Accepted Manuscript Coumarin Hybrids As Novel Therapeutic Agents Sonali Sandhu, Yogita Bansal, Om Silakari, Gulshan Bansal PII: DOI: Reference:

S0968-0896(14)00381-2 http://dx.doi.org/10.1016/j.bmc.2014.05.032 BMC 11593

To appear in:

Bioorganic & Medicinal Chemistry

Received Date: Revised Date: Accepted Date:

26 February 2014 8 May 2014 14 May 2014

Please cite this article as: Sandhu, S., Bansal, Y., Silakari, O., Bansal, G., Coumarin Hybrids As Novel Therapeutic Agents, Bioorganic & Medicinal Chemistry (2014), doi: http://dx.doi.org/10.1016/j.bmc.2014.05.032

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COUMARIN HYBRIDS AS NOVEL THERAPEUTIC AGENTS Sonali Sandhu, Yogita Bansal*, Om Silakari, Gulshan Bansal Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala - 147002, Punjab.

*Corresponding author Phone: +91-175-3046255 Fax: +91-175-2283073 E-mail: [email protected]

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Abstract Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, antiinflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer’s disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure-activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.

Keywords: Coumarin, Anticancer, Antimicrobial, Antioxidant, Anti-inflammatory, Antiviral, MAO-B inhibitor, Hybrid.

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Abbreviations: MAO-B, Monoamineoxidase-B; DU145, Androgen receptor negative prostate cell line; DLD-1, Colorectal cell line; H157, Non-small cell lung carcinoma cell line; BT20, Estrogen receptor negative breast cell line; K562, Chronic myeloid leukemia cell line; GI50, Growth inhibition by 50%; JNK, c-Jun N-terminal Kinases; JNK1, c-Jun N-terminal Kinase-1; MCF-7, T47D, MDA-MB-231, Breast cancer cell lines; PI3K, Phosphatidylinositol-3 kinase; C33A, Cervical carcinoma cell line; NIH3T3, Normal fibroblast cell line; SGC-7901, Human gastric cancer cell line; A549, Lung adenocarcinoma cell line; HeLa, Cervical cancer cell line; AAPH, 2,2’-azobis(2-amidinopropane hydrochloride); HL-60, Human promyelocytic leukemia cell line; SK-OV-3, Ovarian adenocarcinoma cell line; CCRF-CEM, leukemia cell line; ROS, Reactive oxygen species; COX, Cyclooxygenase; LOX, Lipoxygenase; LDL, Low-density lipoproteins; DPPH, 2,2-diphenyl-1-picrylhydrazyl; MAOIs, Monoamineoxidase inhibitors; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; MDR, Multidrug resistant; MRSA, Methicillin-resistant Staphylococcus aureus; AChE, Acetylcholinesterase; BuChE, Butylcholinesterase; SH-SY5Y, Neuroblastoma cell line; CAS, Catalytic active site; PAS, Peripheral anionic site; NNRTIs, Non-nucleoside reverse transcriptase inhibitors; RT mutant HIV-1, HIV-1 reverse transcriptase mutant, AR inhibitors; Aromatase inhibitors, SAR; Structure-activity relationship, tVB; trans-vinylbenzene, 4-C-tVB; 4-coumarinyl-tVB, H460; lung carcinoma cell lines, IC50; Half maximal inhibitory concentration, TNF-α; tumor necrosis factor-α, ORAC; oxygen radical absorbance capacity, MIC; minimum inhibitory concentration, TG; triglycerides, TC; Total cholesterol, AD; Alzheimer’s disease, t-RESV; Trans-resveratrol, Aβ; β-amyloid, ALP; Alkaline phosphatase, OCN; Osteocalcin, Col1; type-1 collagen.

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1. INTRODUCTION Coumarins, also known as benzopyran-2-ones, form an elite class of naturally occurring compounds that possess promising therapeutic perspectives. Due to diversity in their structural complexity, these range from simple substituted coumarins to polysubstituted polycyclic/fused coumarins. These belong to the flavonoid class of plant secondary metabolites and have a variety of biological activities, usually associated with low toxicity [1,2]. Scopoletin and esculetin (Figure 1.) are the natural coumarin analogs having antiproliferative, antioxidant and antiinflammatory activities. Cloricromene (Figure 1.) is one of the most exhaustively studied coumarin based anti-inflammatory drug. This inherent biological relevance has attracted significant interest of medicinal chemists in development of novel biologically active molecules using benzopyran-2-one nucleus as a molecular template. The major challenge in developing appropriately functionalized synthetic coumarins is the translation of current knowledge into new potential lead compounds. Beside clinically proven anticoagulant and antithrombotic actions, various coumarin based natural and synthetic derivatives are also found to have anticancer [3], anti-HIV [4,5], antimicrobial [6,7], antioxidant and anti-inflammatory [8,9], antituberculosis [10], anti-influenza [11], anti-Alzheimer [12,13], antiviral [14] and antihyperlipidemic [15,16] activities. Some of the coumarin derivatives, which have made their way to clinics include warfarin

(anticoagulant),

hymecromone

(choleretic

acenocoumarol and

(anticoagulant),

antispasmodic),

armillarisin

carbochromen

A

(coronary

(antibiotic), disease),

phenprocoumon (anticoagulant) and novobiocin (antibiotic) (Figure 1.) [17-19]. Over the last few years, molecular hybridization strategy has emerged as a novel approach that involves conglomeration of two or more pharmacophores in one molecular

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scaffold to develop hybrid multifunctional molecules. The latter have multiple biological activities, modified selectivity profile, different or dual modes of action and/or reduced undesired side effects due to mixing of pharmacophores in one molecule. Such molecules may be further modified to exhibit favorable pharmacokinetics and oral bioavailability. Using this approach, several research groups have designed and synthesized many hybrid molecules. Some prominent examples of such molecules include ziprasidone, duloxetine and ladostigil for multifactorial CNS diseases, and sunitinib and lapatinib for treatment of cancers. Many more hybrid molecules for treatment of other multifactorial diseases (that are highly variable and heterogeneous involving multiple organ systems and targets) such as metabolic disorders, malaria, inflammation, organophosphorous poisoning and ischaemia have been reported, and are reviewed [20-23]. Hybridization or coupling of different coumarin derivatives with varied bioactive molecules such as resveratrol, maleimide sulfonamides, pyrazoline, chalcone, triazoles and α-lipoic acid has produced novel hybrid molecules, which are endowed with vasorelaxant, platelet antiaggregating, anticancer, Monoamineoxidase-B (MAO-B) inhibitory, antimicrobial, antioxidant and anti-inflammatory properties [24-26]. Therefore, molecular hybridization approach is playing an important role in development of novel molecules for treatment of numerous multifactorial diseases. The present review reveals critical analysis of various research reports on development of different coumarin hybrids. The hybrids have been classified on the basis of their biological activities, and structural features pertinent to particular activity are discussed to propose a suitable structure-activity relationship (SAR). This comparative information may help the medicinal chemist to design new coumarin hybrids exhibiting varied bioactivities. 2. BIOLOGICAL ACTIVITIES 2.1 ANTICANCER ACTIVITY

