%: IR (KBr): 3260 cm'"' (NH2), 1720 cm" (C=O); 1H NMR (CDCI3): 5 8.10 (d, 1H, 4-Ar-H, J= 7.9 Hz), 7.82 (m, 4H, Ar-H), 7.40 (m, 5H. Ar-H), 7.37 (dd, 1H. 3-Ar-H, J= 8.0 Hz), 6.84 (s, 1H, 7-Ar-H), 4.81 (bs, 1H, NH), 3.97 (s, 3H. 5-OCH3), 3.86 (s. 3H, 6-OCH3) 3.52 (m, 3H, N-CH and N-CH?), 1.70 (m, 2H, CH2), 1.46 (m, 2H, CH2), 1.32 (d, 6H, 2xCH3), 0.98 (d, 3H. CH3); MS (El): m/z 462 (M*). Example 40 2-[4-(2-fert-Butyl-4-ethyl-6-methoxy-5-pentoxy-quinolin-8-yiamino)- pentyl]-isoindole-1,3-dione Yield: 67%; yellow oil; IR (KBr): 3379 cm'1 (NH2), 1712 (C=O); 1H NMR (CDCI3): 7.82 (m, 2H, Ar-H), 7.71 (m, 2H, Ar-H), 7.10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.75-3.67 (m, 3H, N-CH, and N-CH2), 3.24 (m, 2H, CH2), 1.85-1.41 (m, 10H, 5 x CH2), 1.34 (s, 9H, 3xCH3), 1.3 (m, 6H, 2 x CH3), 0.95 (t, 3H, CH3, J= 7.9 Hz); HRMS (APCI): m/z 560 (M+1). Example 41 2-[4-(2-te/t-Butyl-4-ethyl-6-methoxy-5-octoxy-quinolin-8-ylamino)-pentyl]-isoindole-1,3-dione Yield: 75%; yellow oil; IR (KBr): 3407 crrf1 (NH2), 1713 (C=O); 1H NMR (CDCI3): 7.82 (m, 2H, Ar-H), 7.71 (m, 2H, Ar-H), 7.10 (d, 1H, 3-Ar-H, J= 4.4 Hz), 6.44 (s, 1H, 7-Ar-H), 6.07 (bs, 1H, NH), 3.96 (s, 3H, OCH3), 3.87 (t, 2H, OCH2, J= 6.9 Hz), 3.75-3.67 (m, 3H, N-CH, and N-CH2), 3.25 (m, 2H, CH2), 1.89-1.61 (m, 16H, 8 x CH2), 1.37 (m, 9H, 3xCH3), 1.30 (m, 6H, 2 x CH3), 1.04 (t, 3H, CH3, J= 7.9 Hz); HRMS (APCI): m/z 602 (M+1). Example 42 2-[4-(2-tert-Butyl-5,6-methoxy-4-methyi u.nolin-8-ylamino)-pentyl]-isoindole-1,3-dione Yield: 87%; yellow oil; IR (KBr): 3410 cm"1 (NH2), 1713 fC=O); 'H NMR (CDCI3): 7.85 (m, 2H, Ar-H), 7.75 (m, 2H, Ar-H), 7.13 (d, 1H. 3-Ar-H, J= 4.4 Hz), 6.49 (s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 4.01 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 3.63 (m, 3H. N-CH, and N-CH2), 2.59 (t. 2H, CH2), 1.60 (m 4H, 2xCH2), 1.34 (s, 9H, 3xCH3). 1.23 (m. 3H, CH3); HRMS (APCI): m/z 504 (M+1). Typical procedure for the synthesis of ring-substituted A/8-(4-Amino-1-methylbutyl)-6-methoxy-8-quinolinamine To a solution of ring-substituted 2-[4-(6-methoxy-8-quinolinamino)pentyl]-1,3-isoindolinedione (4 mmol) in 95% ethanol (20 ml), was added hydrazine hydrate (100 mmoi) and the reaction mixture was stirred with refluxing for 6 h. Solvent was removed under reduced pressure and the residue was diluted with water (20 ml). The reaction mixture was basified with 8N NaOH solution, extracted with chloroform (3x20 ml), washed with water, dried over sodium sulfate and concentrated under reduced pressure to yield ring-substituted N8-(4-amino-1-methylbutyl)-6-methoxy-8-quinolinamine (14) as oil, which on treatment