manzamine alkaloids as antileishmanial agents: a review

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European Journal of Medicinal Chemistry xxx (2014) 1e9

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European Journal of Medicinal Chemistry

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Mini-review

Manzamine alkaloids as antileishmanial agents: A review

Penta Ashok, Hiren Lathiya, Sankaranarayanan Murugesan*

Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, India

a r t i c l e i n f o

Article history:Received 9 April 2014Received in revised form30 June 2014Accepted 3 July 2014Available online xxx

Keywords:AlkaloidsCytotoxicityChemotherapyNeglected diseases

* Corresponding author.E-mail addresses: [email protected] (P. Ash

pilani.ac.in (S. Murugesan).

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a b s t r a c t

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, causedby protozoan parasites of the genus Leishmania. Leishmaniasis control profoundly depends uponchemotherapy which includes pentavalent antimonials, paromomycin, pentamidine, amphotericin B andmiltefosine. Miltefosine is the only oral drug used for the treatment of Visceral Leishmaniasis with highcure rate but decrease in susceptibility is observed in countries like India where it is extensively used.Hence, there is an urgent need to develop novel antileishmanial agents with good potency and bettertherapeutic profile. Manzamines are unique group of b-carboline alkaloids isolated from marine spongesand exhibited potent antileishmanial activity. In the present study, we described antileishmanial activity,cytotoxicity and structure activity relationship of natural manzamine alkaloids.

© 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction

Leishmaniasis is a group of diseases caused by protozoan para-sites of the genus Leishmania. It is considered as one of the mostneglected diseases and is endemic in 90 countries throughout theworld. Leishmaniasis is the most prevalent vector born infectiousdisease after malaria in terms of fatality and total number of pa-tients. It is estimated that, currently 350 millions are living at riskplaces and 1.3 millions affected with annual mortality of 30,000[1e3]. Leishmaniasis traditionally has been classified in threedifferent clinical forms (i. e.) Cutaneous Leishmaniasis (CL), Muco-cutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL)[4,5]. CL is the most common form of the infection, 90% of casesoccur in Afghanistan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia,and Syria. It produces skin lesions on the exposed parts of the body,such as face, arms and legs [6]. Nearly about 20 species of Leish-mania are responsible for CL which includes Leishmania major,Leishmania braziliensis (in Brazil), Leishmania mexicana, Leishmaniainfantum (in southern France) and Leishmania panamensi. AlthoughCL is often self-healing, it can create serious permanent disfiguringscars [7]. Mucocutaneous Leishmaniasis (also called Espundia inSouth America) produces lesion on mucous membranes of thenose, mouth, throat cavities and surrounding tissues. These lesionscan lead to partial or total destruction of the affected organs [8].Around 90% of the cases occur in Brazil, Bolivia and Peru and 20% of

ok), [email protected]

served.

, et al., Manzamine alkaloidsj.ejmech.2014.07.006

the infections caused by Leishmania braziliensis develop as MCL [9].Pathogenesis of MCL is still not clear but genetic factor of infectedperson plays an important role in progression of the disease [10].Visceral Leishmaniasis also known as kala azar (Black Fever inHindi) is the most severe form of Leishmaniasis, is caused byLeishmania donovani and Leishmania infantum. More than 90% ofthe cases occur in five countries: India, Bangladesh, Nepal, Sudan,Ethiopia and Brazil. Symptoms of VL are irregular fever, weight loss,mucosal ulcers, swelling of the liver, spleen and anaemia. Unlikecutaneous forms of Leishmaniasis, VL affects the internal organssuch as liver, spleen, bone marrow and is usually fatal if left un-treated [11,12]. After treatment and recovery of VL, generally pa-tients develop chronic cutaneous Leishmaniasis, known as Post-kala-azar dermal leishmaniasis (PKDL). PKDL is prevalent after re-covery of L. donovani infection but not from L. infantum. PKDL firstappears as small, measle-like skin lesions on the face, whichgradually increase in size and subsequently affect other parts of thebody including conjunctival, nasal, oral and genital mucosa [13].

2. Leishmaniasis chemotherapy

Leishmaniasis control mainly depends upon chemotherapy us-ing decade old drugs due to lack of availability to effective vaccine[14]. Pentavalent antimonials (sodium stibogluconate and meglu-mine antimoniate) are beingused in treatmentof leishmaniasis overmore thanfive decades and still theyare thefirst line drugs of choicewhere resistance is not reported [15]. In spite of its adverse effects,polyene antifungal drug, amphotericin B is the drug of choicewhereresistance to antimonials is reported [16]. Usefulness of second line

as antileishmanial agents: A review, European Journal of Medicinal

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Fig. 1. Basic skeleton of manzamine alkaloids.

