DESC:FIELD OF THE INVENTION
[0001] The present disclosure relates generally to pharmaceutical compounds. More specifically, the disclosure is directed to a quinoline anti-tubercular compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof and a pharmaceutical composition comprising them. The disclosure also provides pharmaceutical compositions comprising quinoline anti-tubercular compound of Formula I.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Tuberculosis (TB) is a chronic granulomatous and lethal communicable disease and a major health problem in developing countries. The causative agent of tuberculosis is a slow growing bacillus Mycobacterium Tuberculosis. Tuberculosis usually affects the lungs but can distress other parts of the body. It is spread from one creature to the next through air when individuals who have active TB in their lungs cough, speak, spit or sneeze.
[0004] Globally, a predictable 10.0 million (range, 8.9–11.0 million) people fell ill with TB in 2019, a numeral that has been declining very gradually in current years. There were a projected 1.2 million (range, 1.1– 1.3 million) TB deaths among HIV-negative people in 2019 (a reduction from 1.7 million in 2000), and an additional 208000 deaths (range, 177 000–242 000) among HIV-positive people (a reduction from 678 000 in 2000).
[0005] TB treatment regimen DOTS (directly observed therapy short course) entails taking INH (Isoniazid), PZA (Pyrazinamide) and RIF (Rifampicin) for 60 days followed by a further 120 days of treatment with INH and RIF (Bass JB, Farer LS, Hopewell PC, Obrien R, Jacobs RF, Ruben F, Snder DE, Thornton G (1994) Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and the centers for Disease Control and Prevention. Am. J. Respir. Crit. Care Med., 149:1359–1374; Davies PDO, Yew WW (2003) Recent developments in treatment of tuberculosis. Expert Opin. Investig. Drugs., 12:1297–1312). For global TB inhibition and treatment, the emergence and transmission of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains is a particular challenge. Due to the resistance attained by the Mycobacterium Tuberculosis against numerous first-line drugs, there is a prerequisite to discover novel and improved drug molecules for the treatment. The extended treatment period, augmented toxicity, and cost of treatment of MDR TB generate significant difficulties and hence hamper the capability to control the widespread MDR TB. It is a universal health alarm to pursue new compounds to combat growing resistance that can reduce the length of treatment and result in decreased toxicity compared to existing regimes.
[0006] Food and Drug Administration (FDA) approved Bedaquiline in 2012 for usage in the treatment of MDR-TB. It is promoted under the name Sirturo. Bedaquiline is a diarylquinoline derivative which is a recently developed class of anti-tubercular drugs (Koul A, Dendouga N, Vergauwen K, et al. (2007) Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol., 3(6): 323–324). In addition to this, including bedaquiline to current MDR-TB standard treatment regimen has proven to be cost-effective as well as cost-saving. Unlike other drugs, bedaquiline targets the energy metabolism of mycobacteria (Berney M, Cook GM. (2010) Unique flexibility in energy metabolism allows mycobacteria to combat starvation and hypoxia. PLOS One., 5(1): e8614). The ability of bedaquiline to be bactericidal for both replicating as well as dormant bacteria could also shorten the prolonged TB treatment. Bedaquiline inhibits the membrane-bound ATP synthase enzyme of M. tuberculosis. ATP synthase converts ADP to ATP by utilizing the transmembrane electrochemical ion (H+ or Na+) gradient. ATP synthase produces ATP through oxidative phosphorylation and is highly conserved in both prokaryotes and eukaryotes (Fillingame RH, Dmitriev OY. (2002) Structural model of the transmembrane F0 rotary sector of H-transporting ATP synthase derived by solution NMR and intersubunit cross-linking in situ. Biochim. Biophys. Acta., 1565 (11): 232–245; Von Ballmoos C, Cook GM, Dimroth P. (2008) Unique rotary ATP synthase and its biological diversity. Annu Rev Biophys.;37:43–64). It is highly selective for mycobacterial ATP synthase in comparison to human ATP synthase where it is 20,000 times less active. Thus, it is less likely to produce target-based toxicity in humans (Haagsma AC, Abdillahi-Ibrahim R, Wagner MJ, et al. (2009) Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob. Agents Chemother., 53(3):1290–1292).
[0007] Bedaquiline is metabolized in liver by cytochrome P450 isoenzyme to a fivefold less potent derivative, N-desmethyl TMC207. However, the terminal elimination half-life of bedaquiline is very high, approximately 4 to 5 months. It is highly lipophilic (logP 7.25) and has cationic amphiphilic properties due to which it interacts with intracellular phospholipids and this ultimately leads to its accumulation in tissues. This results in slow release of bedaquiline from peripheral tissues and leads to a long terminal elimination half-life. The high lipophilicity may also induce phospholipidosis. The drug also has an increased risk of death and arrhythmias, as it might prolong the QT interval by hindering the hERG channel.
[0008] Alternatively, Quinoline and its analogues have continuously engrossed the attention of academic and industrial personnel. It is a privileged nucleus having several fascinating biological properties such as anti-tubercular, antimicrobial, anti-inflammatory, antimalarial, antiprotozoal, antiproliferative, antiviral, antifungal, and anti-Alzheimer. Quinoline is an elementary pharmacophore used for the design of anti-tubercular agents, like mefloquine, moxifloxacin, ciprofloxacin, and bedaquiline which are already in the marketplace.
[0009] ATP synthase is indispensable for the growth of M. tuberculosis as it is a vital enzyme intricated in energy metabolism and is thus, observed as a potential target for anti-TB drugs. It catalyzes the creation of ATP by utilizing the energy collective in the form of variance in the transmembrane electrochemical potential of a connector ion. Thus, ATP synthase can be explored as a striking molecular target for the rationale design of compounds that can overcome the resistant TB.
[0010] There is therefore a need to discover and develop new chemical entities to treat TB.
[0011] Based on the above need to look for alternate treatment options for Bedaquiline, inventors of the present disclosure arrived at novel quinoline based compounds with anti-tubercular activity arising from ATP synthase inhibition.

