FIELD OF INVENTION
This invention relates to aminoquinoline based hybrids, pharmaceutical composition containing the same, and methods of using thereof.
BACKGROUND OF THE INVENTION
Malaria affects over 40% of world's population, causing deaths of 1-3 million people every year [Haynes, R. K. Acc. Chem. Res. 1997, 30, 73; Meunier, B. Acc. Chem. Res. 2002, 35, 167; O'Neill, P. M. J. Med. Chem. 2004, 47, 2945; Jain, R. Med. Res. Rev. 2007, 27, 65; Vennerstrom, J. L. Med. Res. Rev. 2004, 24, 425; Schlitzer, M. Angew. Chem. Int. Ed. Engl. 2003, 42, 5274; Vennerstrom, J. L. Nature 2004, 430, 900; White, N. J.Science 2008, 320, 330]. The incidence of malaria has become a matter of concern because of many Plasmodium falciparum strains have developed resistance to most widely used drugs [Greenwood, B. Nature 2002, 415, 670].
The 4-aminoquinoline class of therapeutics remains a frontline drug of choice for combating malaria even after several decades of drug development efforts [Gomez-Barrio, A. Eur. J. Med. Chem. 2009, 44, 3091].
WO Pub. No. 2005009969 on "AMINOQUINOLINE DERIVATIVES AND THEIR USE AS ADENOSINE A3 LIGANDS" discloses compounds of the general formula (I), and their salts, solvates, isomers (tautomers, desmotrops, optically active isomers) as well as the salts and solvates; are strong adenosine A3 receptor ligands preferably antagonists.
WO Pub. No. 2010089341 on "NOVEL VANCOMYCIN-AMINOQUINOLINE HYBRID MOLECULES THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS"relates to novel vancomycin-aminoquinoline hybrid molecules designated "vancomyquines®", preparation thereof and application thereof in therapeutics. The present invention notably relates to novel hybrid molecules in which vancomycin is bound covalently to substituted 4-aminoquinolines. The present invention describes the preparation of these hybrid molecules designated "vancomyquines®" corresponding to formula (I) as well as their therapeuticuse as an antibacterial agent.
The success of this antimalarial pharmacophore is based on its excellent clinical efficacy, ease of administration, low toxicity and cheap synthesis [Gomez-Barrio, A. Eur. J. Med. Chem. 2009, 44, 3091; Carden Jr., G. A. J. Am. Med. Assoc. 1946, 130, 1069].
US App. No. 20050009815 on "4-AMINOQUINOLINE COMPOUNDS" is concerned with compounds of the general Formula I: 1 and pharmaceutically acceptable salts thereof, which are useful as melanin concentrating hormone receptor antagonists, particularly MCH-1R antagonists. As such, compounds of the present invention are useful for the treatment or prevention of obesity or eating disorders associated with excessive food intake and complications thereof, osteoarthritis, certain cancers, AIDS wasting, cachexia, frailty (particularly in elderly), mental disorders stress, cognitive disorders, sexual function, reproductive function, kidney function, locomotor disorders, attention deficit disorder (ADD), substance abuse
disorders and dyskinesias, Huntington's disease, epilepsy, memory function, and spinal muscular atrophy. Compounds of formula I may therefore be used in the treatment of these conditions, and in the manufacture of a medicament useful in treating these conditions. Pharmaceutical formulations comprising one of the compounds of formula (I) as an active ingredient are disclosed, as are processes for preparing these compounds.
US Pat. No.7132431 on "ANTIMALARIAL COMPOUNDS" relates to pharmaceutical compounds for use in the treatment or porphylaxis of malaria having the general formula: where R is selected from the groups consisting of dimethylamino, diethylamino, di-N-propylamino, diisopropylamino, etc and X is selected from the group consisting of chloro, fluoro, iodo, bromo, trifluoromethyl methoxy and methyl.
US App. No. 20080262031 on "4-AMINOQUINOLINE DERIVATIVES AS ANTIMALARIALS" highlights new 4-aminoquinoline derivatives having the general formula (I) wherein R, M, X, Y and T have the meaning described in the specification, as potent antimalarials active also on chloroquine-resistant Plasmodium falciparum malaria strains.
US App. No. 20100093726on "NOVEL 4-AMINO-QUINOLINE DERIVATIVES USEFUL AS ANTI-MALARIA DRUGS" relates to clotrimazole/quinoline hybrids useful as active ingredients of anti-malaria drugs. The compounds show a remarkable in vitro biological activity especially against the chloroquine-resistant Plasmodium falciparum strains and in vivo activity against P. berghei.
US App. No. 20110045100 on "ANTIMALARIAL QUINOLINES AND METHODS OF USE THEREOF" relates to substitute quinolines with antimalarial activity, and compositions and kits comprising at least one of them. Another aspect of the invention relates to methods for the treatment or prevention or both of malaria comprising administering to a subject a therapeutically effective amount of such a compound. Importantly, a number of the compounds show excellent potency against both chloroquine-sensitive and chloroquine-resistant strains.
These features make this pharmacophore so interesting that it's very difficult to abandon. However, worldwide increase of P. falciparum resistant strains [White, N. J. N. Engl. J. Med. 2009, 361, 455; Vennerstrom, J. L. Ann. Trop. Med. Parasitol. 1997, 91, 559] has severely circumscribed the choice of traditionally used 4-aminoquinoline class of antimalarials namely amodiaquine (AQ) and chloroquine (CQ) (Figure 1) towards antimalarial chemotherapy.
(Formula Removed)
Figure 1: Structure of Amodiaquine (AQ) and Chloroquine (CQ)

But, despite this global diffusion of resistance at an alarming speed, 4-aminoquinoline derivatives continues to be the most sought out antimalarial agents for chemical modification.