Fig. 2. Structures of natural

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drugs like diamidine, pentamidine and aminoglycoside antibioticparomomycin has been limited due to their toxicity [17,18]. Milte-fosine is the first oral drug used for the treatment of VL, originallydeveloped as anticancer agent [19,20]. Parasite can easily developresistance to miltefosine because of its long half-life (150 h) and itsuse during pregnancy is restricted [21]. Lowefficacy ofMiltefosine isobserved in countries like India where it is extensively used [22].Hence, there is an urgent need to develop novel antileishmanialagents with good potency and better therapeutic profiles againstboth wild as well as resistant strains of Leishmania.

3. Manzamine alkaloids

Nature is an important source of discovery of medicinallyimportance compounds and the use of alkaloids for the treatmentof parasitic infections is well known from the ages [23]. Hence

manzamine alkaloids.


P. Ashok et al. / European Journal of Medicinal Chemistry xxx (2014) 1e9 3

identification of natural products and their semi-synthetic de-rivatives with antileishmanial activity is one of the effectivemethods to develop novel antileishmanial agents [24,25]. Manz-amines are a unique group of b-carboline alkaloids isolated fromvarious species of marine sponges found in the Indian and PacificOcean. Manzamines are complex structured natural alkaloidshaving b-carboline moiety attached to a pentacyclic diamine ringhaving both eight and thirteen membered rings on a pyrrolo[2,3-i]isoquinoline framework (Fig.1) [26]. First alkaloid frommanzaminegroup, Manzamine A was reported in 1986 [27,28]. Currently morethan 100 manzamine natural alkaloids were isolated from morethan 16 species of marine sponges belonging to 8 families



distributed from red sea to Indonesia [29e31]. Large number ofalkaloids from this group has been reported for their potent anti-malarial [32,33] and antileishmanial activity [34]. A few naturalalkaloids exhibited potent antileishmanial activity than standardantileishmanial drug pentamidine. But unfortunately, semi-synthetic analogues of manzamines are not explored significantlyas antileishmanial agents. In the present review, we are describingthe isolation, antileishmanial activity, cytotoxicity and anti-leishmanial structure activity relationship of manzamine alkaloids.This study may be helpful to develop semi-synthetic derivatives ofmanzamine alkaloids with potent antileishmanial activity andbetter therapeutic efficacy.




3.1. Isolation of manzamine alkaloids

Sakai et al., reported the isolation and structure of manzamine A(1, Fig. 2) from Okinawa sponge, genus Haliclona in 1986, as potentantitumor alkaloid with IC50 value of 0.07 mg/mL against P388mouse leukemia cells [27]. First total synthesis of manzamine Awasreported by Winkler et al., in 1998 [26] and first enantioselectivetotal synthesis was reported by Humphrey et al., in 2002 [35]. In theyear 1987, Nakamura group reported manzamine A and keram-amine B from Okinawan marine sponge Pellina sp, and their anti-microbial activity [36]. Higa et al., 1987, reported two new alkaloids,manzamine B & C (2 & 3 respectively, Fig. 2) from genus Halicona[37]. In subsequent studies, 1,2,3,4-tetrahydro analogue of manz-amine A was isolated as minor component from the species that



producemanzamine A andwas reported asmanzamine D (4, Fig. 2).In 1988, two new carbonyl analogues of manzamine A, manzamineE and manzamine F (5 & 6 respectively, Fig. 2) were reported fromOkinawan Xestospogia sp. by Ichiba et al., 1988 [38]. Later on,structure of keramamine B was revised and corrected structure isidentical to structure of manzamine F [38].

Kondo et al., 1992, reported the isolation and structures ofmanzamine H & J (7 & 8, Fig. 2) along with two biogenetic pre-cursors of manzamine alkaloids ircinal A & B (9 & 10, Fig. 2) fromOkinawan Marine Sponge Ircinia sp. Isolation of ircinal A & B fromsponge gave further insights about biogenetic pathway of manz-amine alkaloids [39]. Ichiba et al., 1994, reported an 8-hydroxyderivative of manzamine A (8-hydroxymanzamine) (11, Fig. 2)from a sponge, Pachypellzna sp. and its structure was confirmed by