OBJECTS OF THE INVENTION
[0012] An object of the present disclosure is to provide novel quinolin-2-amine derivatives.
[0013] Another object of the present disclosure is to provide a quinoline anti-tubercular compound that can target ATP synthase of M. tuberculosis, has low lipophilicity and less side-effects.
[0014] Another object of the present disclosure is to provide anti-tubercular compounds that are effective even against the multi-drug resistant Mycobacterium tuberculosis.
[0015] Another object of the present disclosure is to design and synthesize quinoline derivatives with lesser lipophilicity by incorporating hydrophilic functional groups in the molecules which in turn reduces the side effects.
[0016] Yet another object of the present disclosure is to provide Molecular docking studies for designing of lead compounds as well as ADME parameters prediction and in silico toxicity predictions shall be done before commencing synthesis.

SUMMARYOF THE INVENTION
[0017] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in Detailed Description section. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
[0018] Aspects of the present disclosure relate to 6-bromo-2-aminoquinoline compounds with anti-tubercular activity.
[0019] In an aspect, the present disclosure provides a quinoline anti-tubercular compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof,

Formula I
wherein R1 may be selected from hydrogen, C1-C6 alkyl or C1-C6 alkoxy;
R2 may be selected from -N=CH, or -O-CH2;
R3 may be selected from C6-C14 aryl;
R4 may be selected from C1-C6 alkoxy, –OOC-C1-C6 alkyl, or –OOC-C1-C6 alkenyl which are unsubstituted or substituted with one or more of -NH2, -N(R5)2, C3-C7 cycloalkyl, C6-C14 aryl, or C5-C14 heterocyclyl; and
R5 may be C1-C6 alkyl.
[0020] In some embodiments, R1 is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy.
[0021] In some embodiments, R2 is -N=CH, R3 is phenyl or napthyl, and R4 is ethoxy which is further unsubstituted or substituted with one or more of –N(R5)2 or C5-C14 heterocyclyl.
[0022] In some embodiments, R2 is -O-CH2, R3 is napthyl, and R4 is ethoxy or –OOC-ethenyl which is further unsubstituted or substituted with one or more of –N(R5)2, C5-C14 heterocyclyl, C3-C7 cycloalkyl, or C6-C14 aryl.
[0023] In some embodiments, R4 is ethoxy it may be substituted with -NH2, -N(CH3)2, -N(CH2CH3)2, pyridine, piperidine, pyrazine, thiophene, furan, pyrrole, cyclopropyl, cyclohexyl, or phenyl.
[0024] In some embodiments, the compound may be selected from:
(E)-2-(4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N-dimethylethan-1-amine;
(E)-2-(2-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methoxyquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-diethylethan-1-amine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromoquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methylquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methoxyquinolin-2-yl)methanimine;
6-bromo-3-methoxy-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-3-methyl-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
2-((4-(((6-bromo-3-methylquinolin-2-yl)oxy)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
6-bromo-3-methoxy-2-((2-(2-(thiophen-2-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-2-((2-(2-cyclopropylethoxy)naphthalen-1-yl)methoxy)-3-methoxyquinoline;
6-bromo-3-methyl-2-((2-phenethoxynaphthalen-1-yl)methoxy)quinoline; or
1-(((6-bromo-3-methoxyquinolin-2-yl)oxy)methyl)naphthalen-2-yl cinnamate.
[0025] In still another aspect, the present disclosure provides a pharmaceutical composition comprising the compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof and one or more pharmaceutically acceptable excipient(s),