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Anti-cancer drugs, being cytotoxic, exhibit severe side effects, particularly on normal proliferating tissues such as haematopoietic system [27,28]. Often combination therapies, wherein several cytotoxic agents are combined in anticancer treatment regime, offer better results with fewer side effects. Currently, combination of chemotherapy, radiotherapy and surgery offers the best outcomes for cancer patients. Such combinations have been successfully used in treatment of particular cancer types, for example, Hodgkin’s lymphoma, testicular cancer and various leukemias. Researchers are now exploiting natural products having anticancer profile to develop drugs with fewer side effects. Among various phytochemicals, coumarins have attracted considerable interest in the past few years. Coumarins have the potential not only to treat cancer but also to counter the side effects associated with radiotherapy [29]. Hybridizing the coumarin nucleus with other moieties has afforded new molecules with improved anticancer activity profile. Novobiocin (Figure 1), which is an antibiotic that acts through inhibition of DNA gyrase, has been structurally modified to develop series of selective Hsp90 inhibitors (1) [30]. SAR has also been developed, which revealed that replacement of noviose sugar and phenyl ring of benzamido moiety with appropriate groups incur anticancer activity in nM range against a panel of cancer cell lines. Various structural modifications in the sugar moiety revealed that pyranose, a sugar mimic, and piperidine, an aza sugar mimic, are optimal sugar replacements for excellent anticancer activity. Aliphatic sugar replacements (also produced potent novobiocin analogs as cytotoxic agents. The amide linker between coumarin and aryl moiety is important for anticancer activity. Substitution of phenyl ring of the benzamido moiety with biaryl and indole moieties yielded the compounds with low µM (IC50) values against the cell lines.

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Arylsulfonamides, reported as potent inhibitors of various cancer cell lines [31] have been coupled with multifacet coumarin to form a series of coumarin-3-sulfonamides which also possessed potent anticancer activity at very low concentration against androgen receptor negative prostate (DU145), colorectal (DLD-1), non-small cell lung carcinoma (H157), estrogen receptor negative breast (BT20), and chronic myeloid leukemia (K562) cell lines. Exploration of varied substituents at different positions of phenyl and coumarin nuclei has produced compound 2 with GI50 value of less than 16 µM. The compound was suggested to act via activation of c-Jun NH2 kinases (JNK) pathway either by interacting with c-Jun N-terminal Kinase-1 (JNK1) or with one of the upstream kinases in this pathway [32]. Overlapping of coumarin with stilbene led to development of molecules with substituted trans-vinylbenzene (tVB) moiety at 3 or 4-position of coumarin nucleus. The 4-coumarinyl-tVB hybrids (4-C-tVB) were found to possess potent antiproliferative activity against lung carcinoma cell lines (H460). SAR studies revealed that methoxy group at 7-position of coumarin and 3, 5disubstituted pattern of vinylbenzene (3 and 4) show excellent activity with apoptosis inducing capability. Shifting of tVB from C-4 to C-3 on coumarin led to two fold decrease in the activity. The sustituents at para position on vinylbenzene decrease the activity, whereas methoxy group at meta position increase the activity to the level of well known anticancer agent resveratrol. Replacement of methoxy group on coumarin ring with hydroxyl group resulted in two fold decrease in the activity [33].

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3-Arylcoumarins are another type of coumarin-stilbene hybrids, amongst which 5 and 6 are the protypical compounds. Compound 5 exhibits potent anticancer activity with IC50 value of 5.18 mM against KB cell lines [34]. On the other hand, compound 6 is most active against 2,2’azo-bis(2-amidinopropane hydrochloride) (AAPH) induced plasmid pBR322 DNA strand breakage, and exhibit excellent antiproliferative activity against human promyelocytic leukemia cell line (HL-60) and lung adenocarcinoma cell line (A549) [35]. The activity of 6 has been postulated to be due to stabilization of ortho-hydroxyphenoxyl radical through formation of intra-molecular H-bonds. Replacement of the hydroxyl group with methoxy groups produces compound 7 which exhibit though weak antioxidant but highest antiproliferative activity (IC50 value of 5.2 and 7.5 µM in HL-60 and A549 cells). In general, it has been found that hydroxyl group on ring A rather than on ring B incurs higher anticancer activity. Sashidhara et al. have reported coumarin-monastrol hybrids as potential anti breast tumor specific agents, which selectively induce apoptosis in primary and metastatic breast cancer cell lines [36]. SAR studies have shown that increase in number of methoxy groups on phenyl ring present at 3-position of coumarin increases the activity whereas tert-butyl group at 4-position of coumarin is critical for activity. Compound 8 significantly inhibited the proliferation of MCF-7 breast cancer cell lines (IC50 value of 2.4 mM), T47D (IC50 value of 3.1 mM) and MDA-MB-231 (IC50 value of 3.9 mM) at all concentrations in a time dependant manner. It is found equipotent to tamoxifen but less active in comparison to epirubicin. Amin et al. have developed various

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coumarin-pyrazoline hybrids and evaluated against different cancer cell lines [37]. The maximum anticancer activity is exhibited against gastric cancer cell lines with IC50 values ranging from 10 µM to 2.8 mM. Wide range of the aromatic groups are tolerated at 5-position of pyrazoline. In general strong electron withdrawing groups on phenyl ring at 5-position increases the activity. Compound 9 is the most active hybrid with IC50 value of 10 µM.

Benzimidazole nucleus is an important heterocyclic core that provides large artillery of compounds having wide spectrum of pharmacological activities [38]. Conjugation of this nucleus with coumarin has generated benzimidazole-coumarin hybrids, which are screened for in vitro antitumor activity on different cell lines. The representative compound 10 at a concentration of 10 µM causes more than 50% inhibition of most of the cell lines, with higher selectivity against leukemic cancer cell lines [39]. Hybridization of variedly substituted coumarins with different chalcones has yielded a series of molecules exemplified by compound 11, which exhibit good anticancer activities (IC50 value of 3.59-8.12 µM) [40]. SAR study has revealed that a substituent at 3-position of coumarin plays a pivotal role in incurring anticancer activity. Esteric groups incur/increase the activity significantly better than ketones. On the other hand, an electron withdrawing group such as chloro at para position of chalcone diminishes the selectivity for

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cancer cell lines. Compound 11 is the most promising member from the series which shows around 30-fold more selectivity towards cervical carcinoma cell lines (C33A) over normal fibroblast cell line (NIH3T3). A series of novel potential telomerase inhibitors has been synthesized by hybridizing coumarin with substituted 4,5-dihydropyrazoles [41]. Compound 12, prototype of the series, has been found to exhibit high activity against human gastric cancer cell (SGC-7901) having IC50 value of 2.69 µg/mL. Docking studies have suggested that 4,5-dihydropyrazole ring, acyl group and coumarin nucleus are critical elements for potent inhibitory activity and key factors in controlling telomerase selectivity. Another series of coumarin-pyrazole hybrids (13 and 14) has been found to exhibit good in vitro cytotoxicity against DU-145, A549 and cervical cancer cell line (HeLa). SAR studies have revealed that substituents, irrespective of their electronic nature, on pyrazole nucleus display very good activity when compared to substitution present on coumarin [42].