In order to overcome the problem of drug resistance, combination therapy has been used with limited success [Meek, S. Bull. World Health Org., 2000, 78, 1378], and recently concept of hybrid molecules has been introduced in an anticipation that these kind of molecules may overcome drug resistance problems [Meunier, B. Acc. Chem. Res. 2002, 35, 167; Meunier, B. Acc. Chem. Res. 2008, 41, 69; Meunier, B. ChemBioChem 2000, 1, 281].
In hybrid molecules two or more pharmacophores are linked together covalently and it is believed that these compounds act by inhibiting simultaneously two conventional target. This multiple target strategy led to the discovery of various hybrid molecules including 4-aminoquionline-trioxane [Meunier, B. ChemBioChem 2000, 1, 281; Singh, C. Bioorg. Med. Chem. 2004, 12, 1177], 4-aminoquinoline-triazine [Chauhan, P. M. S. Eur. J. Med. Chem. 2009, 44, 2081], 4-aminoquinoline-isatin [Chibale, K. Bioorg. Med. Chem. 2005, 13, 3249], 4-aminoquinoline-ferrocene [Brocard, J. S. J. Med. Chem. 1997, 40, 3715] and more recently 4-aminoquinoline based mannich bases [Davioud-Charvet, E. J. Med. Chem. 2010, 53, 3214] and 4-aminoquinoline-artemisinin conjugates [Lategan, C. A. Bioorg. Med. Chem. Lett. 2011, 21, 1683].
Some of these compounds have also entered into the clinical trials [Meunier, B. Acc. Chem. Res. 2008, 41, 69; Millet, P. Antimicrob. Agents Chemother. 1998, 42, 540].
The P. falciparum dihydrofolatereductase (pf-DHFR) is
significant target in malaria chemotherapy [Yuthavong, Y.
Pharmacol. Ther. 1999, 81, 91; Chitnumsub, P. Future Microb.
2006, 1, 113] and it has been found that pyrimidine based
compounds like pyrimethamine exhibit antimalarial activity due
to their ability to inhibit plasmodial DHFR [Figueroa-Villar, J. D.
J. Braz. Chem. Soc. 2002, 13, 727]. Many authors have
subsequently reported antimalarial potency of pyrimidine based
molecules [Yuthavong, Y. J. Med. Chem. 2002, 45, 1244;
Chauhan, P. M. S. Bioorg. Med. Chem. Lett. 2005, 15, 1881;
Rathod, P. K. J. Med. Chem. 2008, 51, 3649] and more recently
Chauhan et al reported antimalarial activity of 4-aminoquinoline-pyrimidine conjugates in which 4-aminoquinoline and pyrimidine moieties were linked through an aromatic ring [Chauhan, P. M. S. Eur. J. Med. Chem. 2009, 44, 2081]. However, these compounds showed moderate antimalarial activity.
Based on these observations and in continuation of our efforts to develop new structurally diverse molecular scaffolds for the treatment of malaria [Rawat, D. S. Bioorg. Med. Chem. Lett. 2008, 18, 1446; Rawat, D. S. Bioorg. Med. Chem., 2009, 17, 5632; Rawat, D. S. Eur. J. Med. Chem. 2011, 46, 2816], an effort has been initiated to link 4-aminoquinoline and pyrimidine entities together via flexible linker so that molecule has enough flexibility to fit in the binding site of the target and as a result this kind of hybrid molecules may show better antimalarial activity.
OBJECTS OF THE INVENTION
The object of this invention is to develop a method for the preparation aminoquinoline based hybrids in which 4-aminoquinoline, 8-aminoquinoline, mefloquine, amidoquine, are covalently attached to pyrimidine, pyrazine, triazine C7/C5 curcuminods, heteroaromatics, aromatics, amino acids, peptides, sugar, steroids, or any other antimalarial pharmacophores and all related possible combinations.
Another object of the invention is to synthesis aminoquinoline based hybrids in which aminoquinoline is attached with various pharamacophores which are known for their antimalarial activity.
An additional object of this invention is to use these aminoquinoline based hybrids for the treatment of malarial using any delivery agent.
Yet another object of the invention is to attach these aminoquinoline based hybrids to biocompatible polymers, dendimers and nano materials for the treatment of infectious diseases.
Further object of the invention is to use these compounds for the treatment of antimalarial as such or in combination of any other antimalarial drugs.
The foregoing has outlined some of the pertinent objectives of the invention. These objectives should be construed to be merely illustrative of some of the more prominent features and
applications of the intended invention. Many other beneficial
results can be obtained by applying the disclosed invention in a
different manner or modifying the invention within the scope of
disclosure. Accordingly, other objectives and a full understanding
of the invention and the detailed description of the preferred
embodiment in addition to the scope of invention are to be
defined by the claims.