with ethereal Hydrochloric acid provided ring-substituted A/8-(4-amino-1-methylbutyl)-6-methoxy-8-quinolinamine dihydrochloride. Example 43 A/8-(4-Amino-1-methylbutyl)-2-tert-butyl-6-methoxy-8-quinolinamine Yield: 90%; IR (KBr): 3393 cm'1 (NH), 3019-2968 cm'1 (amine); 1H NMR (free base, CDCI3): 6 7.84 (d, 1H, 4-Ar-H, J= 8.6 Hz), 7.42 (d, 1H, 3-Ar-H, J= 8.5 Hz), 6.30 (dd, 1H, 7-Ar-H, J= 2.3 Hz), 6.25 (dd, 1H, 5-Ar-H, J= 2.2 Hz), 6.16 (bs, 1H, NH), 3.87 (s, 3H, OCH3), 3.61(bs, 1H, N-CH), 2.73 (t, 2H, N-CH2), 1.59 (m, 4H, 2xCH2), 1.42 (s, 9H, 3xCH3), 1.31 (d, 3H, CH3); 13C NMR (CDCI3): 5 163.36, 158.83, 144.86, 134.96, 133.56, 127.48, 118.80, 96.71, 91.60, 55.19, 47.93, 41.22, 40.59, 37.70, 33.95, 30.28, 29.69, 27.67, 26.66, 20.72, 20.63; HRMS (ESI): m/z 316 (M+1). Example 44 W8-(4-Amino-1-methylbutyl)-5-cyclopentyl-6-methoxy-8-quinolinamine Yield: 62%; IR (KBr): 3294 cnV1 (NH); 2953-2864 cnT1 (amine); 1H NMR (free base, CDCI3): 8 8.59 (d, 1H, 2-Ar-H), 7.94 (d, 1H, 4-Ar-H), 7.26 (m, 1H, 3-Ar-H), 6.67 (s, 1H, 7-Ar-H), 3.89 (s, 3H, OCH3), 3.71 (m. 1H, N-CH) 3.48 (m, 2H, N-CH2) 3.12 (m, 1H, CH), 2.64 (m, 4H, 2xCH2) 1.75 (m, 8H, 4xCH2), 1.11 (d, 1H, CH3); MS (El): m/z 327 (IVT). Example 45 A/8-[4-Amino-1-methylbutyl)-2-adamantyl-6-methoxy-8-quinolinamine Yield: 88%; IR (KBr): 3384 cm ^1 (amme); 1H NMR (free base, CDCI3): 6 7.86 (d, 1H, 4-Ar-H, J= 8.6 Hz), 7.39 (d, 1H, 3-Ar-H, J= 8.6 Hz), 6.29 (d, 1H, 7-Ar-H), 6.26 (d, 1H, 5-Ar-H), 6.17 (bs, 1H, NH), 3.87 (s, 3H, OCH3), 3.59 (m, 1H, N-CH), 2.75 (m, 2H, N-CH2), 1.97 (m, 15H, 12xCH2 and CH) 1.32 (d, 3H, CH3); 13C NMR (CDCI3): 6 163.18, 158.84, 45.10, 134.90, 133.86, 127.63, 118.41, 96.43, 91.38, 69.94, 55.19, 48.10, 42.11, 39.30, 38.86. 36.95, 36.56, 34.19, 33.24, 30.17. 29.71, 28.89, 28.01, 20.69, 19.97; HRMS (ESI): 394 (M+1). Example 46 A/a-(4-Amino-1-methylbutyl)-5-isopropyl-6-methoxy-8-quinolinamine Yield: 61%; IR (KBr): 3422 cm'1 (NH); 1H NMR (free base, CDCI3): 5 8.61 (d, 1H. 2-Ar-H), 8.1 (d, 1H. 4-Ar-H), 7.61 (dd, 1H, 3-Ar-H), 7.11 (s, 1H. 7-Ar-H), 3.49 (s, 3H, OCH3), 3.25 (m, 3H, N-CH and N-CH2), 2.71 (m, 1H, CH), 1.52 (d, 6H, 2xCH3), 1.15 (d, 3H, CH3); MS (El): m/z 301 (M+). Example 47 /V8-(4-Amino-1-methylbutyl)-5-cyclohexyl-6-methoxy-8-quinolinamine Yield: 59%; IR (KBr): 3417 cm'1 (NH); 1H NMR (free base, CDCi3): 5 8.47 (d, 1H, 2-Ar-H), 7.97 (d, 1H, 4-Ar-H), 7.24 (d, 1H, 3-Ar-H), 6.68 (s, 1H, 7-Ar-H), 3.91 (s, 3H, OCH3), 3.73 (m. 1H, N-CH) 3.48 (m, 2H, N-CH2) 3.12 (m, 1H, CH), 2.64 (m, 4H, 2xCH2) 1.75 (m, 10H, 5xCH2), 1.11 (d, 1H, CH3); MS (El): m/z 341 (M*). Example 48 A/8-(4-Amino-1-methylbutyl)-2,5-dicyclopentyl-6-methoxy-8-quinolinamine