Src kinase is key modulator of cancer cell invasion and metastasis activity. Evaluation of a series of 6- and 8- cinnamoylchromen-2-one and dihydropyranochromen-2-one derivatives for Src kinase inhibitory activity as well as antiproliferative activities against three human cancer cell lines revealed that 8-cinnamoylchromen-2-one have higher antiproliferative activity than 6cinnamoyl analogues. Compound 15 was found to be the most toxic to all tested cancer cell lines i.e. Ovarian adenocarcinoma cell line (SK-OV-3), leukemia cell line (CCRF-CEM) and MCF-7

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with growth inhibition of 63%, 50% and 43% at the concentration of 50 µM, respectively. It also exhibited the highest Src kinase inhibition with IC50 value of 14.5 µM. SAR studies further indicate that a 3,5-disubstitution on phenyl ring of the cinnamoyl moiety enhances the antiproliferative activity and presence of cinnamoyl moiety at 6-position of coumarin is more favorable for Src kinase inhibition [43].

Imidazole or triazole ring are important components of anastrozole, vorozole and letrozole, which are clinically available selective aromatase (AR) inhibitors. Leonetti et al have hybridized these heteronuclear rings with fluorene, indenodiazine and coumarin scaffolds and evaluated the hybrid compounds for their inhibitory activities against AR (CYP 19) and 17Rhydroxylase/C17,20-lyase (CYP17) [44]. Coumarin hybrids displayed high potency and selectivity against AR. Compound 16 emerged as the most potent molecule with an IC50 value of 51 nM (363 fold more active than aminoglutethimide) and also with good degree of selectivity for CYP19. Expanding the scope of the coumarin hybrids as selective AR inhibitors, the same authors further explored different functional groups on 16. Replacement of phenoxy group with benzyloxy group decreased the activity whereas different substituents on the phenoxy ring maintained the AR inhibitory activity [45]. 2.2 ANTIOXIDANT AND ANTI-INFLAMMATORY ACTIVITIES Inflammation is a self-protective response of body, which induces physiological adaptations to reduce tissue damage and to eliminate the inflammatory stimuli. Reactive oxygen species (ROS)

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like superoxide radical anion, hydrogen peroxide and hydroxyl radical produced during inflammation act indirectly as cellular messengers and elicit an inflammatory response through different mechanism [46-48]. Gastric ulceration is the major side effect associated with NSAID therapy, and it is overwhelmed by antioxidants [49]. Since oxidative stress has been associated with inflammation process, the discovery of molecules eliciting both anti-inflammatory and antioxidant activities may lead to drugs with an improved therapeutic index [50]. Coumarin and related derivatives intercept arachidonic acid metabolism through lipoxygenase (LOX) or cycloxygenase (COX) inhibition [51]. These also possess good antioxidant activity, and for this, Kostova et al. has provided a complete update in very comprehensive manner [52]. Umbelliferone, fraxetin and daphnetin are three prominent examples of naturally derived coumarin derivatives that have potent anti-inflammatory activity. Various reports on coupling of individual pharmacophores responsible for antioxidant and anti-inflammatory activities to yield novel anti-inflammatory-antioxidant coumarin hybrids are reviewed. Coupling of chalcones (butein, licochalcones), having radical scavenging activity [5356], with coumarin has yielded a series of compounds, amongst which compounds 17-19 exhibited 29%, 26% and 33% (200 µg/ml) anti-inflammatory activity as well as 47%, 43% and 21% inhibition (400 µg/ml) of tumor necrosis factor-α (TNF-α), respectively [57]. However, there is no correlation found between anti-inflammatory and radical scavenging potential of the active molecules. It may be attributed to variation in proton–electron transfer by the derivatives due to difference in their structures and stability. Further exploring the potential of coumarinchalcone hybrids, Perez-cruz et al. have reported synthesis, electrochemical and biological evaluation of these hybrids. Electrochemical studies revealed all compounds to possess high radical scavenging potential. Compound 20 presented the highest oxygen radical absorbance

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capacity (ORAC) value (14.1), good scavenging capacity, low cytotoxicity, and high cytoprotection values (almost 100% cell viability at 20 µM), especially against ONOO− induced cell death. The antioxidant activity has been attributed to the –OH group, which form intramolecular H-bond with carbonyl oxygen of the pyrone ring, and hence disfavoring the H-transfer [58].

Coupling of heterocyclic pharmacophore such as chromone (21), benzofuran (22) and 4hydroxycoumarin (23), which are known to have anti-inflammatory activity, with a coumarin moiety at its 4-position through an ether linkage has revealed that benzofuranyl ethers incurs higher activity than the other heterocycles. SAR studies around the coumarin ring revealed that methoxy and chloro substituent at 6-position on coumarin ring increase the activity [59]. Another series of anti-inflammatory-antioxidant adducts has been developed by coupling coumarin-3-carboxamides with α-lipoic acid or aminoamide. While the α-lipoic acid adduct (24) shows moderate LOX inhibitory activity (18%), the aminoamide adduct 25 shows 100% LOX inhibition at concentration of 0.1 mM [26]. Jayashree et al. have reported a series of pyrazoles conjugates of coumarins, amongst which compounds 26 and 27 have potent anti-inflammatory and analgesic activities [60]. All compounds showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity with IC50 value of 60 to 280 µg/ml. The anti-inflammatory and

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antioxidant activities were comparable to aspirin with longer duration of action. Similarly, conjugation of pyrazoline derivatives (potent anti-inflammatory agents) with coumarin has yielded adducts (28) with significant analgesic and antipyretic activities but less ulcerogenic potential [61].

2.3 MAO INHIBITORY ACTIVITY MAO inhibitors (MAOIs) are used for the treatment of depressive disorders, anxiety disorders, Parkinson’s and Alzheimer’s disease. The classical, nonselective and irreversible MAOIs have the risk of inducing hypertensive crisis. On the other hand, selective MAOIs are though free from this risk but have other side effects such as agitation, hallucinations, hyperpyrexia and convulsions. So, there is a challenge for researchers to develop a preventive medication that can slow down the decline of catecholaminergic system in aged brain but has fewer side effects. Different research groups have reviewed research reports on variedly substituted coumarin derivatives as MAOIs, which may aid to develop more selective and safe agents [62-64]. Matos et al. have explored the potential of variedly substituted 3-phenylcoumarins (coumarin-resveratrol hybrids) to inhibit MAO [65-67]. All compounds from the series showed high selectivity for MAO-B isoenzyme with very low IC50 values. Initial reports suggested

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compound 29 (3’,5’-dimethoxyphenyl derivative) to be the most potent. Increase in number of methoxy groups decreased the activity. Subsequent studies have revealed that 5’-methoxy analog (30) exhibits an extraordinary low IC50 value of 802.6 pM against MAO-B. Further, a bromine at 8-position of coumarin nucleus (31) enhanced the MAO-B inhibitory property than at 2-position of phenyl ring (15 times loss of the activity).