STATEMENT OF INVENTION
Accordingly the present inventions there are provided
aminoquinoline based hybrids and uses thereof, comprising of 4-
aminoquinoline, 8-aminoquinoline, mefloquine, amidoquine and
combinations thereof, with general formula:
Wherein R is independently absent or selected from the group of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxyl, phenoxy,
thio, and substituted or unsubstituted aryl or hetero-aryl; R1-R7 are independently absent or selected from the group of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxy!, phenoxy, thio, and substituted or unsubstituted aryl or hetero-aryl; the six membered ring X, Y, Z may be all CH or combination of CH, X/Y/Z or any other combination where X, Y, Z can be N, O, S or any other biologically relevant atoms. It may also be fused heteroaromatic system with various substitution patterns and n = 0 - 16, the (CH2)n is a linker or spacer, and it can be aromatic, hetero-aromatic or cyclic systems.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of promoting an understanding of the principles of the invention, reference is now to be made to the embodiment illustrated in the figures and specific language is used to describe the same. It is nevertheless to be understood that no limitations of the scope of invention is hereby intended, such alterations and further modifications in the illustrated bag and such further applications of the principals of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
The current invention illustrates a novel method which can be applied to a range of various aminoquinoline based hybrids, comprising of 4-aminoquinoline, 8-aminoquinoline, mefloquine, amidoquine, acridine and all related possible combinations, in which 4-aminoquinoline, 8-aminoquinoline, mefloquine, amidoquine,, was covalently attached to any pharmacophore
that shows antimalarial activity such as triazine, pyrimidine,

pyrazine, C-5 curcuminoids, C-7 curcuminoids, tetraoxane,
trioxane or any other N, S or O heterocycle that is active against

P. falciparum or other infectious diseases.
Accordingly, the present invention provides compounds
with general formula 1-7 as depicted in the following Figure:

Wherein
R is independently absent or selected from the group consisting of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxyl, phenoxy, thio, and substituted or unsubstituted aryl or hetero-aryl.
R1-R7 are independently absent or selected from the group consisting of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxyl, phenoxy, thio, and substituted or unsubstituted aryl or hetero-aryl.

The six membered ring with X, Y, Z may be all CH or combination of CH, X/Y/Z or any other combination where X, Y, Z can be N, O, S or any other biologically relevant atoms. It may also be fused heteroaromatic system such as pyrimidine,
pyrazine, triazine and all other heteroaromatics with various
substitution patterns and n = 0 - 16, the (CH2)n is a linker or
spacer, and it can be aromatic, hetero-aromatic or cyclic systems.
The compound(s) can be formulated with one or more pharmaceutically acceptable carriers and/or excipients to prepare pharmaceutical compositions. The compositions can be formulated for enteral (e.g., oral), parenteral (e.g., intravenous), topical, or transdermal administration.
The compounds can be administered to treat infectious diseases such as malarial or any other disease in question. The compounds described herein showed significant in vitro/in vivo activity against Plasmodium falciparum, without any toxicity.
An "effective amount", e.g., of the compounds described herein, refers to an amount of the compound in a composition or formulation which, when applied as part of a desired dosage regimen brings about, e.g., a change in the growth of the parasite and/or rate of survival of an animal according to clinically acceptable standards for the disorder to be treated.
The term "patient" or "subject" to be treated refers to either a human or non-human animal.
The term "prodrug", as used herein, refers to compounds which, under physiological conditions, are converted into the therapeutically active described herein. A common method for making a prodrug is to include selected moieties which are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.
As generally used herein "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
"Half maximal inhibitory concentration, IC50", as used herein, refers to a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbony1 (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a

substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters),-CF3, -CN and the like. Cycloalkyls can be substituted in the same manner.
The term "heteroalkyr, as used herein, refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, ethylthio, and the like. The term "alkylthio" also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. "Arylthio" refers to aryl or heteroaryl groups.
The terms "alkenyl" and "alkynyl", refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy can be represented by -O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below. The alkoxy and aroxy groups can be substituted as described above for alkyl.
The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines. The term "amido" is art-recognized as an amino-substituted carbonyls.
The term "aryl" also includes polycyclic ring systems having
two or more cyclic rings in which two or more carbons are
common to two adjoining rings (i.e., "fused rings") wherein at
least one of the rings is aromatic, e.g., the other cyclic ring or
rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls
and/or heterocycles. Examples of heterocyclic rings include, but
are not limited to, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3
b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,
isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-
oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-
pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined above for "aryl".
The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
The term "carbocycle", as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
"Heterocycle" or "heterocyclic", as used herein, refers to a cyclic radical attached via a ring carbon or nitrogen of a monocyclic or bicyclic ring containing 3-10 ring atoms, and preferably from 5-6 ring atoms, consisting of carbon and one to
four heteroatoms each selected from the group consisting of non-
peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O,
(CI-CIO) alkyl, phenyl or benzyl, and optionally containing 1-3
double bonds and optionally substituted with one or more
substituents. Examples of heterocyclic ring include, but are not
limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-
1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,
furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl,
indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl,
isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,
isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-
oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,
oxazolyl, oxepanyl, oxetanyl, oxindolyl, pyrimidinyl,
phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,
phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl,
purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,
pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-
pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl,
tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl,
thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,
thienoimidazolyl, thiophenyl and xanthenyl. Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
5
hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
Many types of linkers are known in the art and may be used in the creation of conjugates. A non-limiting list of exemplary linkers is shown in Table 1.
Table 1: Examples of hetero-bifunctional cross linking agents
(Table Removed)

Synthetic protocol (representative examples):
Among the prototype structures of figure 1, synthesis of 4-aminoquinoline-pyrimidine hybrids is described here. Similarly, other compounds as depicted in figure 1 were also synthesized. The 4-aminoquinoline-pyrimidine conjugates were synthesized using three step procedure as outlined in scheme 1. The commercially available starting material 4,7-dichloroquinoline (8) was reacted with an excess of aliphatic linear chain diaminoalkanes via SNAr type of reaction in neat conditions as reported in literature to afford substituted 4-aminoquinolines (9a-d) with free terminal amino group in goodto excellent yield [Roepe, P. D. J. Med. Chem. 2008, 51, 3466]. These intermediates (9a-d) on reaction with commercially available 2,4-dichloro-6-methyl-pyrimidine yielded two regioisomersvizlOa-d in major and lla-d in minor yield. The major regioisomerslOa-d was subjected to nucleophillic substitution with different cyclic secondary amines at an elevated temperature in DMF as solvent,
to yield 4-aminoquinoline-pyrimidine conjugates (12a-n) in excellent yield.