Yield: 75%; IR (KBr): 3300 cm'1 (NH); 2955 cm'1 (amine); 1H NMR (free base, CDCI3): 5 7.98 (d, 1H, 4-Ar-H), 7.22 (d, 1H, 3-Ar-H), 6.61 (s, 1H, 7-Ar-H), 3.89 (s, 3H, OCH3), 3.71 (m. 1H, N-CH) 3.45 (m 2H, N-CH2) 3.15 (m, 2H, 2xCH), 2.65 (m.4H,2xCH2) 1.79 (m, 16H,8xCH 2 (d, 1H, CH3); MS (El): m/z 395 Example 49 A/8-(4-AmJno-1-methylbutyl)-2,5-diisopropyl-6-methoxy-8-quinolinamine Yield: 79%; IR (KBr): 3430 cm'1 (NH); 1H NMR (free base, CDCI,);.o 8.15 (d, 1H. 4-Ar-H), 7.65 (d, 1H, 3-Ar-H), 7.18 (s, 1H. 7-Ar-H). 3.45 (s. 3H. OCH3), 329 (m, 3H, N-CH and N-CH2), 2.73 (m, 2H, 2xCH), 1.55 id. 6H. 2xCH3), 1.54 (d, 6H, 2xCH3), 1.19 (d, 3H, CH3); MS (El): m/z 343 (M+). Example 50 A/s-(4-Amino-1-methylbutyl)-2,5-dicyclohexyl-6-methoxy-8-quinolinamine Yield: 55%; IR (KBr): 3400 cm'1 (NH); 1H NMR (free base, CDCI3): 6 7.93 (d, 1H. 4-Ar-H), 7.28 (d, 1H, 3-Ar-H), 6.75 (s, 1H, 7-Ar-H), 3.95 (s, 3H, OCH3), 3.71 (m. 1H, N-CH) 3.42 (m, 2H, N-CH2) 3.05 (m, 2H, 2xCH), 2.62 (m, 4H, 2xCH2)1.78(m, 20H, 10xCH2), 1.15(d, 1H, CH3); MS (El): m/z 423 (M+). Example 51 A/^^-Amino-l-methylbutyO-Z-tert-butyl-S^-dimethoxy-S-quinolinamine Yield: 96%; IR (KBr): 3388 cm'1 (NH), 2958 cm'1 (amine); 1H NMR (free base, CDCI3): 5 8.23 (d, 1H, 4-Ar-H, J= 9 Hz), 7.48 (d, 1H, 3-Ar-H, J= 9Hz). 6.40 (s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 3.97 (s, 3H, 5-OCH3), 3.86 (s, 3H, 6-OCH3) 3.62 (m, 1H, N-CH), 2.78 (t, 2H, N-CH2), 1.78 (m, 4H, 2xCH2), 1.42 (s, 9H, 3xCH3), 1.33 (d, 3H, CH3); MS (El): 345 (M+). Example 52 /V8-(4-Amino-1-methylbutyl)-2-cyclohexyl-5,6-dimethoxy-8-quinolinamine Yield: 67%; IR (KBr): 3310 cm'1 (NH2); 1H NMR (free base, CDCI3): 6 8.21 (d, 1H, 4-Ar-H, J= 9.2 Hz), 7.49 (d, 1H, 3-Ar-H, J= 9 Hz), 6.41 (s, 1H, 7-Ar-H), 6.03 (bs, 1H, NH), 3.97 (s, 3H, 5-OCH3), 3.86 (s, 3H, 6-OCH3) 3.62 (m, 1H, N-CH), 2.78 (t, 2H, N-CH2), 1.78 (m, 4H, 2xCH2), 1.42 (m, 10H, 5xCH2), 1.31 (d, 3H, CH3); MS (El): m/z 368 (M+). Example 53 A^^-Amlno-l-methylbutyO-Z-isopropyl-S.S-dimethoxy-S-quinolinamine Yield: 95%; IR (KBr): 3330 cm'1 (NH), 2900 cm'1 (NH2); 1H NMR (free base, CDCI3): 5 8.18 (d, 1H, 4-Ar-H, J= 7.8 Hz), 7.35 (m, 1H, 3-Ar-H), 6.87 (s, 1H, 7-Ar-H), 3.95 (s, 3H, 5-OCH3), 3.82 (s, 3H, 6-OCH3) 3.55 (m, 3H, N-CH and N- CH2), 1.70 (m, 2H, CH2), 1.46 (m, 2H, CH2), 1.32 (d, 6H, 2xCH3), 0.98 (d. 3H, CH3); HRMS (ESI): m/z 331 (M+1). Example 54 W3-(4-Amino-1-methylbutyl)-2-fert-butyl-4-ethyl-6-methoxy-5-pentoxy-8-quinolin-amine Yield: 98%; 1H NMR (free base, CDCI3): 5 6.91 (s, 1H, 3-Ar-H), 6.43 (s. 1H, 7-Ar-H), 3.94 (s, 3H, 5-OCH2), 3.73 (s, 3H, OCH3) 2.70 (m, 3H, N-CH and N-CH2), 