2.4 ANTIVIRAL ACTIVITY Viral and Human immunodeficiency viral (HIV) infections have no complete and effective remedy, and hence are posing the greatest threats to human health. The classical treatment involves use of drugs that have serious side effects. Owing to the urgent need for new drugs, compounds having multiple functional scaffolds are synthesized [68].

Heteronuclei such as imidazopyridine (32), purine (33), benzoxazole (34), benzothiazole (35) and benzimidazole (36) and its nucleoside (37) have been linked to the coumarin nucleus via methylenethio linker, and evaluated for antiviral activity on HUH 5-2 cells. SAR study suggested that while coumarin is an essential scaffold for the activity, the potency decreased in the order of purine conjugates (33, EC50 values of 2.0 µM), imidazopyridine conjugates (32, EC50

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values of 6.8 µM) and benzoxazole conjugates (34, EC50 values of 12 µM). Further, presence of a bromo or methoxy substituent on coumarin nucleus increases the activity of the conjugates. Incorporation of an arene moiety on benzimidazole does not improve the activity whereas peracetyl 2-deoxy-β-D-glucose increases the Hepatitis C virus (HCV) inhibition by 8.2 fold compared to unsubstituted benzimidazole conjugates [69]. A recent study by Tsay et al reports that direct hinging of benzimidazole nucleus with coumarin (38-40) affords better antiviral profile (IC50 value of 3.0 µM) in comparison to compounds 36 (IC50 value of 10 µM). It is attributed to methylenethio linker in 36, which discourages intra-molecular H-bond between benzimidazole and coumarin. Compounds 38-40 exhibited potent anti-HCV activity with IC50 values of 3.0, 5.5 and 20 µM, respectively. SAR studies have revealed that attachment of methyl group(s) to benzimidazole (38, 39) lead to remarkable increase in the activity. Appendage of methyl, bromo or methoxy substituent on coumarin nucleus reduces cytotoxicity and anti-HCV activity whereas fusion of benzene ring (39) increases the activity. Incorporation of β-Dribofuranose (40) also leads to potent compounds [70].

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A series of coumarin-triazine hybrids, reported as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), has been explored against different strains of HIV i.e., HIV-1 (III-B), HIV-2 (ROD), and double RT mutant HIV-1 (K103N and Y181C). Compound 41 is the most potent with IC50 value of 1 µg/ml against all strains whereas compounds 42-45 display selective activity against HIV-1 [71]. Coumarin-chalcone hybrids are inactive against both HIV1 and HIV-2 strains [72]. 2.5 ANTIMICROBIAL ACTIVITY Conventional antimicrobial therapy is going through an efficacy crisis due to rapidly developing resistance to existing antimicrobial agents [73]. Till date, the number of multidrug-resistant (MDR) bacteria is increasing, and of particular importance is the gram-positive methicillinresistant Staphylococcus aureus (MRSA). The ability of S. aureus to develop resistance to virtually all antibiotics is a major concern, and it is essential that new antimicrobial agents are discovered to combat this problem. A few antibiotics with coumarin skeleton have been isolated that are active against these MDR bacteria. The most active of these is novobiocin isolated from Streptomyces niveus, which is mainly active against gram-positive bacteria. These coumarin antibiotics are potent inhibitors of DNA replication [74]. Importance of coumarins for their antibacterial properties, and presence of triazole in antifungals such as fluconazole, itraconazole and voriconazole prompted Shi et al. to develop coumarin-triazole hybrids having antimicrobial activity against gram-positive, gram-negative bacteria as well as some fungi. The resultant hybrid compounds exhibit antimicrobial activity comparable to or even greater than reference drugs such as enoxacin, chloromycin and fluconazole. Bis-triazoles (46) display much stronger antimicrobial efficay than the monotriazoles. The linker between triazole and coumarin nucleus is optimised to be butylene ((CH2)4)

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as in compound 46 MIC of 2 µg/ml, which is two and eight fold more active than enoxacin and chloromycin, respectively [75]. O

4

N

R

N N

O

O

O

4

H N

N

O

O

N

N

O

46 N3

O

O H N S O

S

47

O2N R

O

S N H

OH

N O

48

O

49

A thiazolidine ring, which is an important component of penicillin is appended to coumarin to generate 7-(2-substituted phenylthiazolidinyl)-benzopyran-2-ones (47). These compounds exhibit antimicrobial activity comparable to ciprofloxacin and griesofulvin. Replacement of phenyl ring with furan decreases the activity. Further, substitution at p-position of the phenyl ring is important for the activity [76]. The coumarin-sulfonamide hybrids (48) show significant antimicrobial activity against both gram-positive and gram-negative species, in most cases equivalent to ciprofloxacin. The compounds having methoxy, chloro and nitro substituents at either o-, m- or p-position have MIC ranging from 1-2 µg/ml. It suggested that activity is neither influenced by the position of the substituent nor by its electronic nature [77]. 2-Aminothiazole hybrids of coumarin exhibit moderate in vitro activity with MIC in the range of 31.25 µg/mL-500 µg/mL. Compound 49 (MIC of 31.25 µg/ml) emerged as the most potent antibacterial agent having activity equal to streptomycin [78].

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Coumarin-pyrazole hybrids (50) as well as bis-coumarins linked via hydroxyl ethers (51) have also potent in vitro antimicrobial activities against gram-positive bacteria, Staphylococcus aureus, Bacillus cereus, and gram-negative salmonella, at concentration of 1 mg/ml. Biscoumarins inhibit the bacterial growth with greater potency in comparison to coumarin-pyrazole derivatives [79].

1,2,4-Triazolo[1,5-a]pyridines (52), pyrido[1,2-b][1,2,4]triazines (53), and pyrido[1,2b][1,2,4]triazepines (54) having a wide spectrum of pharmacological activities have been linked with a chromone moiety to obtain potent antimicrobial agents. All compounds exhibit moderate to high antimicrobial activity. The triazole-pyridine conjugate (52) show the highest activity with an average zone of inhibition being 20.5, against gram-positive, gram-negative and some fungal strains [80].

Trioxane is reported to be essential for antimalarial activity of artimisinin. Its appendage to coumarin has yielded coumarin-trioxane hybrids, which have IC50 in the range of 39.28– 360.53 ng/mL against CQ sensitive 3D7 strain of P. falciparum. A bulky aliphatic group at 8-

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position on coumarin nucleus increases the activity whereas substitution of phenyl ring on trioxane moiety by either an electron-donating or withdrawing group does not affect the activity. Out of these hybrids, compound 55 has shown an in vivo suppression of 41.1% MDR P. yoelii nigeriensis at the dose of 96 mg/kg/day administered for 4 days [81].