(Formula Removed)
Scheme 1: a) diaminoalkanes, neat, 120-130 oC, 6-8 h, 80-90%; b) 2,4-dichloro-6-methyl-pyrimidine, TEA, EtOH, RT, overnight, (lOa-d, 70-80 % and lla-d, 15-25 %); c) R = secondary amines, DMF, 100-120 oC, 10-12 h, 80-85%.
In vitro antimalarial activity of all the conjugates was studied against both CQ-sensitive (D6 clone) and CQ-resistant (W2 clone) strains of P. falciparum while mammalian cell cytotoxicity was determined against Vero, LLC-PK-1, HepG2 cells (Table 2) using procedure as described earlier [Jain, R. Bioorg. Med. Chem. 2005, 13, 4458; Khan, I. A. Lipids 2004, 37, 169]. Most of the compounds have shown very promising antimalarial activity. Out of these, eleven compounds (12b-c, 12e-f, 12h-n) have displayed better antimalarial activity (IC50 = 0.006 µM to 0.041 µM) against CQ-sensitive strain, while thirteen compounds (10a, 12b-f, 12h-n) have displayed better antimalarial activity (IC50 = 0.016 |iM to 0.34 µM) against CQ-resistant strains of P. falciparum. The selectivity index of antimalarial activity (calculated as a ratio of IC50 for cytotoxicity to Vero cells and

IC50 for antimalarial activity) was very high for most of these compounds as compared to standard drug chloroquine (CQ). The activity of (12i, 12j, 121 and 12m) was 7-8 fold higher than CQ and 2 fold higher than artemisinin in CQ-sensitive strain revealing their strong potency. The comparison of antimalarial activity of lOa-d with 12a-n clearly showed that substitution of CI from compounds lOa-d (IC50 = 0.15 µM to 0.46 µM for CQ-sensitive and 0.34 pM to 0.74 pM for CQ-resistant) with secondary amines (12b-f and 12h-n, IC50 = 0.006 pM to 0.066 pM for CQ-sensitive and 0.016 pM to 0.211 pM for CQ-resistant) improves antimalarial activity of these compounds. The comparision of antimalarial activity of two groups of regioisomerslOa-d (IC50 = 0.15 pM to 0.46 pM for CQ-sensitive and 0.34 pM to 0.74 pM for CQ-resistant) and lla-d (IC50 = 0.16 pM to 0.27 pM for CQ-sensitive and 0.56 pM to 0.1.24 pM for CQ-resistant) clearly indicates that both the regioisomers displayed more or less similar potency against both the strains of P. falciparum. These results indicate that the point of attachment of the spacer to the pyrimidine nucleus may not have a great impact on activity profile. For a particular amino substituted 4-aminoquinoine-pyrimidine hybrids (12a-d or 12e-h or 12i-l), structure activity relationship (SAR) study demonstrated no obvious trend of activity with increasing or decreasing carbon spacer from C2 to C6 but changing the amino groups for a particular C2 (12e, 12i), C3 (12b, 12f, 12j, 12m), C4 (12c, 12k, 12n) or C6 (12d, 12h, 121) spacer changes the activity significantly in a decreasing order of 4-ethyl piperazine> 4-methyl piperazine>morpholine>piperidine.
Among the most active compounds (12b-12f, 12h-12n), although 12d, 12h, and 121 showed toxicity to all the three cell
lines (VERO, LLC-PK-1, and HepG2) but their selectivity index of antimalarial activity was considerably high (table 3). In general, the cytotoxicity of the most of the conjugates appreared at much higher concentrations than the conentrations responsible for their antimalarial activity. Some of the hybrids were not cytotoxic at all upto the highest tested concentration of 60 µM indicating their high selectivity index of antimalarial activity versus cytotoxicity to mammalian cells.
Table 2: In-vitro antimalarial activity of 4-aminoquinoline-pyrimidine hybrids
(Table Removed)

Table 3: In vitro cytotoxicity of 4-aminoquinoline-pyrimidine hybrids to mammalian cells.
(Table Removed)
Considering the excellent in-vitro activity of these compounds, two of the hybrids 12i and 12m (table 4) were

subjected to in-vivo antimalarial activity evaluation. The results showed 100% parasitemia suppression on day 5 for both the compounds (12i and 12m) with the survival rate of 5/5 and 4/5 respectively on day 28 when the mice's are given a dose of 30 mg/kg for 3 days post infection. No apparent toxicity is also observed for these compounds. These results are found to be better than the standard drug (Chloroquine) which gives 100% parasitemia suppression on day 5 when a 100 mg/kg dose was given for 3 days post infection.
These excellent results on animal models clearly depicted the potency of these compounds and give an insight about considering them for future drug candidates.
Table 4: In-vivo antimalarial activity of 4-aminoquinoline-pyrimidine hybrids 12i and 12m.
(Table Removed)

11% suppression in parasitemia is calculated by considering the mean marasitemia in the vehical control as 100%. Parasitemia suppression <80% is considered as non-significant. 2Number of animals that survived day 28/total animals in group (the day of the death-post-infection) 3MST - mean survival time (days)
4Number of mice without parasitemia (cured) till day 28 post¬infection *Not included in analysis
Pharmaceutical compositions:
The compounds described herein can be formulated for enteral, parenteral, topical, or pulmonary administration. The compounds can be combined with one or more pharmaceutically acceptable carriers and/or excipients that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients.