2.60 (m, 2H, CH2), 1.50 (m, 6H, 3xCH2), 1.34 (s, 9H, 3xCH3), 1.30 (m, 4H, 2xCH2), 1.23 (m, 3H, CH3), 0.96 (m, 3H, CH3); HRMS (ESI): m/z 430 (M+1). Example 55 A/8-(4-Amino-1-methylbutyl)-2-tert-butyl-4-ethyl-6-methoxy-5-octoxy-8-quinolin-amine Yield: 99%; 1H NMR (free base, CDCI3): 5 6.95 (s, 1H, 3-Ar-H), 6.49 (s, 1H, 7~ Ar-H), 3.97 (s, 3H, 5-OCH2), 3.75 (s, 3H, OCH3) 2.72 (m, 3H, N-CH and N-CH2), 2.61 (m, 2H, CH2), 1.53 (m, 10H, 5xCH2), 1.35 (s, 9H, 3xCH3), 1.31 (m, 6H, 3xCH2), 1.21 (m, 3H, CH3), 0.99 (m, 3H, CH3), HRMS (ESI): m/z 472 (M+1). Example 56 W8-(4-Amino-1-methylbutyl)-2-te/t-butyl-5,6-methoxy-4-methyl-8-quinolinamine Yield: 89%; 1H NMR (free base, CDCI3): 5 6.99 (s, 1H, 3-Ar-H), 6.49 (s, 1H, 7-Ar-H), 3.73 (s, 6H, 2xOCH3) 2.79 (m, 3H, N-CH and N-CH2), 2.37 (s, 3H, CH3), 1.53 (m, 4H, 2xCH2), 1.35 (s, 9H, 3xCH3), 1.23 (m, 3H, CH3); HRMS (ESI): m/z 360 (M+1). Typical procedure for the synthesis of ring-substituted protected amino acid quinoline derivatives To an ice cooled stirred solution of ring-substituted A/8-(4-amino-1-methylbutyl)-6-methoxy-8-quinolinamine [(free base), 1 mol] and suitably A/protected amino acid (1.1 mol) in dichloromethane (15 ml), 1,3-dicyclohexylcarbodiimide (1.1 mol) was added. Reaction mixture was allowed to attain room temperature and stirring is continued for another 4 h. The reaction mixture was kept in refrigerator overnight and the separated 1,3- dicyclohexylurea (DCU) filtered, and filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and the additional quantity of separated DCU was again removed by filtration. The filtrate was washed with saturated sodium bicarbonate solution (3x10 ml) followed by water (2x10 ml), and dried over Na2SO4. The solvent was removed in vacua to afford the crude product, which was purified by flash column chromatography on silica gel (230-400 mesh) using 2% methanol in chloroform to afford the product. Example 57 {4-Benzyloxycarbonylamino-4-[2-fert-butyl-6-methoxy-quinolin-8-ylamino)-pentyl-carbamoyl]-butyl}-carbamic acid benzyl ester Yield: 98%; IR (KBr): 3430 cm'1 (NH), 1714 cm'1 (ester), 1666 cm 1 (amide carbonyl); 1H NMR (CDCI3): 6 7.85 (d, 1H, 4-Ar-H, J= 8.6 Hz), 7.42 (d, 1H, 3-Ar-H. J= 8.6 Hz), 7.34 (m, 10H, Ar-H), 6.44 (bs, 1H, NH), 6.29 (s, 3H, 7-Ar-H), 6.24 (s, 1H, 5-Ar-H), 6.12 (bs, 1H, NH), 5.56 (bs, H, NH), 5.50 (bs, 1H, NH), 5.08 (m, 4H, 2xOCH2Ph), 4.36 (bs, 1H, N-CH), 4.23 (bs, 1H, N-CH), 3.88 (s, 3H. OCH3), 3.72 (s, 4H, 2xN-CH2), 3.56 (bs, 1H, N-CH), 3.21 (m, 4H, 2/CH2), 1.55 (m, 4H, 2xCH2), 1.42 (s, 9H, 3xCH3), 1.26 (d, 3H, CH3); 13C NMR (CDCI3): 5 172.61, 171.59, 163.35, 158.73, 