Coumarin-triazole coupled hybrids exhibit antitubercular and antimicrobial activities better than the coumarin-triazole fused hybrids. From the coupled hybrid series, compound 56 is found as active as streptomycin with MIC of 6.25 µg/mL whereas compound 57 (the methoxy substituted analog) has antifungal activity higher than fluconazole. Fusion of a benzene unit with benzo ring of coumarin also increases the antimicrobial activity [82]. 2.6 ANTIHYPERLIPIDEMIC ACTIVITY ‘Statins’ constitute the major therapeutic force for treatment of hyperlipidemia. However, these have some side effects like muscle fatigue, type 2 diabetes, liver damage and digestive problems [83]. In addition to this, some clinical trials have reported that statins do not show significant effect, and are being used indiscriminately even when the patient has no history of cardiovascular disease. Naturally derived coumarins such as esculetin inhibit oxidative low density lipoproteins (LDL) and umbelliferone possess good lipid lowering potential [84]. Many synthetic derivatives of coumarins have also emerged as good leads. Hybridization of coumarin with an indole moiety, which is present in various synthetic statins like fluvastatin and antiostatins, has yielded coumarin-indole hybrids. Among these,

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compound 58 at the dose of 10 mg/kg significantly decrease the plasma triglycerides (TG) and total cholesterol (TC) by 55% and 20%, respectively, and increase the HDL-C/TC ratio by 42 [85]. The same research group has also synthesized coumarin-chalcone fibrates, and these are found to reverse the triton-induced increased plasma levels of lipid. These hybrids inhibited the biosynthesis of cholesterol and enhanced the activity of lipolytic enzyme, lipoprotein lipase, to facilitate early clearance of lipids from circulation in triton-induced hyperlipidemia. Compound 59 has been found to be the most persuasive as it shows 26%, 24% and 25% lowering in TC, PL and TG levels, respectively at the dose of 100 mg/kg [86].

2.7 MISCELLANEOUS ACTIVITIES Trans-resveratrol (t-RESV) provides protection against coronary heart disease due to its significant antioxidant activity, ability to modulate lipoprotein metabolism, vasodilatory and platelet antiaggregatory properties [87-90]. Its coupling with coumarin has yielded a coumarinresveratrol hybrid (60), which is a potent vasorelaxant and platelet aggregation inhibitor. Its inhibitory activity is greater (IC50 value of 10.55 µM) than that of t-RESV (IC50 value of 19.95 M). Replacement of hydroxyl group with methoxy decreases the activity [24]. These hybrids have also been explored for in vitro tyrosinase inhibitory activity [91]. Comparative study on the importance of number and position of ether, hydroxyl and bromo group has revealed that halogen, particularly bromo, increases the activity whereas hydroxyl groups incur more activity in comparison to methoxy and ethoxy groups.

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A series of novel coumarin-tacrine hybrids has been synthesized and evaluated for their efficacy in Alzheimer’s disease (AD) through assessment of cholinesterase inhibition, selfinduced β–amyloid (Aβ) (1-42) aggregation inhibition and metal chelation. Compound 61 exhibits maximum acetylcholinesterase (AChE) inhibition (IC50 value of 0.092 µM), being 3 and 29 times higher than that by tacrine (IC50 value of 0.3 µM) and galanthamine (IC50 value of 2.67 µM), respectively. The compound is also devoid of any toxicity as tested on neuroblastoma cells (SH-SY5Y). In contrast, compound 62 exhibits the strongest inhibition against BuChE (IC50 value of 0.099 µM), 128 fold more higher than galanthamine (IC50 value of 12.7 µM). The results have suggested that increase in length of linker decreases the selectivity towards butylcholinesterase (BuChE). A methyl group at 4-position of coumarin increases the activity, and its replacement by methoxy group decreases the AChE inhibitory activity to lesser extent but the BuChE inhibitory activity to greater extent. Introduction of a bulky or phenyl group at 4position of coumarin causes a significant decrease in inhibitory activities against both AChE and BuChE. Kinetic study has revealed the compounds to exhibit mixed type of inhibition. Compound 61 has also shown the greatest inhibition of self-induced Aβ (1-42) aggregation

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(67.8%) at concentration of 20 µM. All compounds effectively chelate Cu2+ and Fe2+, and therefore, can serve as metal chelators to treat AD. Molecular docking studies have suggested that compounds can bind to catalytic active site (CAS), peripheral anionic site (PAS) and midgorge site of AChE [92]. An alkylamine placed at appropriate distance from a heterocyclic moiety interacts with additional bindig site of AChE. Based on this structural feature, Catto et al. have synthesized two series of coumarin-alkylamine conjugates linked via amide/ether linker for the treatment of AD. Compounds are found very potent with IC50 value as low as 30 nM for AChE inhibition. Compound 63 has emerged as the most potent and selective AChE inhibitor with IC50 value of 7.6 nM, and acts as a dual binding site inhibitor. SAR studies reveal that replacing an amide linker with an ether linker leads to increase in the activity. However, elongation of the ether linker decreases the activity [93]. Elsinghorst has reported gorge spanning, high affinity competitive inhibitor of cholinesterase as probe for characterizing AChE inside Aβ plaques. The novel probe is designed as a non-irreversible, mixed-type inhibitor having a fluorophore located at the PAS, and the linker spanning across the gorge to place a tacrine-derived moiety at the active site. Compound 64 exhibits inhibition of human AChE with IC50 value in pM range, but 15-fold less active against human BChE. It also shows high fluorescence intensity, which facilitates imaging of Aβ plaques leading to the hypothesis that it binds to plaques themselves or to cholinesterase inside the plaques [94].

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Sashidhara et al. have synthesized coumarin-dihydropyridine hybrids for the treatment of postmenopausal osteoporosis. The hybrid compounds exhibit significant activity against alkaline phosphatase (ALP, a marker of osteoblast differentiation) activity in primary calvarial osteoblasts at, as low as, 1 pM concentration, and are devoid of any toxicity to osteoblast cells. Compound 65 (with substituted or fused dihydropyridine) has anti-ALP activity as well as increases the mineralizing ability, which is an indicator of osteogenic activity. The fused dihydropyridine derivatives are more potent and show approximately 65−70% (100 pM) increased mineralization. These compounds also increase the expression of osteogenic genes including Runx-2, BMP-2, ALP, osteocalcin (OCN), and type I collagen (ColI) in calvarial osteoblast cells from ~1.5 to ~3.0 fold [95]. 3. CONCLUSION Conjugation of coumarin with varied pharmacophores responsible for different biological activities has yielded many novel hybrid molecules, which have improved therapeutic profile and/or pharmacokinetics. The present review provides a wide outlook on the research and developments on these coumarin hybrids. The purpose is to develop structure-activity relationships for such hybrids, which can help a medicinal chemist to choose appropriate core and functional groups in order to design effective and safer molecules for treatment of varied disorders. The most explored therapeutic areas for development of these molecules include cancer, inflammation and microbial infections. A critical analysis of various reports on coumarin hybrids developed as anticancer, anti-inflammatory and antimicrobial is summarized in Table 1. Various moieties explored at different positions of coumarin core for each of the three above mentioned activities are given in the left column. Based on the structural similarities among different categories of heterocycles and functional groups, we have proposed other possible