Formula I
wherein R1, R2, R3, R4 and R5 have meanings as defined above.
[0026] Other embodiments of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The following drawings form part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.
[0028] Figure 1 pictorially represents the binding mode analysis of compound 5, as per an embodiment of the present disclosure, in the active site of FoF1 ATP synthases of Mycobacterium tuberculosis (dotted line represent hydrogen bond).
[0029] Figure 2 pictorially provides the binding mode analysis of compound 11, as per an embodiment of the present disclosure, in the active site of FoF1 ATP synthases of Mycobacterium tuberculosis (p-p interaction).
[0030] Figure 3 pictorially provides the binding mode analysis of compound 14, as per an embodiment of the present disclosure, in the active site of FoF1 ATP synthases of Mycobacterium tuberculosis.

DETAILED DESCRIPTION OF THE INVENTION
[0031] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0032] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0033] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0034] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
[0035] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0036] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.
[0037] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0038] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
[0039] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0040] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0041] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0042] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0043] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0044] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0045] The term "or", as used herein, is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
[0046] The term, “C1-C6 alkyl”, as used herein, refers to the radical of saturated aliphatic groups, including straight or branched-chain alkyl groups having six or fewer carbon atoms in its backbone, for instance, C1-C6 for straight chain and C3-C6 for branched chain. As used herein, C1-C6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl and 3-methylbutyl.
[0047] Furthermore, unless stated otherwise, the alkyl group can be unsubstituted or substituted with one or more substituents, for example, from one to four substituents, independently selected from the group consisting of halogen, hydroxy, cyano, nitro and amino. Examples of substituted alkyl include, but are not limited to hydroxymethyl, 2-chlorobutyl, trifluoromethyl and aminoethyl.
[0048] The term, “C1-C6 alkenyl”, as used herein, refers to straight or branched-chain alkyl groups having six or fewer carbon atoms in its backbone with at least one unsaturated carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, and propenyl. Furthermore, unless stated otherwise, the alkenyl groups can be unsubstituted or substituted with one or more groups. A substituted alkenyl refers to a C1-C6 alkenyl substituted with one or more groups, particularly one to four groups independently selected from the groups indicated above as the substituents for the alkyl group.
[0049] The term, “C1-C6 alkoxy" refers to a C1-C6 alkyl having an oxygen radical attached thereto. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Furthermore, unless stated otherwise, the alkoxy groups can be unsubstituted or substituted with one or more groups. A substituted alkoxy refers to a C1-C6alkoxy substituted with one or more groups, particularly one to four groups independently selected from the groups indicated above as the substituents for the alkyl group.
[0050] The term "C6-C14 aryl" or "aryl" as used herein refers to monocyclic, bicyclic or tricyclic hydrocarbon groups having 6 to 14 ring carbon atoms, wherein at least one carbocyclic ring is having a p electron system. Examples of C6-C14 aryl ring systems include, but are not limited to, phenyl, naphthyl, and anthracenyl. Unless indicated otherwise, aryl group can be unsubstituted or substituted with one or more substituents, for example 1-4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxy, cyano, nitro, -COOH, amino and C1-C6 alkoxy.