156.95, 156.40, 155.90, 144.80, 136.22, 134.99, 133.53, 128.22, 128.22, 128.12, 118.83, 96.61, 91.48, 55.16, 53.50, 52.50, 47.84, 40.43, 39.66, 37.67, 33.83, 29.91, 29.58, 26.05, 25.89, 20.59, 14.19; HRMS (APCI) m/z 698 (M+1). Example 58 {1-4-[2-fert-Butyl-6-methoxy-quinolin-8-ylamino)-pentylcarbamoyl]-ethylj-carbamic acid benzyl ester Yield: 93%; IR (KBr): 3293 cm'1 (NH), 1647 (amide carbonyl); 1H NMR (CDCI3): 5 7.88 (d, 1H, 4-Ar-H, J= 8.5 Hz), 7.44 (d, 1H, 3-Ar-H, J= 8.6 Hz), 7.33 (m, 5H, Ar-H), 6.32 (s, 1H, 7-Ar-H), 6.27 (s, 1H, 5-Ar-H), 5.88 (bs, 1H, NH), 5.34 (bs, 1H, NH), 5.08 (s, 2H, OCH2Ph), 3.87 (s, 4H, OCH3 and N-CH), 3.59 (s, 1H, N-CH), 3.30 (s, 2H, N-CH2), 1.66 (m, 4H, 2xCH2), 1.42 (s, 9H, 3xCH3), 1.31 (d, 3H, CH3), 0.91 (m, 6H, 2xCH3); 13C NMR (CDCI3): 5171.03, 158.81, 135.09, 128.17, 118.86, 96.90, 91.63, 67.03, 60.63, 55.20, 48.02, 39.4S. 37.70, 33.84, 30.26, 26.08, 25.62, 24.94, 20.57, 19.83, 19.26 , 17.71, 14.21; HRMS (ESI) m/z 549 (M+1). Example 59 {5-Benzyloxycarbonylamino-5-[4-(2-fert-butyl-6-methoxy-quinolin-8-ylamino)-pentyl-carbamoyl]-pentyl}-carbamic acid benzyl ester Yield: 91%; IR (KBr): 3304 cm ' (NH), 1719 cm"1 (ester), 1590 crrf'1 (amide carbonyl); 1H NMR (CDCI3): 6 7.86 (d, 1H, 4-Ar-H, J~ 8.6 Hzi. 7.43 (d. 1H, 3-Ar-H, J= 8.6 Hz), 7.31 (m, 10H, Ar-H), 6.31 (s, 1H. 7-Ar-H), 6.25 (s, 1H. 5-Ar-H), 6.15 (bs, 1H, NH), 5.50 (bs. 1H, NH), 5.07 (s, 4H, 2xOCH2Ph), 4.82 (bs, 1H, NH), 4.13 (m, 1H, CH), 3.85 (s, 3H, OCH3), 3.58 (s, 1H. N-CH), 3.27 (s, 2H, N-CH2), 3.12 (s, 2H, N-CH2), 1.67 (m, 10H, 5xCH2) , 1.41 (s, 9H, 3xCH3), 1.25 (d, 3H, CH3); 13C NMR (CDCI3): 8 171.52, 163.44. 158.7 , '56.63, 156.34, 144.76, 136.59 136.18. 135.07, 133.55, 128.07, 127.53, 118.86, 96.76, 91.63, 67.05, 55.19, 53.50, 47.95, 40.23, 39.48, 33.79, 31.88, 30.26, 23.38, 26.07, 22.31, 20.59, 14.20; HRMS (ESI) m/z 712 (M+1). Example 60 {1-[4-(2-fert-Butyl-6-methoxy-8-ylamino)-pentylcarbamoyl]-2-methyl-propyl}-carbamic acid tert-butyl ester Yield: 100%; IR (KBr): 3394cm 1 (NH), 1712 (ester), 1655 (amide carbonyl); 1H NMR (CDCI3): 5 7.87 (d, 1H. 4-Ar-H, J=8.5 Hz), 7.43 (d, 1H, 3-Ar-H, J=8.3 Hz), 6.31 (s, 1H, 7-Ar-H), 6.25 (s, 1H, 5-Ar-H), 6.20 (bs, 1H, NH), 5.04 (bs, 1H, NH), 4.13 (m, 1H, N-CH), 3.87 (s, 3H, OCH3), 3.60 (m, 1H, N-CH), 3.30 (m, 2H, N-CH2) 1.68 (m, 4H, 2xCH2), 1.42 (s, 9H, 3xCH3), 1.39 (s, 9H, 3xCH3), 1.31 (d, 4H, 2xCH2); 13C NMR (CDCI3): 5 172.55. 163.35. 158.7, 155.55, 144.84, 135.00. 