General procedure for the synthesis of selected compounds:
(lOa-dand lla-d)
To a well stirred solution of 2,4-dichloro-6-methyl-pyrimidine (2.0 g, 12.2 mmol) and triethylamine (2.48 g, 24.5 mmol) in ethanol (50 ml) at room temperature was added diamines9a-d (12.2 mmol). The reaction mixture was allowed to stir overnight at room temperature. After completion of reaction as evident by TLC, reaction mixture was poured into ice cold
6.56-6.72 (m, 2H), 7.34 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.41 (brs, 1H), 7.68 (d, 1H, J =2.3 Hz); 8.07 (d, 1H, J = 8.7 Hz), 8.28 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 397.22 (M+H)+; Anal. Calcd for C21H25C1N6: C, 63.55; H, 6.35; N, 21.17; Found: C, 63.53; H, 6.39; N, 21.26.
N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-piperidin-1 -yl-pyrimidin-4-yl)-propane-l,3-diamine (12b): Pale yellow solid; Yield: 82 %; mp 194-196 oC; IR (cm-1, KBr): 3241, 3079, 1940, 1615, 1587, 1361, 1208, 1001, 804; 1H NMR (400 MHz, CDC13): 1.46-1.56 (m, 6H), 1.87 (quin, 2H), 2.16 (s, 3H), 3.36 (q, 2H), 4.45 (t, 4H), 3.49 (q, 2H), 4.86 (brs, 1H), 5.72 (s, 1H), 5.92 (brs, 1H), 6.32 (d, 1H, J = 5.4 Hz), 7.22 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.66 (d, 1H, J = 8.7 Hz), 7.85 (d, 1H, J = 2.3 Hz), 8.41 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 24.36, 24.67, 25.45, 29.06, 38.55, 40.34, 44.89, 92.36, 98.86, 117.43, 121.55, 124.83, 128.53, 134.63, 149.18, 149.91, 151.96, 162.42, 162.84, 165.62; ESI-MS (m/z): 411.23 (M+H)+; Anal. Calcd for C22H27C1N6: C, 64.30; H, 6.62; N, 20.45; Found: C, 64.42; H, 6.68; N, 20.41. N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-piperidin-l-yl-pyrimidin-4-yl)-butane-l,4-diamine (12c): White solid; Yield: 88 %; mp 187-189 oC; IR (cm-1, KBr): 3247, 3067, 2935, 1581, 1364, 1210, 1079, 848; 1H NMR (400 MHz, CDC13): 1.49-1.65 (m, 6H), 1.73-1.79 (m, 2H), 1.83-1.89 (m, 2H), 2.17 (s, 3H), 3.35 (q, 2H), 3.45-3.52 (m, 6H), 4.79 (brs, 1H), 5.25 (brs, 1H), 5.76 (s, 1H), 6.38 (d, 1H, J = 5.5 Hz), 7.31 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.63 (d, 1H, J = 8.7 Hz), 7.93 (d, 1H, J = 2.3 Hz), 8.50 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 24.09, 24.67, 25.43, 25.75, 27.64, 40.64, 43.02, 44.87, 91.91, 98.92, 117.14, 121.21, 125.04, 128.56, 134.66, 149.05, 149.76, 151.93, 162.17, 162.90, 165.67; ESI-MS (m/z): 425.28 (M+H)+; Anal. Calcd for
water (250 ml) and precipitate thus formed was filtered and washed with excess of water at vaccum pump. The crude precipitate was then dried, dissolved in 100 ml of CHC13 and extracted with water (2 * 500 ml) and finally with brine. Excess of solvent was evaporated to dryness under vaccum and the crude product thus obtained was purified by Si02 column using MeOH/CHC13 as eluent to yield respective compounds 13a-d and 14a-d.
General Procedure for the synthesis of selected compounds:
(12a-n)
In a 100 ml round bottom flask, compound lOa-d (1 eq.) was taken and dissolved in 10 ml of DMF. To this, a solution of respective amine (3 eq.) in DMF (5 ml) was added dropwise. Reaction mixture was allowed to stir at 100-120 oC for 10 hours monitored by TLC. After completion, water (50 ml) was added to reaction mixture and it was extracted with EtOAc (2 x 25 ml). Organic layer was then collected, washed with water (2 x 100 ml) and brine, dried over Na2S04 and finally excess of solvent was evaporated under vaccum. The crude residue thus obtained was purified by Si02 column using MeOH/CHC13 as eluent to afford respective compounds 15a-n.
Spectral data of selected compounds:
N-(7-chloro-quinolin-4-yl)-N'-(6-methyl-2-piperidin-l-yl-pyrimidin-4-yl)-ethane-l,2-diamine (12a): White solid. Yield: 85 %; mp 177-179 oC; IR (cm-1, KBr): 3385, 3344, 2941, 1580, 1447, 1331, 1237, 1141, 790; 1H NMR (400 MHz, DMSO-d6): 1.36-1.49 (m, 6H), 2.02 (s, 3H), 3.31-3.41 (m, 8H), 5.85 (s, 1H),
C23H29C1N6: C, 65.00; H, 6.88; N, 19.78; Found: C, 64.98; H, 6.90; N, 19.81.