[0051] The term "C3-C7 cycloalkyl" as used herein refers to monocyclic hydrocarbon groups having 3 to 7 ring carbon atoms. Examples of C3-C7 cycloalkyl systems include, but are not limited to, cyclopropyl, and cyclohexyl. Unless indicated otherwise, the cycloalkyl group can be unsubstituted or substituted with one or more substituents, for example 1-4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxy, cyano, nitro, -COOH, amino and C1-C6alkoxy.
[0052] The term, “C5-C14 heterocyclyl”, as used herein refers to a 5- to 14-membered, saturated, partially unsaturated or unsaturated monocyclic or bicyclic ring system containing 1 to 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur. Saturated heterocyclic ring systems do not contain any double bond, whereas partially unsaturated heterocyclic ring systems contains at least one double bond, and unsaturated heterocyclic ring systems form an aromatic system containing heteroatom(s). The oxidized form of the ring nitrogen and sulfur atom contained in the heterocyclyl to provide the corresponding N-oxide, S-oxide or S,S-dioxide is also encompassed in the scope of the present disclosure. Representative examples of heterocyclyls include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, dihydropyran, tetrahydropyran, thio-dihydropyran, thio-tetrahydropyran, piperidine, piperazine, morpholine, 1,3-oxazinane, 1,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, benzofuran, indole, benzoxazole, benzothiazole, isoxazole, triazine, purine, pyridine, pyrazine, quinoline, isoquinoline, phenazine, oxadiazole, pteridine, pyridazine, quinazoline, pyrimidine, isothiazole, benzopyrazine and tetrazole. Unless stated otherwise, (C5-C14)heterocyclyl can be unsubstituted or substituted with one or more substituents, for example, substituents independently selected from the group consisting of oxo, halogen, hydroxy, cyano, nitro, amine, C1-C6alkyl and COOH.
[0053] The term, "halogen" as used herein refers to chlorine, fluorine, bromine or iodine atom.
[0054] The term, "therapeutically effective amount" as used herein refers to an amount of a compound of Formula (I) or a composition comprising a compound of Formula (I) effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder.
[0055] The term "pharmaceutically acceptable excipient(s)" as used herein refers to a diluent, binder, disintegrant, glidant, lubricant, coating material or the like, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said agent.
[0056] The term, "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" used herein refers to warm-blooded vertebrate animals of the class 'mammalia', including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young, the term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0057] The terms, “treatment", "treat" and "therapy" and the like as used herein refer to alleviate, slow the progression, attenuation, prophylaxis or as such treat the existing diseases or condition, i.e., tuberculosis. Treatment also includes treating, preventing development of, or alleviating to some extent, one or more of the symptoms of the diseases or condition.
[0058] The present disclosure relates to organic compounds. Specifically, the present disclosure provides a 6-bromo-2-aminoquinoline compound of Formula (I), its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt thereof, or mixtures thereof and pharmaceutical compositions comprising them. The present disclosure also provides a process for preparing the compound of Formula (I) or a pharmaceutically acceptable salt thereof and use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof as anti-tuberculars.
[0059] In an embodiment, the present disclosure provides a quinoline anti-tubercular compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof,