preparing its O-methyl derivative (8-methoxymanzmine A (12,Fig. 2) [40]. Crews et al. 1994, reported, 8-hydroxymanzamine Aderivatives with reduced tetrahydro-b-carboline scaffold 1,2,3,4-tetrahydro-2-N-methyl-8-hydroxymanzamine A and 1,2,3,4-tetrahydro-8-hydroxymanzamine A (13 & 14, Fig. 2) from twodifferent haplosclerid sponges of the genera Petrosia and Cri-bochalina respectively [41]. Kobayashi et al., 1994, reported newmanzamine alkaloids 6-hydroxymanzamine A (manzamine Y) and3,4-dihydromanzamine A (15 & 16, Fig. 2), from Okinawan marinesponge Amphimedon sp. In the same year Tsuda et al., isolated twoalkaloids, keramaphidin C and keramamine C (17 & 18, Fig. 3) fromOkinawan marine sponge Amphimedon sp. Keramaphidin C andkeramamine C are plausible biogenetic precursors of manzamine C[42,43]. Kobayashi et al., 1995, reported isolation of three novelmanzamine alkaloids xestomanzamine A, B and manzamine X(19e21, Fig. 3) from the Okinawan marine sponges of Xestospongiasp. along with one known alkaloid manzamine Y (15) from anOkinawan marine sponge of Haliclona sp. [44]. Scheuer et al., 1995,reported isolation of an unsymmetrical manzamine dimer, Kaulu-amine (22, Fig. 3) from an Indonesian marine sponge Prianos sp.[45]. Tsuda et al., 1996, reported manzamine alkaloid, manzamine L(23, Fig. 3) from Amphimedon sp. [46]. In the same year, Edrada et al.reported isolation of four new manzamine alkaloids, 6-deoxymanzamine X, manzamine J N-oxide, 3,4-dihydromanzamine A N-oxide and manzamine A N-oxide (24e27



respectively, Fig. 3) with four known alkaloids manzamine A,manzamine E, manzamine F and manzamine J from the spongeXestospongia ashmorica [47]. Watanabe et al., 1998, reported isola-tion and structure of three new manzamine alkaloids manzamineM, 3,4-dihydromanzamine J, 3,4-dihydro-6-hydroxymanzamine A(28e30 respectively, Fig. 3) from sponge Amphimedon sp. [48].Tsuda et al., 1998, reported isolation of one manzamine relatedtetrahydro-b-carboline alkaloid, Maeganedin A (31, Fig. 3) fromsponge Amphimedon sp. [49]. Zhou et al., 2000, reported the isola-tion, structure and methionine aminopeptidase-2 inhibitory ac-tivity of two new manzamine alkaloids epimanzamine D and N-methyl epimanzamine D (32 & 33, Fig. 3) from Palaun Sponge [50].Sayed et al., 2001, reported isolation of ent-8-hydroxymanzamine A,ent-manzamine F and unprecedented manzamine dimer, neo-kauluamine (34e36 respectively, Fig. 4) from Prianos and Pachy-pellina sp. [51]. Isolation of three new manzamine alkaloids, ent-12,34-oxamanzamine E, ent-12,34-oxamanzamines F and 12,34-oxamanzamine A (37e39 respectively, Fig. 4) from three differentIndo-Pacific sponges was reported by Yousaf et al., 2002 [52]. Raoet al., 2003, reported isolation of five new manzamine alkaloids,32,33-dihydro-31-hydroxymanzamine A, 32,33-dihydro-6-hydroxymanzamine A-35-one, des-N-methylxestomanzamine A, 32,33-dihydro-6,31-dihydroxymanzamine A and 1,2,3,4-tetrahydronorharman-1-one (40e44 respectively, Fig. 4) along with six knownmanzamine alkaloids from an Indonesian sponge [34]. Yousaf et al.,




2004 isolated three new manzamine alkaloids 12,28-oxamanz-amine A, 12,28-oxa-8-hydroxymanzamine A and 31-keto-12,34-oxa-32,33-dihydroircinal A (45e47 respectively, Fig. 4) fromAcanthostrongylophora sp. [53]. In subsequent studies on Acan-thostrongylophora genus sponge, three new manzamine alkaloids,12,34-oxamanzamine E, 8-hydroxymanzamine J and 6-hydroxymanzamine E (48e50 respectively, Fig. 4) along withtwelve known manzamine alkaloids were isolated by Rao et al.,2004 [54]. Four new manzamine alkaloids 12,28-oxamanzamine E,12,34-oxa-6-hydroxymanzamine E, 8-hydroxymanzamine B,12,28-oxaircinal A (51e54 respectively, Fig. 5) were isolated from Acan-thostrongylophora sp. by Rao et al., 2006 [55]. Yamada et al. 2009,reported isolation, structure and antitrypanosomal activity of threenew manzamine alkaloids zamamidine C, 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A and 3,4-dihydromanzamine J N-oxide(55e57 respectively, Fig. 5) from an Okinawan marine spongeAmphimedon sp. [56]. A novel manzamine alkaloid acantholactone(58, Fig. 5), with an unprecedented d-lactone and ε-lactam ringsystem was isolated from an Indonesian sponge belongs to thegenus of Acanthostrongylophora by Wahba et al., 2012 [57].

3.2. In-vitro antileishmanial activity of manzamine alkaloids(Table 1)

Manzamine A was first reported in 1986 as potent antitumoragent. Nearly after two decades of its isolation, manzamine A alsoreported for its antileishmanial activity. Rao et al., 2003, reportedantileishmanial potency ofmanzamine alkaloids against L. donovanipromastigotes. Among these manzamine alkaloids, manzamine A

Table 1In-vitro antileishmanial activity and cytotoxicity of manzamine alkaloids.