N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-piperidin-1-yl-pyrimidin-4-yl)-hexane-l,6-diamine (12d): Light brown solid; Yield: 82 %; mp 97-99 oC; IR (cm-1, KBr): 3314, 2933, 1579, 1368, 1232, 1134, 983, 853, 789; 1H NMR (400 MHz, CDC13): 1.47-1.64 (m, 12H), 1.72-1.79 (m,2H), 2.17 (s, 3H), 3.29 (q, 2H), 3.39 (q, 2H), 3.54 (t, 4H), 4.76 (brs, 1H), 5.07 (brs, 1H), 5.74 (s, 1H), 6.39 (d, 1H, J = 5.5 Hz), 7.34 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.67 (d, 1H, J = 8.7 Hz), 7.95 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 453.12 (M+H)+; Anal. Calcd for C25H33C1N6: C, 66.28; H, 7.34; N, 18.55; Found: C, 66.32; H, 7.35; N, 18.49.
N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-morpholin-4-yl-pyrimidin-4-yl)-ethane-l,2-diamine (12e): Pale yellow solid; Yield: 86 %; mp 165-167 oC; IR (cm-1, KBr): 3391, 3245, 2954, 1585, 1438, 1228, 1110, 993; 1H NMR (400 MHz, DMSO-d6): 2.09 (s, 3H), 3.35-3.48 (m, 8H), 3.57 (t, 4H), 5.91 (s, 1H), 6.62-6.70 (m, 2H), 7.41 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.44 (brs, 1H), 7.74 (d, 1H, J = 2.3 Hz), 8.14 (d, 1H, J = 9.1 Hz), 8.35 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 399.20 (M+H)+; Anal. Calcd for C20H23C1N6O: C, 60.22; H, 5.81; N, 21.07; Found: C, 60.34; H, 5.79; N, 21.09. N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-morpholin-4-yl-pyrimidin-4-yl)-propane-l,3-diamine (12f): White solid; Yield: 82 %; mp 165-167 oC; IR (cm-1, KBr): 3233, 3063, 2954, 1576, 1366, 1247, 1123, 791; 1H NMR (400 MHz, CDC13): 1.92 (quin, 2H), 2.20 (s, 3H), 3.39 (q, 2H), 3.47 (t, 4H), 3.52 (q, 2H), 3.66 (t, 4H), 5.22 (brs, 1H), 5.71 (s, 1H), 5.95 (brs, 1H), 6.34 (d, 1H, J = 5.4 Hz), 7.25 (dd, 1H, J = 11.0 Hz, 2.2 Hz), 7.72 (d, 1H, J = 8.7
Hz), 7.89 (d, 1H, J = 2.3 Hz), 8.44 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 24.10, 28.85, 38.56, 40.34, 44.09, 66.46, 92.27, 98.85, 117.35, 121.52, 124.93, 128.46, 134.73, 149.06, 149.90, 151.83, 161.87, 163.27, 165.70; ESI-MS (m/z): 413.21 (M+H)+; Anal. Calcd for C21H25C1N60: C, 61.08; H, 6.10; N, 20.35; Found: C, 61.12; H, 6.17; N, 20.40.
N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-morpholin-4-yl-pyrimidin-4-yl)-butane-l,4-diamine (12g): White solid; Yield: 80 %; mp 214-216 oC; IR (cm-1, KBr): 3256, 3066, 2964, 1583, 1367, 1245, 1122, 994, 790; 1H NMR (400 MHz, CDC13): 1.72-1.80 (m, 2H), 1.83-1.91 (m, 2H), 2.20 (s, 3H), 3.36 (q, 2H), 3.48 (q, 2H), 3.52 (t, 4H), 3.71 (t, 4H), 4.83 (brs, 1H), 5.19 (brs,lH), 5.75 (s, 1H), 6.40 (d, 1H, J = 5.5 Hz), 7.32 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.63 (d, 1H, J = 8.7 Hz), 7.95 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 22.75, 24.18, 25.83, 41.39, 42.69, 64.93, 89.96, 97.19, 122.10, 122.28, 122.80, 126.34, 132.68, 147.77, 149.11, 150.43, 160.69, 161.99, 164.64; ESI-MS (m/z): 427.12 (M+H)+; Anal. Calcd for C22H27C1N60: C, 61.89; H, 6.37; N, 19.68; Found: C, 61.99; H, 6.45; N, 19.70.
N-(7-Chloro-quinolin-4-yl)-N'-(6-methyl-2-morpholin-4-yl-pyrimidin-4-yl)-hexane-l,6-diamine (12h): Pale yellow solid; Yield: 90 %; mp 107-109 oC; IR (cm-1, KBr): 3245, 2935, 2855, 1579, 1366, 1220, 1123, 994, 789; 1H NMR (400 MHz, CDC13): 1.44-1.46 (m, 4H), 1.55-1.62 (m, 2H), 1.69-1.74 (m, 2H), 3.27 (q, 2H), 3.36 (q, 2H), 3.54 (t, 4H), 3.78 (t, 4H), 4.88 (brs, 1H), 5.26 (brs, 1H), 5.73 (s, 1H), 6.37 (d, 1H, J = 5.1 Hz), 7.31 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.70 (d, 1H, J = 8.7 Hz), 7.93 (d, 1H, J = 2.2 Hz), 8.50 (d, 1H, J = 5.1 Hz); 13C NMR (100 MHz, CDC13): 24.13,
26.62, 26.82, 28.66, 29.60, 41.04, 43.06, 44.09, 66.53, 91.58, 98.93, 117.07, 121.00, 125.08, 128.62, 134.67, 149.04, 149.68, 151.94, 162.00, 163.45, 166.31; ESI-MS (m/z): 456.21 (M+H)+; Anal. Calcd for C24H31C1N60: C, 63.35; H, 6.87; N, 18.47; Found: C, 63.29; H, 6.91; N, 18.46.