133.58, 127.49, 118.49, 118.80, 96.66, 91.50, 60.41, 54.74, 50.83, 50.18, 49.14, 47.93, 39.44, 37.69, 33.95, 32.66, 31.71, 30.27, 28.30, 29.38, 26.18, 25.62, 25.51, 25.36, 21.05, 20.64, 18.61, 14.20; HRMS (ESI) m/z 487 (M+1). Typical procedure for the synthesis of ring-substituted W}-[4-(6-methoxy-8-quinolylamino)pentyl]-(2S)-2-amino/diaminoalkanamides To a mixture of ring-substituted benzyl esters (0.5 mmol), glacial acetic acid (1 ml) and 10% Pd-C (0.1g) in methanol (20 mL) was bubbled hydrogen gas for 1 h. The catalyst was filtered and filtrate was concentrated in vacuo to afford tr.s product as oily syrup, which on treatment with a solution of ethereal HCI provided the corresponding hydrochloride salt derivatives. Alternatively, in the cases involving the use of f-Boc protected amino acids, a solution of protected derivative (0.5 mmol) in methanolic hydrogen chloride (20 ml) was stirred for overnight at room temperature. The solvent was removed in vacua to afford orange solid. Recrystallized from methanoi/diethyl ether. Example 61 Wl-[4-(2-tert-Butyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2,5- diaminopentamide Yield: 99%; IR (KBr): 3018 cm'1 (NH2); 1H NMR (free base, CDCI3): 5 8.92 (bs, 4H. 2xNH2), 7.85 (d, 1H, 4-Ar-H), 7.42 (d, 1H, 3-Ar-H), 6.30 (bs, 1H. 7-Ar-H), 6.23 (s, 1H, 5-Ar-H), 3.85 (s, 3H, OCH3), 3.58 (s, 1H, N-CH), 3.44 (s, 1H, N- CH), 3.25 (s, 4H, 2xN-CH2), 2.95 (m, 4H, 2xCH2), 1.40 (s, 9H, 3xCH3), 1.26 (d, 3H, CH3); 13C NMR (CDCI3): 5 177.38, 170.11, 163.32, 158.79, 144.85, 134.99. 133.57, 127.47, 118.79, 96.61, 91.46, 55.13, 52.68, 49.67, 47.82, 41.74. 39.78, 39.74, 37.66, 34.11, 33.67, 30.24, 28.90, 25.85, 24.85, 22.98, 22.16. 20.73; HRMS (ESI) m/z 429 (M+1). Example 62 Wt-[4-(2-fert-Butyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2-ammo-3- methyl-butanamide Yield: 94%; IR (KBr): 3243 cm'1 (NH2), 1663 cm'1 (CONH); 1H NMR (free base, CDCI3): 5 7.86 (d, 1H, 4-Ar-H, J= 8.5 Hz), 7.61 (bs, 1H, NH), 7.43 (d, 1H, 3-Ar-H, J=8.5 Hz), 6.31 (s, 1H, 7-Ar-H), 6.26 (s, 1H, 5-Ar-H), 3.87 (s, 3H, OCH3), 3.62 (s, 1H, N-CH) 3.35 (m, 2H, N-CH2), 2.72 (s, 1H, N-CH), 1.68 (m, 4H, 2xCH2), 1.41 (s, 9H, 3xCH3), 1.29 (d, 3H, CH3), 0.945 (m, 6H, 2xCH3); 13C NMR (CDCI3): 5 176.68, 171.63, 163.34, 158.86, 144.89, 134.98, 133.6, 127.49, 118.79, 96.69, 91.50, 67.47, 55.17, 47.90, 43.02, 39.24, 37.69, 34.16, 33.74, 30.80, 30.27, 26.16. 25.56, 24.87, 21.50, 20.65, 19.39, 18.90, 18.23, 16.57, 13.94; HRMS (ESI) m/z 414 (M+1). Example 63 A/'-[4-{2-fert-Butyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2-6- diaminohexanamide Yield: 100%; IR (KBr): 3435 crrf1 (NH2), 1667 cm'1 (amide carbonyl); 1H NMR (free base, CDCI3): 5 7.85 (d, 1H, 4-Ar-H, J= 8.5 Hz), 7.42 (d, 1H, 3-Ar-H, J= 8.5 Hz), 6.29 (s, 1H, 7-Ar-H), 6.24 (s, 1H, 5-Ar-H), 