Formula I
wherein R1 may be selected from hydrogen, C1-C6 alkyl or C1-C6 alkoxy; R2 may be selected from -N=CH, or -O-CH2; R3 may be selected from C6-C14 aryl; R4 may be selected from C1-C6 alkoxy, –OOC-C1-C6alkyl, or –OOC-C1-C6alkenyl which are unsubstituted or substituted with one or more of -NH2, -N(R5)2, C3-C7 cycloalkyl, C6-C14 aryl, or C5-C14 heterocyclyl; and wherein R5 may be C1-C6 alkyl.
[0060] The compounds of the present disclosure were synthesized with the aim to develop new quinoline compounds with lesser lipophilicity by incorporating hydrophilic functional groups in the molecules which in turn reduces the side effects, compared to bedaquiline.
[0061] In some embodiment, R1 may be selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy. In a preferred embodiment, R1 may be selected from hydrogen, methyl, or methoxy.
[0062] In some embodiments, R2 is -N=CH, R3 is phenyl or napthyl, and R4 is ethoxy which is further unsubstituted or substituted with one or more of –N(R5)2 or C5-C14 heterocyclyl.
[0063] In some embodiments, R2 is -O-CH2, R3 is napthyl, and R4 is ethoxy or –OOC-ethenyl which is further unsubstituted or substituted with one or more of –N(R5)2, C5-C14 heterocyclyl, C3-C7 cycloalkyl, or C6-C14 aryl.
[0064] In some embodiments, R4 is ethoxy it may be substituted with -NH2, -N(CH3)2, -N(CH2CH3)2, pyridine, piperidine, pyrazine, thiophene, furan, pyrrole, cyclopropyl, cyclohexyl, or phenyl.
[0065] In some embodiments, R3 may be C6-C14 aryl. In preferred embodiment R3 is phenyl, or napthyl.
[0066] In some embodimenst, R4 may be selected from methoxy, ethoxy, –OOC-methyl, –OOC-ethyl or –OOC-ethenyl. In a preferred embodiment, R4 may be ethoxy, or –OOC-ethenyl.
[0067] In some embodiment, when R2 is -N=CH, R3 is phenyl or napthyl, and R4 is ethoxy which is further unsubstituted or substituted with one or more of –N(R5)2 or C5-C14 heterocyclyl. In a preferred embodiment, when R2 is -N=CH, R3 is phenyl or napthyl, and R4 is ethoxy which is further substituted with –N(CH3)2, –N(CH2CH3)2 or pyridine.
[0068] In some embodiment, when R2 is -O-CH2, R3 is napthyl, and R4 is ethoxy or –OOC-ethenyl which is further unsubstituted or substituted with one or more of –N(R5)2, C5-C14 heterocyclyl, C3-C7 cycloalkyl, or C6-C14 aryl. In a preferred embodiment, when R2 is -O-CH2, R3 is napthyl, and R4 is ethoxy or –OOC-ethenyl which is further substituted with –N(CH3)2, thiophene, pyridine, cyclopropyl, or phenyl.
[0069] In some embodiment, when R4 is ethoxy it is substituted with -NH2, -N(CH3)2, -N(CH2CH3)2, pyridine, piperidine, pyrazine, thiophene, furan, pyrrole, cyclopropyl, cyclohexyl, or phenyl. In a preferred embodiment, when R4 is ethoxy it is substituted with -N(CH3)2, -N(CH2CH3)2, pyridine, thiophene, cyclopropyl, or phenyl.
[0070] In some embodiment, when R4 is –OOC-ethenyl it is substituted with phenyl.
[0071] In some embodiment of the present disclosure, the compound may be selected from:
(E)-2-(4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N dimethylethan-1-amine;
(E)-2-(2-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methoxyquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-diethylethan-1-amine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromoquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methylquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methoxyquinolin-2-yl)methanimine;
6-bromo-3-methoxy-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-3-methyl-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
2-((4-(((6-bromo-3-methylquinolin-2-yl)oxy)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
6-bromo-3-methoxy-2-((2-(2-(thiophen-2-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-2-((2-(2-cyclopropylethoxy)naphthalen-1-yl)methoxy)-3-methoxyquinoline;
6-bromo-3-methyl-2-((2-phenethoxynaphthalen-1-yl)methoxy)quinoline; and
1-(((6-bromo-3-methoxyquinolin-2-yl)oxy)methyl)naphthalen-2-yl cinnamate.
[0072] In an embodiment, the compound of Formula (I) can be converted into a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the compound of Formula (I) according to the disclosure are prepared in a manner known to one skilled in the art. Pharmaceutically acceptable salts of the compound of the present disclosure include but are not limited to, an acid salt of a compound of the present disclosure containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms. Examples of anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts.
[0073] In yet another embodiment, the pharmaceutically acceptable salts of the compound of the present disclosure containing acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
[0074] In an embodiment, stereoisomers include diastereomers and enantiomers of the compounds; while solvates include hydrates such as monohydrate, dihydrate, or sesquihydrates.
[0075] The compounds of the present disclosure are effective against Mycobacterium Tuberculosis the microbe responsible for causing tuberculosis. The compounds are also effective against multi-drug resistant Mycobacterium tuberculosis variant. The efficacy is due to the effective binding of the compounds at ATP synthase rotor ring complex and destabilization of the complex formation. The binding affinity of the compounds with ATP synthase is more than 7.5kcal/mole. The compounds of the present disclosure also have lower toxicity compared to bedaquiline.
[0076] The compounds of the present disclosure have lower lipophilicity and reduced side effects.
[0077] The compounds can be used for bacterial infection without inducing cell toxicity in the absence of bacterial infection.
[0078] In still another embodiment, the present disclosure provides a pharmaceutical composition comprising the compound of Formula I, a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt or mixtures thereof and one or more pharmaceutically acceptable excipient(s).