N-(7-Chloro-quinolin-4-yl)-N'-[6-methyl-2-(4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-ethane-l,2-diamine (12i): White solid 83 %; Yield: ; mp 134-136 oC; IR (cm-1, KBr): 3385, 3066, 2940, 1581, 1445, 1305, 1139, 997, 793; 1H NMR (400 MHz, CDC13): 2.29 (s, 3H), 2.30 (s, 3H), 2.42 (t, 4H), 3.41 (q, 2H), 3.62 (t, 4H), 3.84 (q, 2H), 5.51 (brs, 1H), 5.87 (s, 1H), 6.30 (d, 1H, J = 5.5 Hz), 6.90 (brs, 1H), 7.21 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.55 (d, 1H, J = 8.7 Hz), 7.89 (d, 1H, J = 2.3 Hz), 8.46 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 412.26 (M+H)+; Anal. Calcd for C21H26C1N7: C, 61.23; H, 6.36; N, 23.80; Found: C, 61.18; H, 6.51; N, 23.85. N-(7-Chloro-quinolin-4-yl)-N'-[6-methyl-2-(4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-propane-l,3-diamine (12j): Off white solid; Yield: 80 %; mp 176-178 oC; IR (cm-1, KBr): 3257, 3065, 2938, 1580, 1369, 1236, 1142, 1001, 789; 1H NMR (400 MHz, CDC13): 1.94 (quin, 2H), 2.21 (s, 3H), 2.28 (s, 3H), 2.36 (t, 4H), 3.42 (q, 2H), 3.52-3.56 (m, 6H), 5.32 (brs, 1H), 5.74 (s, 1H), 6.01 (brs, 1H), 6.37 (d, 1H, J = 5.4 Hz), 7.27 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.75 (d, 1H, J = 8.7 Hz), 7.91 (d, 1H, J = 2.3 Hz), 8.46 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 426.32 (M+H)+; Anal. Calcd for C22H28C1N7: C, 62.03; H, 6.63; N, 23.02; Found: C, 62.11; H, 6.68; N, 22.95.
N-(7-Chloro-quinolin-4-yl)-N'-[6-methyl-2-(4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-butane-l,4-diamine (12k): White solid; Yield: 87 %; mp 183-185 oC; IR (cm-1, KBr): 3248, 3072,
2927, 1581, 1367, 1280, 1139, 997, 790; 1H NMR (400 MHz, CDC13): 1.75-1.91 (m, 4H), 2.19 (s, 3H), 2.29 (s, 3H), 2.39 (t, 4H), 3.36 (q, 2H), 3.48 (q, 2H), 3.56 (t, 4H), 4.86 (brs, 1H), 5.23 (brs, 1H), 5.77 (s, 1H), 6.39 (d, 1H, J = 5.5 Hz), 7.32 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.94 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 24.15, 25.79, 27.65, 40.65, 43.04, 43.64, 46.10, 54.61, 92.00, 98.97,
117.12, 121.09, 125.09, 128.69, 134.67, 149.11, 149.68, 151.99,
162.13, 163.16, 166.16; ESI-MS (m/z): 440.19 (M+H)+; Anal.
Calcd for C23H30C1N7: C, 62.79; H, 6.87; N, 22.28; Found: C,
62.80; H, 6.85; N, 22.30.
N-(7-Chloro-quinolin-4-yl)-N'-[6-methyl-2-(4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-hexane-l,6-diamine (121): Light brown solid; Yield: 85 %; mp 152-154 oC; IR (cm-1, KBr): 3266, 3068, 2931, 1580, 1367, 1279, 1164, 993, 789; 1H NMR (400 MHz, CDC13): 1.46-1.55 (m, 4H), 1.59-1.61 (m, 2H), 1.74-1.77 (m, 2H), 2.19 (s, 3H), 2.30 (s, 3H), 2.42-2.44 (m, 4H), 3.29 (q, 2H), 3.38 (q, 2H), 3.60 (t, 4H), 4.77 (brs, 1H), 5.02 (brs, 1H), 5.75 (s, 1H), 6.40 (d, 1H, J = 5.5 Hz), 7.35 (dd, 1H, J = 11.0 Hz, 2.1 Hz), 7.66 (d, 1H, J = 8.7 Hz), 7.95 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 5.5 Hz); 13C NMR (100 MHz, CDC13): 24.14, 26.62, 26.82, 28.70, 29.63, 41.05, 43.10, 43.64, 46.12, 54.67, 91.72, 98.98, 117.08, 120.96, 125.14, 128.70, 134.71, 149.07, 149.67, 151.98, 162.05, 163.21, 166.09; ESI-MS (m/z): 468.32 (M+H)+; Anal. Calcd for C25H34C1N7: C, 64.15; H, 7.32; N, 20.95; Found: C, 64.09; H, 7.31; N, 20.98.
N- (7-Chloro-quinolin-4 -yl) -N' - [2 - (4-ethyl-piperazin-1 -yl) -6-methyl-pyrimidin-4-yl]-propane-l,3-diamine (12m): White solid; Yield: 82 %; mp 184-186 oC; IR (cm-1, KBr): 3233, 2967, 2812,
i l
1579, 1366, 1250, 1132, 998; 1H NMR (400 MHz, CDC13): 1.10 (t, 3H), 1.95 (quin, 2H), 2.24 (s, 3H), 2.40-2.44 (m, 6H), 3.43 (q, 2H), 3.55-3.59 (m, 6H), 4.94 (brs, 1H), 5.78 (s, 1H), 5.92 (brs, 1H), 6.40 (d, 1H, J = 5.4 Hz), 7.30 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.73 (d, 1H, J = 8.7 Hz), 7.93 (d, 1H, J = 2.3 Hz), 8.49 (d, 1H, J = 5.4 Hz); 13C NMR (100 MHz, CDC13): 11.86, 24.38, 29.05, 38.50, 40.31, 43.64, 52.26, 52.34, 92.35, 98.85, 117.38, 121.47, 124.84, 128.53, 134.61, 149.15, 149.84, 151.94, 162.34, 163.04, 166.03; ESI-MS (m/z): 440.16 (M+H)+; Anal. Calcd for C23H30C1N7: C, 62.79; H, 6.87; N, 22.28; Found: C, 62.75; H, 6.89; N, 22.20.