5.64 (bs, 4H, 2xNH2), 3.89 (s, 3H, OCH3), 3.68 (s, 1H, N-CH), 3.24 (m, 4H, 2xN-CH2), 2.87 (bs, 1H. N-CH), 1.63 (m, 10H, 2xCH2), 1.41 (s, 9H, 3xCH3), 1.24 (d. 3H, CH); HRMS (ESI) m/z444(M+1). Example 64 A/f-[4-(2-fert-Butyl-6-methoxy-8-quinolylamino)pentyl]-(2S)-2-aminopropanamide Yield: 98%; IR (KBr): 3018 cm'1 (NH2), 1710 cm'1 (amide carbonyl); 1H NMR (free base, CDCI3): 6 7.86 (d, 1H, 4-Ar-H), 7.65 (d, 1H, 3-Ar-H), 7.15 (s, 1H, 7-Ar-H), 6.81 (s, 1H, 5-Ar-H), 5.48 (bs, 1H, NH), 4.3 (bs, 1H, NH), 3.99 (m, 1H, N-CH), 3.71 (m, 1H, N-CH), 1.84(m, 4H, 2xCH2), 1.50 (s, 9H. 3xCH3), 1.25 (d, 6H, 2xCH3); HRMS (ESI) m/z 387 (M+1). Biological Activity Blood schizontocidal activity evaluation of potential antimalarial compounds against Plasmodium berghei (sensitive strain) and P. yoelii nigeriensis (resistant strain) infection in mice Test Procedure: On day '0', groups of 6 mice each were inoculated, intraperitoneally, with 1x107 infected-erythrocytes, from a donor mouse. Four hours later, mice were administered test compounds/chloroquine primaquine/vehicle, orally. A total of 4 doses were given on days D'O', D+1, D+2, and D+3. The tail blood smears were made on day D+4 and D+7, stained with Geimsa, and examined microscopically. The minimum dose which completely suppressed parasitaemia on days D+4 and D+7 was designated "minimum effective dose (MED)" or "suppressive dose" and, the minimum dose, which cleared the parasitaemia for up to 28 days, was termed "curative dose". The results of blood-schizontocidal activities for the-synthesized compounds are given below in Table 1. Table 1. In vivo blood-schizontocidal activity of compounds against P. berghei infection in mice* "Standard drug chloroquine has Suppressive activity at 8 mg/kg, and curative activity at 12 mg/kg As evident from Table 1, the most effective compound of the series 1 [R=Ri=R3=H, R2=C(CH3)3] is curative at a dose of 10 mg/kg in P. berghei infected mice model thereby indicating its superiority over chloroquine in this test model. On the other hand, compounds (12-15, 17-18) were found to be curative at the initial tested dose of 100 mg/kg in P. berghei infected mice model. Further screening of compounds (17-18) indicated them to , ave suppressive activity at 10 mg/kg P. berghei infected mice model. Compound (1) found curative at 10 mg/kg against P. berghei infected mice model was then tested against chloroquine and mefloquine drug-resistant P. voelii nigeriensis strain in mice at the initial tested dose of 100 mg/kg and results are summarized in Table 2. Table 2. In vivo blood-schizontocidal activity of compounds