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moieties around the coumarin core for each activity in the right column. Though coumarin derivatives constitute a large chunk of natural and synthetic compounds belonging to different therapeutic classes, these are not extensively explored for the development of novel molecules. Molecular hybridization is an attractive strategy, through which coumarin pharmacophores can be coupled or fused with other pharmacophores to develop novel therapeutic drugs that can be used for treatment of even complex multifactorial diseases. REFERENCE [1]

Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem. 2005, 12, 887.

[2]

Borges, M. F. M.; Roleira, F. M. F.; Villares, E. U.; Penin, L. S. In: Frontiers in Medicinal Chemistry; Atta-ur-Rahman, A. B. Reitz, M. I. Choudhary, Eds.; Bentam Science Publishers Ltd., 2008; Vol. 4, pp 23-85.

[3]

Riveiro, M. E.; Moglioni, A.; Vazquez, R.; Gomez, N.; Facorro, G.; Piehl, L.; de Celis, E. R.; Shayo, C.; Davio, C. Bioorg. Med. Chem. 2008, 16, 2665.

[4]

Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H.; McMahon, J. B.; Currens, M. J.; Buckheit, R. W.; Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1993, 36, 1110.

[5]

Shikishima, Y.; Takaishi, Y.; Honda, G.; Ito, M.; Takfda, Y.; Kodzhimatov, O. K.; Ashurmetov, O.; Lee, K. H. Chem. Pharm. Bull. 2001, 49, 877.

[6]

Ostrov, D. A.; Hernandez Prada, J. A.; Corsino, P. E.; Finton, K. A.; Le, N.; Rowe, T.C. Antimicrob. Agents Chemother. 2007, 51, 3688.

[7]

Gormley, N. A.; Orphanides, G.; Meyer, A.; Cullis, P. M.; Maxwell, A. Biochemistry. 1996, 35, 5083.

25

[8]

Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10, 3813.

[9]

Bansal, Y.; Sethi, P.; Bansal, G. Med. Chem. Res. 2013, 22, 3049.

[10]

Manvar, A.; Bavishi, A.; Radadiya, A.; Patel, J.; Vora, V.; Dodia, N.; Rawal, K.; Shah, A. Bioorg. Med. Chem. Lett. 2011, 21, 4728.

[11]

Yeh, J. Y.; Coumar, M. S.; Horng, J. T.; Shiao, H. Y.; Lee, H. L. J. Med. Chem. 2010, 53, 1519.

[12]

Anand, P.; Singh, B.; Singh, N. Bioorg. Med. Chem. 2012, 20, 1175.

[13]

Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancinni, F.; Recanatini, M.; Andrisana, V.; Rampa, A. Bioorg. Med. Chem. Lett. 2008, 18, 423.

[14]

Curini, M.; Epifano, F.; Maltese, F.; Marcotullio, M. C.; Gonzales, S. P.; Rodriguez, J. C. Aust. J. Chem. 2003, 56, 59.

[15]

Yuce, B.; Danis, O.; Ogan, A.; Sener, G.; Bulut, M.; Yarat, A. Arzneim. Forsch. Drug Res. 2009, 59, 129.

[16]

Madhavan, G. R.; Balraju, V.; Mallesham, B.; Chakrabarti, R.; Lohray, V. B. Bioorg. Med. Chem. Lett. 2003, 13, 2547.

[17]

Wu, L.; Wang, X.; Xu, W.; Farzaneh, F.; Xu, R. Curr. Med. Chem. 2009, 16, 4236.

[18]

Kulkarni, M. V.; Kulkarni, G. M.; Lin, C. H.; Sun, C. M. Curr. Med. Chem. 2006, 13, 2795.

[19]

Heide, L. Nat. Prod. Rep. 2009, 26, 1241.

[20]

Bansal, Y.; Silakari, O. Eur. J. Med. Chem. 2014, 76, 31.

[21]

Geldenhuys, W. J.; Youdim, M. B. H.; Carroll, R. T.; Van der Schyf, C. J. Prog. Neurobiol. 2011, 94, 347.

26

[22]

Zhang, H. Y. FEBS Lett. 2005, 579, 5260.

[23]

Geldenhuys, W. J.; Van der Schyf, C. J. Int. Rev. Neurobiol. 2011, 100, 107.

[24]

Vilar, S.; Quezada, E.; Santana, L.; Uriarte, E.; Yanez, M.; Fraiz, N.; Alcaide, C.; Cano, E.; Orallo, F. Bioorg. Med. Chem. Lett. 2006, 16, 257.

[25]

Song, H. Y.; Ngai, M. H.; Song, Z. Y.; MacAry, P. A.; Hobley, J.; Lear, M. J. Org. Biomol. Chem. 2009, 7, 3400.

[26]

Melagraki, G.; Afantitis, A.; Igglessi, M. O.; Detsi, A.; Koufaki, M.; Kontogiorgis, C.; Hadjipavlou, L. D. Eur. J. Med. Chem. 2009, 44, 3020.

[27]

Fesik, S. W. Nat. Rev. Cancer. 2005, 5, 876.

[28]

Sloane, D. Methods Mol. Biol. 2009, 471, 65.

[29]

Agarwal, R. Biochem. Pharmacol. 2000, 6, 1042.

[30]

Zhao, H.; Donnelly, A. C.; Kusuma, B. R.; Brandt, G. E. L.; Brown, D.; Rajewski, R. A.; Vielhauer, G.; Holzbeierlein, J.; Cohen, M. S.; Blagg, B. S. J. J. Med. Chem. 2011, 54, 3839.

[31]

Rubenstein, S. M. ;Baichwal, V.; Beckmann, H.; Clark, D. L.; Frankmoelle, W.; Roche, D.; Santha, E.; Schwender, S.; Thoolen, M.; Ye, Q.; Jaen, J. C. J. Med. Chem. 2001, 44, 3599.

[32]

Reddy, N. S.; Mallireddigari, M. R.; Cosenza, S.; Gumireddy, K.; Bell, S. C.; Reddy, E. P.; Reddy, M. V. R. Bioorg. Med. Chem. Lett. 2004, 14, 4093.

[33]

Belluti,

F.;

Fontana, G.; Bo, L. D.; Carenini, N.; Giommarelli, C.; Zunino, F. Bioorg. Med. Chem. 2010, 18, 3543.