N-(7-Chloro-quinolin-4-yl)-N'-[2-(4-ethyl-piperazin-l-yl)-6-methyl-pyrimidin-4-yl]-butane-l,4-diamine (12n): White solid; Yield: 86 %; mp 101-103 oC; IR (cm-1, KBr): 3255, 2939, 2813, 1583, 1372, 1249, 1127, 994, 791; 1H NMR (400 MHz, CDC13): 1.09 (t, 3H), 1.73-1.80 (m, 2H), 1.84-1.91 (m, 2H), 2.19 (s, 3H), 2.38-2.43 (m, 6H), 3.35 (q, 2H), 3.48 (q, 2H), 3.57 (t, 4H), 4.83 (brs, 1H), 5.23 (brs, 1H), 5.77 (s, 1H), 6.39 (d, 1H, J = 5.5 Hz), 7.31 (dd, 1H, J = 11.0 Hz, 2.0 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.94 (d, 1H, J = 2.3 Hz), 8.51 (d, 1H, J = 5.5 Hz); ESI-MS (m/z): 454.11 (M+H)+; Anal. Calcd for C24H32C1N7: C, 63.49; H, 7.10; N, 21.60; Found: C, 63.59; H, 7.18; N, 21.63.
All documents cited in the description are incorporated herein by reference. The present invention is not intended to be limited in scope by the specific embodiments and examples which are intended as illustration of a number of aspects of the scope of this invention. Those skilled in art will know or to be able to ascertain using no more than routine experimentations many
equivalents to the specific embodiments of the invention described herein.
It is to be further noted that present invention is susceptible to modifications, adaptations and changes by those skilled in the art. Such variant embodiments employing the concepts and features of this invention are intended to be within the scope of the present invention which is further set forth under the following claims:

1. Aminoquinoline based hybrids and uses thereof, comprising of 4-aminoquinoline, 8-aminoquinoline, mefloquine, amidoquine and all combinations thereof, with general formula (I) as herein described:
(Formula Removed)
Wherein
R is independently absent or selected from the group of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxyl, phenoxy, thio, and substituted or unsubstituted aryl or hetero-aryl;
R1-R7 are independently absent or selected from the group of substituted or un-substituted, linear, branched, or cyclic alkyl, alkenyl, or alkynyl; halogen, substituted or unsubstitutedalkoxy, nitro, cyno, carbonyl, hydroxyl, phenoxy, thio, and substituted or unsubstituted aryl or hetero-aryl; the six membered ring with X, Y, Z be all CH or combination of CH, X/Y/Z or any other combination where X, Y, Z being N, O, S or any other biologically relevant atoms or fused heteroaromatic system such as pyrimidine, pyrazine, triazine and all other heteroaromatics with various substitution patterns and n = 0 - 16, the (CH2)n being a linker or spacer, and/or aromatic, hetero-aromatic or cyclic systems.
2. Aminoquinoline based hybrids as claimed in claim 1 wherein aminoquinoline is substituted at any or all the positions.
3. Aminoquinoline based hybrids as claimed in claim 1, wherein R2-R7 may be H, branched, straight chain alkyl, cyclic, alkylenic, acerylenic, OH/OR, SH/SR, NH2/NHR, S02R, aromatic, heteroaromatic, amino acid, sugar or combination of any of these groups.
4. Aminoquinoline based hybrids as claimed inproceeding
claims, wherein the linker may be branched, straight chain alkyl, cyclic, alkylenic, acetylenic, OH/OR, SH/SR, NH2/NHR, S02R, aromatic, heteroaromatic, amino acid, sugar or combination of any of these groups.
5. Aminoquinoline based hybrids as claimed in proceeding
claims, wherein the attached heterocycle may be substituted pyrimidine, with all possible combinations, having R and Rl as defined under claim 1-3.
6. Aminoquinoline based hybrids as claimed in proceeding claims, wherein the attached heterocycle may be substituted pyrimidine, triazine, teterazoles, triazole, purine, xanthenes, fused or substituted N, S, O heterocycle with all possible combinations, it may be C5 or C7 curcuminoids, or any other pharmacophore that has antimalarial activity.
7. Aminoquinoline based hybrids as claimed in proceeding
claims where in X = Y = Z = CH or any other heteroatom such as N, O, S or other biologically relevant atoms and n = 0-16, the (CH2)n is a linker or spacer, and it can be aromatic, hetero-aromatic or cyclic systems.
8. Aminoquinoline based hybrids as claimed in proceeding
claims and a pharmaceutical compositions comprising it
therein, or/and a salt thereof, or/and a solvate thereof,
or/and a pro-drug thereof; in combination with one, two or
more kinds selected drugs from an antibacterial/antifungal
or anti-tubercular.
9. Aminoquinoline based hybrids as claimed in proceeding
claims converted to corresponding pharmaceutically
acceptable salts thereof.
10. Aminoquinoline based hybrids as claimed in proceeding claims and pharmaceutical compositions comprising it therein and the use thereof for the prevention and/or treatment of malaria or any other infectious disease.