[0079] In an embodiment, the composition may comprise the compound in a therapeutically effective amount.
[0080] In an embodiment, the composition may be in the form of a tablet, a capsule, a solution, a gel, a suspension, microparticles, nanoparticles, suppositories, or a powder.
[0081] The present invention also relates to a process for the production of the pharmaceutical composition, which includes bringing a compound of Formula (I), into a suitable administration form using a pharmaceutically acceptable excipient or a carrier and, if appropriate, further suitable a pharmaceutically acceptable carrier, additives or auxiliaries. The pharmaceutical compositions containing the compound of Formula (I) according to the disclosure are prepared in a manner known to one skilled in the art.
[0082] In an embodiment, the pharmaceutical compositions can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
[0083] For the production of oral dosages form of the compound of Formula (I) such as the pills, tablets, coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, corn starch or compounds thereof, gum arabica, magnesia or glucose. Pharmaceutically acceptable excipients that can be used for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils. Suitable pharmaceutically acceptable excipients for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the said solvents.
[0084] In another embodiment, the pharmaceutical compositions normally contain about 1% to 99%, for example, about 5% to 70%, or from about 10% to about 30% by weight of the compound of Formula (I). The amount of the compound of Formula (I) in the pharmaceutical compositions normally is from about 5 to 500 mg or may be lower than or higher than the lower and the upper limit respectively. The dose of the compound of Formula (I), which is to be administered, can cover a wide range depending on the type of disease or disorder to be treated. The dose to be administered daily is to be selected to suit the desired effect. A suitable dosage is about 0.01 to 100 mg/kg of the compound of Formula (I) depending on the body weight of the recipient (subject) per day, for example, about 0.1 to 50 mg/kg/day of a compound of Formula (I) or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.
[0085] The selected dosage level will depend upon a variety of factors including the activity of a compound of the present disclosure, the route of administration, the time of administration, the rate of excretion of the particular compound being administered, the duration of the treatment, other concurrently administered drugs, compounds and/or materials, the age, sex, weight, condition, general health and prior medical history of the patient (subject) being treated, and like factors well known in the medical arts.
[0086] In addition to the compound of Formula (I) and the pharmaceutically acceptable carrier substances, the pharmaceutical compositions of the present disclosure can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. Furthermore, in addition to a compound of Formula (I), the compositions can also contain one or more other therapeutically or prophylactically active agents.
[0087] In yet another embodiment, the present disclosure provides a process of preparation of compounds of the Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof.
[0088] In an embodiment, the present disclosure provides a compound of Formula I, a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof for use in the treatment, amelioration or prophylaxis of tuberculosis.
[0089] The present disclosure also encompasses within its scope the use of a compound of Formula (I) in combination, with other therapeutically active agents.
[0090] In an embodiment, the combination of compound of present disclosure with another therapeutic agent or treatment includes co-administration of a compound of Formula (I) with the other therapeutic agent or treatment as either a single combination dosage form or as multiple, separate dosage forms, administration of the compound of the present disclosure first, followed by the other therapeutic agent or treatment and administration of the other therapeutic agent or treatment first, followed by the compound of present disclosure. Further, therapeutic agents are administered either simultaneously or sequentially.
[0091] In another embodiment of the present disclosure, the other therapeutic agent may be any agent that is known in the art to treat, prevent, or reduce the symptoms of a disease or disorder. The selection of other therapeutic agent(s) is based upon the particular disease or disorder being treated. Such choice is within the knowledge of a treating physician. Furthermore, the additional therapeutic agent may be any agent when administered in combination with the administration of a compound of the present invention provides benefit to the subject in need thereof.
[0092] In some embodiment, the present disclosure provides a method of treatment, prophylaxis or amelioration of tuberculosis in a subject by administering a therapeutically effective amount of the compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof.
[0093] In some embodiments in vitro Assays as well as in vivo studies were conducted to test the activity of the present compounds against Mycobacteria including drug resistant strains.
[0094] In some embodiments the compounds of formula I were prepared in accordance with the procedures that are well known in the prior art and would be apparent to the person skilled in the art.
[0095] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
EXAMPLES
[0096] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary.
[0097] EXAMPLE 1: Preparation of compounds and their free binding energies
[0098] Fifteen compounds were prepared and the compounds are listed in Table 1. The free binding energies of the compounds were determined in silico and compared with Bedaquiline.