27

[34]

Xiao, C. F.; Tao, L. Y.; Sun, H. Y.; Wei, W.; Chen, Y.; Fu, L. W.; Zou, Y. Chin. Chem. Lett. 2010, 21, 1295.

[35]

Yang, J.; Liu, G. Y.; Dai, F.; Cao, X. Y.; Kang, Y. F.; Hu, L. M.; Tang, J. J.; Li, X. Z.; Li, Y.; Jin, X. L.; Zhou, B. Bioorg. Med. Chem. Lett. 2011, 21, 6420.

[36]

Sashidhara, K. V.; Avula, S. R.; Sharma, K.; Palnati, G. R.; Bathula, S. R. Eur. J. Med. Chem. 2013, 60, 120.

[37]

Amin, K. M.; Eissa, A. A. M.; Abou-Seri, S. M.; Awadallah, F. M.; Hassan, G. S. Eur. J. Med. Chem. 2013, 60, 187.

[38]

Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208.

[39]

Paul, K.; Bindal, S.; Luxami, V. Bioorg. Med. Chem. Lett. 2013, 23, 3667.

[40]

Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem. Lett. 2010, 20, 7205.

[41]

Liu, X. H.; Liu, H. F.; Chen, J.;Yang, Y.; Song, B. A.; Bai, L. S.; Liu, J. X.; Zhu, H. L.; Qi, X. B. Bioorg. Med. Chem. Lett. 2010, 20, 5705.

[42]

Kumar, J. A.; Saidachary, G.; Mallesham, G.; Sridhar, B.; Jain, N.; Kalivendi, S. V.; Rao, V. J.; Raju, B. C. Eur. J. Med. Chem. 2013, 65, 389.

[43]

Chand, K.; Shirazi, A. N.; Yadav, P.; Tiwari, R. K.; Kumari, M.; Parang, K.; Sharma, S. K. Can. J. Chem. 2013, 91, 741.

[44]

Leonetti, F.; Favia, A.; Rao, A.; Aliano, R.; Paluszcak, A.; Hartmann, R. W.; Carotti, A. J. Med. Chem. 2004, 47, 6792.

[45]

Stefanachi, A.; Favia, A. D.; Nicolotti, O.; Leonetti, F.; Pisani, L.; Catto, M.; Zimmer, C.; Hartmann, R. W.; Carotti, A. J. Med. Chem. 2011, 54, 1613.

28

[46]

Halliwell, B.; Aeschbach, R.; Loliger, J.; Aruoma, O. I. Food Chem. Toxicol. 1995, 33, 601.

[47]

Garrido, G.; Lez, D. G.; Del porte, C.; Backhouse, N.; Quinterno, G.; Nunez-Selles, A. J.; Morales, M. A. Phytother. Res. 2001, 15, 18.

[48]

Winrow, V. R.; Winyard, P. G.; Morris, C. G.; Blake, D. R. Br. Med. Bull. 1993, 49, 506.

[49]

Kourounakis, P. N.; Tsiakitzis, K.; Kourounakis, A.P.; Galanakis, D. Toxicology. 2000, 144, 205.

[50]

Detsi, A.; Bouloumbasi, D.; Prousis, K. C.; Koufaki, M.; Athanasellis, G.; Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Kontogiorgis, C.; Hadjipavlou-Litina, D. J. J. Med. Chem. 2007, 50, 2450.

[51]

Kontogiorgis, C. A.; Hadjipavlou-Litina, D. J. Enzyme Inhib. Med. Chem. 2003, 18, 63.

[52]

Kostova, I.; Bhatia, S.; Grigorov, P.; Balkansky, S.; Parmar, V. S.; Prasad, A. K.; Saso, L. Curr. Med. Chem. 2011, 18, 3929.

[53]

Bandgar, B. P.; Gawande, S. S.; Bodade, R. G.; Totre, J. V.; Khobragade, C. N. Bioorg. Med. Chem. 2010, 18, 1364.

[54]

Kontogiorgis, C. A.; Hadjipavlou, L. D. J. Med. Chem. 2005, 48, 6400.

[55]

Nowakowska, Z. Eur. J. Med. Chem. 2007, 42, 125.

[56]

Okada, K.; Tamura, Y.; Yamamoto, M. Y.; Inoue, R.; Takagaki, K.; Takahashi, S.; Demizu, K.; Kajiyama,Y.; Kinoshita, T. Chem. Pharm. Bull. 1989, 37, 2528.

[57]

Sashidhara, K. V.; Kumar, M.; Modukuri, R. K.; Sonkar, R.; Bhatia, G.; Khanna, A. K.; Rai, S.; Shukla, R. Bioorg. Med. Chem. Lett, 2011, 21, 4480.

29

[58]

Perez-Cruz, F.; Vazquez-Rodriguez, S.; Matos, M. J.; Herrera-Morales, A.; Villamena, F. A.; Das, A.; Gopalakrishnan, V.; Olea-Azar, C.; Santana, L.; Uriarte, E. J. Med. Chem. 2013, 56, 6136.

[59]

Ghate, M.; Kusanur, R. A.; Kulkarni, M. V. Eur. J. Med. Chem. 2005, 40, 882.

[60]

Jayashree, B. S.; Arora, S.; Nayak, Y. Pharmacologyonline. 2008, 2, 404.

[61]

Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P. K.; Mamledesai, S.; Thippeswamy, A. H. M.; Satyanarayana, D. Eur. J. Med. Chem. 2009, 44, 1682.

[62]

Yamada, M.; Yasuhara, H. Neurotoxicology. 2004, 25, 215.

[63]

Joao, M.; Maria-Vina, D.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L. Curr. Top. Med. Chem. 2012, 12, 2210.

[64]

Patil, P. O.; Bari, S. B.; Firke, S. D; Deshmukh, P. K.; Donda , S. T.; Patil, D. A. Bioorg. Med. Chem. 2013, 21, 2434.

[65]

Matos, M. J.; Vina, D.; Quezada, E.; Picciau, C.; Delogu, G.; Orallo, F.; Santana, L.; Uriarte, E. Bioorg. Med. Chem. Lett. 2009, 19, 3268.

[66]

Matos, M. J.; Vina, D.; Picciau, C.; Orallo, F.; Santana, L.; Uriarte, E. Bioorg. Med. Chem. Lett. 2009, 19, 5053.

[67]

Matos, M. J.; Vina, D.; Janeiro, P.; Borges, F.; Santana, L.; Uriarte, E. Bioorg. Med. Chem. Lett. 2010, 20, 5157.

[68]

Asres, K.; Seyoum, A.; Veeresham, C.; Bucar, F. Phytother. Res. 2005, 19, 557.

[69]

Neyts, J.; Clercq, D. E.; Singha, R.; Chang, Y. H.; Das, A. R.; Chakraborty, R. K.; Hong, S. C.; Tsay, S.; Hsu, M.; Hwu, J. R. J. Med. Chem. 2009, 52, 1486.