against chloroquine and mefloquine drug-resistant P. yoelii nigeriensis strain in mice (Table Removed)The most effective compound 1 [R=Ri=R3=H, R2=C(CH3)3] of the series was further evaluated for acute toxicity studies in Swiss mice. A group of six mice with equal ratio of male and female were subjected to a single dose of 50 mg/kg. The compounds were evaluated for acute toxicity as per the protocols of Schedule 'Y" of Drug and Cosmetic Act, 1988, Govt of India, Ministry of Health and Family Welfare, except the number of animals used in the present investigation and results are as given in Table 3 indicates that compound is completely safe at 50 mg/kg. The pronounced activity of 1 [R=Ri=R3=H, R2=C(CH3)3] against the chloroquine, mefloquine and quinine resistant strain of P. yoelii nigeriensis has made this compound a very attractive molecule for clinical drug development. Since, the basic sub-structure in our study is primaquine (clinically used radical curative drug), thus we anticipate observing the same (as primaquine) or increased degree of tissue-schizontocidal activity of this molecule. It is expected that this unique blend of broad-spectrum of antimalarial activity against blood stages, tissue stages, and resistant strains of the human malaria parasites may make these compounds very attractive in the cure and prevention of malaria. It is further expected that the development of these compounds may offer the possibility of a single drug that can cure all of the relapsing and non-relapsing forms of malaria. We Claim: 1. Design and synthesis of potential antimalarial agent of formula 1 (Formula Removed) Wherein R represents H, straight chain alkoxy groups containing 1 to 8 carbon atoms, branched chain alkyl groups containing 3 to 7 carbon atoms, cycloalkyl group containing 3 to 15 carbon atoms, phenoxy, and substituted phenoxy groups, R1 represent H, CH3, C2H5, R2 represents straight chain alkyl group containing 1 to 5 carbons, branched alkyl groups, and cycloalkyi group containing 3 to 15 carbon atoms, R3 represents various (R) - and (S) - amino acids or L-unnatural amino acids, and pharmacologically acceptable salts thereof, wherein the salt - forming acid may be organic or inorganic in nature. 2. Potential antimalarial agent as claimed in claim 1 wherein the preferred compounds of formula 1, wherein the value of R,R1,R2 and R3 are given below: (Table Removed) 3. Design and synthesis of potential antimalarial agents substantially as herein described with reference to examples accompanying this specification.

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