Table 1: Structure of anti-tubercular compounds and their characterization

Compounds Free Binding energy

Compound 1 -7.47

Compound 2 -7.20

Compound 3 -7.60

Compound 4 -7.44

Compound 5 -7.78

Compound 6 -7.49

Compound 7 -7.76

Compound 8 -7.54

Compound 9 -7.67

Compound 10 -8.12

Compound 11 -8.21

Compound 12 -7.31

Compound 13 -7.11

Compound 14 -8.02

Compound 15 -8.04

Bedaquiline -7.57

[0099] EXAMPLE 2: In silico binding studies of compounds against ATP synthase of Mycobacterium tuberculosis
[00100] All the fifteen compounds were docked with X-ray crystal structure of FoF1 ATP synthases of Mycobacterium tuberculosis (PDB ID: 4V1H) (Narang, Rakesh, et al. “Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent.” Eur. J. Med. Chem.182 (2019): 111644), using AutoDock4.2. Ligand structures were drawn using build panel and prepared using Ligprep module implemented Maestro-8.4 (Schrodinger LLC). Energy minimization was carried out using OPLS-2005 force field. Structures were saved in .pdb format and rewritten using open bable for AutoDock compatible atom type. For docking, grid parameter ?le (.gpf) and docking parameter ?les (.dpf) were written using MGL Tools-1.5.6. Receptor grids were generated using 60×60×60 Grid points in xyz with grid spacing of 0.37Å. Grid box was generated by considering active residues (59.822; Y=74.436; Z=30.666). Map types were generated using autogrid 4.2. Docking was carried out with following parameters with number of runs: 50, population size: 150, number of evaluations: 2,500,000 and number of generations: 27,000, using autodock 4.2. Analysis of docking results was done using MGL Tools-1.5.6. Top scoring molecule in the largest cluster was analyzed for its interaction with the protein.
[00101] The in-silico studies confirmed the effective binding at ATP synthase rotor ring complex and destabilization of the complex formation (refer Figures 1, 2 and 3). The binding affinity of the compounds to Mycobacterium tuberculosis FoF1 ATP synthases rotor ring complex was computed to be more than 7.5 kcal/mole.
[00102] EXAMPLE 3: Physicochemical properties of compounds
[00103] In route to evaluate the pharmacokinetic behavior of the compounds, the in-silico ADME parameters of the compounds (Table 1) were calculated using the SwissADME software (http://www.swissadme.ch). While using rational drug design, Lipinski’s rule of five is a precondition to ensure drug-like properties (A. Daina, O. Michielin, V. Zoete (2017) Swiss ADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep. 7: 42717; V.N. Badavath, B.N. Sinha, V. Jayaprakash (2015) Design, in-silico docking and predictive adme properties of novel pyrazoline derivatives with selective human MAO inhibitory activity, Int. J. Pharm. Pharm. Sci. 7: 277–282.). The designed derivatives followed the four properties of Lipinski’s rule of five (mol. wt. = 500 Da; log P o/w = 5; HBD = 5; HBA = 10). Solubility (LogS): Should be > -4. All the ligands displayed ADME parameters in an adequate range and possess noteworthy drug-like characteristics based on Lipinski’s rule of 5 as shown in Table 2.
Table 2: Physicochemical properties of compounds based on Lipinski’s rule of five
Compound Mol. Wt. No. of
HBD No. of
HBA cLog P Log S Lipinski
violation
1 412.32 0 4 3.90 -5.54 No violation
2 412.32 0 4 3.90 -5.54 No violation
3 462.38 0 4 4.55 -6.67 No violation
4 478.38 0 5 3.99 -6.44 No violation
5 490.43 0 4 4.95 -7.14 No violation
9 515.40 0 5 4.03 -7.33 No violation
10 499.40 0 4 4.60 -7.56 No violation
11 465.38 0 4 4.22 -6.73 No violation
14 498.41 0 3 5.64 -8.23 No violation
15 540.40 0 5 5.09 -8.07 No violation
Bedaquiline 555.50 1 4 5.08 -7.82 No violation
HBD: Hydrogen bond donors; HBA: Hydrogen bond acceptors