30

[70]

Tsay, S.; Hwu, J. R.; Singha, R.; Huang, W.; Chang, Y. H.; Hsu, M.; Shieh, F.; Lin, C.; Hwang, K. C.; Horng, J.; Clercq, E. D.; Vliegen, I.; Neyts, J. Eur. J. Med. Chem. 2013, 63, 290.

[71]

Mahajan, D. H.; Pannecouque, C.; Clercq, E. D.; Chikhalia, K. H. Arch. Pharm. Chem. Life Sci. 2009, 342, 281.

[72]

Trivedi, J. C.; Bariwal, J. B.; Upadhyay, K. D.; Naliapara, Y. T.; Joshi, S. K.; Pannecouque, C. C.; Clercq, E. D.; Shah, A. Tetrahedron. Lett. 2007, 48, 8472.

[73]

Ojala, T.; Remes, S.; Haansuu, P.; Vuorela, H.; Hiltunen, R.; Haahtela, K.; Vuorela, P. J. Ethnopharmacol. 2000, 73, 299.

[74]

Smyth, T.; Ramachandran, V. N.; Smyth, W. F. Int. J. Antimicrob. Ag. 2009, 33, 421.

[75]

Shi, Y.; Zhou, C. Bioorg. Med. Chem. Lett. 2011, 21, 956.

[76]

Ronad, P. M.; Noolvi, M. N.; Sapkal, S.; Dharbhamulla, S.; Maddi, V. S. Eur. J. Med. Chem. 2010, 45, 85.

[77]

Basanagouda, M.; Shivashankar, K.; Kulkarni, M. V.; Rasal, V. P.; Patel, H.; Mutha, S. S.; Mohite, A. A. Eur. J. Med. Chem. 2010, 45, 1151.

[78]

Vukovic, N.; Sukdolak, S.; Solujic, S.; Milosevic, T. Arch. Pharm. Chem. Life Sci. 2008, 341, 491.

[79]

Hamdi, N.; Saoud, M.; Romerosa, A.; Haseen, R. B. J. Heterocyclic Chem. 2008, 45, 1835.

[80]

Ali, T.; Ibrahim, M. A. J. Braz. Chem. Soc. 2010, 21, 1007.

[81]

Sasidhara, K. V.; Kumar, A.; Dodda, R. P.; Krishna, N. N.; Agarwal, P.; Srivastava, K.; Puri, S. K. Bioorg. Med. Chem. Lett. 2012, 22, 3926.

[82]

Naik, R. J.; Kulkarni, M. V.; Nayak, P. J.; Pai, K. Chem. Biol. Drug. Des. 2012, 80, 516.

31

[83]

La Rosa, J. C.; Hi, J.; Vupputuri, S. J. Am. Med. Assoc. 1999, 282, 2340.

[84]

Lee, M. J.; Chou, F. P.; Tseng, T. H.; Hsieh, M. H.; Lin, M. C.; Wang, C. J. J. Agric. Food Chem. 2002, 50, 2130.

[85]

Sashidhara, K.V.; Kumar, A.; Kumar, M.; Srivastava, A.; Puri, A. Bioorg. Med. Chem. Lett. 2010, 20, 6504.

[86]

Sashidhara, K. V.; Palnati, G. R.; Sonkar, R.; Avula, S. R.; Awasthi, C.; Bhatia, G. Eur. J. Med. Chem. 2013, 64, 422.

[87]

Bradamante, S.; Barenghi, L.; Villa, A. Cardiovasc. Drug Rev. 2004, 22,169.

[88]

Orallo, F.; Alvarez, E.; Camina, M.; Leiro, J. M.; Gomez, E.; Fernandez , P. Mol. Pharmacol. 2002, 61, 294.

[89]

Wu, J. M.; Wang, Z. R.; Hseih, T. C.; Bruder, J. L.; Zou, J. G.; Huang, Y. Z. Int. J. Mol. Med. 2001, 8, 3.

[90]

Hao, H. D.; He, L. R. J. Med. Food. 2004, 7, 290.

[91]

Matos, M. J.; Santana, L.; Uriarte, E.; Delogu, G.; Corda, M.; Fadda, M. B.; Era, B.; Fais, A. Bioorg. Med. Chem. Lett. 2011, 21, 3342.

[92]

Xie, S.; Wang, X.; Li, J.; Yang, L.; Kong, L. Eur. J. Med. Chem. 2013, 64, 540.

[93]

Catto, M.; Pisani, L; Leonetti, F.; Nicolotti, O.; Pesce, P.; Stefanachi, A.; Cellamare, S.; Carotti, A. Bioorg. Med. Chem. 2013, 21, 146.

[94]

Elsinghorst, P. W.; Hartig, W.; Goldhammer, S.; Grosche, J.; Gutschow, M. Org. Biomol. Chem. 2009, 7, 3940.

[95]

Sashidhara, K. V.; Kumar, M.; Khedgikar, V.; Kushwaha, P.; Modukuri, R. K.; Kumar, A.; Gautam, J.; Singh, D.; Sridhar, B.; Trivedi, R. J. Med. Chem. 2013, 56, 109.

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Figure Legends Figure 1. Structures of clinically used coumarin derivatives

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Table 1. Structural features of coumarin hybrids for anticancer, anti-inflammatory and antiviral activities

Coumarin core GROUPS EXPLORED

PREPOSITION ANTICANCER ACTIVITY

Benzimidazole, sulfonamides, dihydropyrazole, substituted phenyl Trans-vinyl benzene (t-VB) Chalcone and cinnamoyl group Electron releasing groups Chalcone

Other substituted heterocycles can potentiate the activity Heterocycles in place of phenyl group in chalcone and t-VB can also incur the activity Aryl groups linked through planar or non-planar, branched or linear linker can increase the activity

ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY α-Lipoic acid, substituted pyrazolines and pyrazole Benzofuran, chromone and 4-hydroxycoumarin Chalcone

Other 5-/6-membered heterocycles can also incur the activity Other benzofused heterocycles such as quinoline, isoquinoline and indole can also be explored

ANTIVIRAL ACTIVITY Imidazopyridine, benzoxazoles, benzothiazole, benzimidazole and purine Triazine

Explored heterocycles with different substituents, or different heterocycles attached directly or through different linkers such as -S-, -NH-, -O- and -CO- can retain or potentiate the activity Heterocycles such as pyridine, pyrimidine and pyrazine can also be explored.

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COUMARIN HYBRIDS AS NOVEL THERAPEUTIC AGENTS Sonali Sandhu, Yogita Bansal*, Om Silakari, Gulshan Bansal Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab.

Fusion of naturally occurring coumarin derivatives, possessing different pharmacological activities such as antioxidant, anti-inflammatory, anticancer, antiviral, antimicrobial, with other pharmacologically active molecules has produced hybrid molecules. These have multiple biological activities and improved pharmacokinetics. The present review compiles information from publications on these coumarin hybrids and proposes structure activity relations.

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