[00104] From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein merely for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention and should not be construed so as to limit the scope of the invention or the appended claims in any way.

ADVANTAGES OF THE PRESENT INVENTION
[00105] The present disclosure provides anti-tubercular compounds that are less lypophilic and possess lower side-effects.
[00106] The present disclosure provides anti-tubercular compounds that are inhibitors of ATP synthases of Mycobacterium tuberculosis.
[00107] The present disclosure provides anti-tubercular compounds that are effective even against the multi-drug resistant Mycobacterium tuberculosis.

,CLAIMS:1. A quinoline anti-tubercular compound of Formula I, its stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt, or mixtures thereof,

Formula I
wherein
R1 is selected from hydrogen, C1-C6 alkyl or C1-C6 alkoxy;
R2 is selected from -N=CH, or -O-CH2;
R3 is selected from C6-C14 aryl;
R4 is selected from C1-C6 alkoxy, –OOC-C1-C6 alkyl, or –OOC-C1-C6 alkenyl which is unsubstituted or substituted with one or more of -NH2, -N(R5)2, C3-C7 cycloalkyl, C6-C14 aryl, or C5-C14 heterocyclyl; and
R5 is selected from C1-C6 alkyl.
2. The compound as claimed in claim 1 wherein R1 is selected from hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy.
3. The compound as claimed in claim 1 wherein R2 is -N=CH, R3 is phenyl or napthyl, and R4 is ethoxy which is further unsubstituted or substituted with one or more of –N(R5)2 or C5-C14 heterocyclyl.
4. The compound as claimed in claim 1 wherein when R2 is -O-CH2, R3 is napthyl, and R4 is ethoxy or –OOC-ethenyl which is further unsubstituted or substituted with one or more of –N(R5)2, C5-C14 heterocyclyl, C3-C7 cycloalkyl, or C6-C14 aryl.
5. The compound as claimed in claim 1 wherein R4 is ethoxy it may be substituted with -NH2, -N(CH3)2, -N(CH2CH3)2, pyridine, piperidine, pyrazine, thiophene, furan, pyrrole, cyclopropyl, cyclohexyl, or phenyl.
6. The compound as claimed in claim 1, wherein the compound is selected from:
(E)-2-(4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N-dimethylethan-1-amine;
(E)-2-(2-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)phenoxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methoxyquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
(E)-2-((4-(((6-bromo-3-methylquinolin-2-yl)imino)methyl)naphthalen-1-yl)oxy)-N,N-diethylethan-1-amine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromoquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methylquinolin-2-yl)methanimine;
(E)-1-(4-(2-(1l4-pyridin-1-yl)ethoxy)naphthalen-1-yl)-N-(6-bromo-3-methoxyquinolin-2-yl)methanimine;
6-bromo-3-methoxy-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-3-methyl-2-((2-(2-(pyridin-4-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
2-((4-(((6-bromo-3-methylquinolin-2-yl)oxy)methyl)naphthalen-1-yl)oxy)-N,N-dimethylethan-1-amine;
6-bromo-3-methoxy-2-((2-(2-(thiophen-2-yl)ethoxy)naphthalen-1-yl)methoxy)quinoline;
6-bromo-2-((2-(2-cyclopropylethoxy)naphthalen-1-yl)methoxy)-3-methoxyquinoline;
6-bromo-3-methyl-2-((2-phenethoxynaphthalen-1-yl)methoxy)quinoline; or
1-(((6-bromo-3-methoxyquinolin-2-yl)oxy)methyl)naphthalen-2-yl cinnamate.

7. A pharmaceutical composition comprising the compound as claimed in any of the claims 1-7 and a pharmaceutically acceptable excipient.