Name of alkaloid L. donavani Cytotoxicitymg/mL

Reference

IC50

mg/mLIC90

mg/mL

Manzamine A 0.9 1.8 1.2 34Manzamine E 3.8 6.8 NCb 34Manzamine F 4.2 7.0 NCb 34Manzamine J 25 45 NCb 54Ircinal A 4.6 8.5 NCb 54(þ) 8-Hydroxymanzamine A 6.2 11 1.1 34Manzamine Y 1.6 8.0 3.9 55Manzamine X 5.7 11 NCb 546-Deoxymanzamine X 3.2 7.5 4.7 3412,28-Oxamanzamine A 7.8 50 NCb 5512,34-Oxamanzamine A 14 40 NCb 3412,28-Oxa-8-hydroxy

manzamine A24 4.0 NCb 55

Manzamine A-N-oxide 1.1 3.8 4.2 546-Hydroxymanzamine E 2.5 4.3 4.3 5412,34-Oxamanzamine E NAa NAa NCb 5412,28-Oxamanzamine E 18 40 NCb 55ent-12,34-Oxamanzamine E NAa NAa NCb 3412,34-Oxa-6-hydroxy

manzamine ENAa NAa NCb 55

ent-12,34-Oxamanzamine F NAa NAa NCb 5532,33-Dihydro-31-hydroxy

manzamine ANAa NAa NCb 34

32,33-Dihydro-6-hydroxymanzamine A-35-one

NAa NAa NCb 34

des-N-methylxestomanzamine A 35 >50 NCb 34Neo-kauluamine 4.2 8.2 NCb 548-Methoxymanzamine A 5 24 980 588-Acetyloxymanzamine A 3.4 7.0 370 5812-Acetyl-8-acetyloxymanzamine A 16 35 NCb 58Pentamidine 2.1 10 e 34Amphotericin-B 0.06 0.15 e 34

a No activity.b No cytotoxicity.


exhibited potent antileishmanial activity (IC50 ¼ 0.9 mg/mL andIC90¼1.2 mg/mL) than standard drug pentamidine (IC50¼ 2.1 mg/mLand IC90¼ 10 mg/mL). 8-hydroxymanzamine A, 6-deoxymanzamineX, manzamine E, manzamine X, manzamine F exhibited significantantileishmanial activity comparable with standard drug. 12,34oxamanzamine A, des-N-methylxestomanzamine A showed mod-erate antileishmanial activity. Fewmanzamine alkaloids like 32,33-dihydro-31-hydroxy-manzamine A, 32,33-dihydro-6-hydroxy-manzamine A-35-one did not showed any antileishmanial activity[34]. In 2004, same group reported antileishmanial activity of fewother manzamine alkaloids, among these manzamine alkaloids,manzamine A N-oxide, 6-hydroxymanzamine E, neo-kauluamine,ircinal A, ircinol A exhibited potent antileishmanial activity, manz-amine J showed moderate activity and 12,34-oxamanzamine E notshowed any antileishmanial activity [54]. With their continuousinterest on biological activities of manzamine alkaloids, Rao et al.,2006 reported antileishmanial activity of some more alkaloids ofsamemanzamine group. Among the reported alkaloids,manzamineYexhibited potent antileishmanial activity,12,28-oxamanzamine A,12,28-oxa-8-hydroxy-manzamine A, 12,28-oxamanzamine Eshowed moderate antileishmanial activity and 12,34-oxamanzamine E, ent-12,34-oxamanzamine F, 12,34-oxa-6-hydroxymanzamine E not showed any antileishmanial activityagainst Leishmania donovani promastigotes [55]. Shilabin et al. 2008reported antileishmanial activity of semi-synthetic derivatives of 8-hydroxymanzamine A. Among these semi-synthetic derivatives, 8-acetyloxymanzamine A (59, Fig. 6) showed increased anti-leishmanial potency, 8-methoxymanzamine A displayed compara-ble potency with 8-hydroxymanzamine A, whereas di-substitutedderivative,12-acetyl-8-acetyloxymanzamine A (60, Fig. 6) exhibiteddecreased antileishmanial potency [58].

3.3. Mechanism of action

The exact mechanism of action of manzamine alkaloids for theirantileishmanial activity is not understood completely. According tothe literature, b-carboline alkaloids inhibit DNA synthesis throughintercalation of DNA base pairs, therefore it is hypothesized thatcompounds containing b-carboline moiety can hamper parasitegrowth by inhibiting parasite DNA synthesis [59].

3.4. Structure activity relationship (SAR)

Manzamines with their excellent antileishmanial potency areone of the important structural targets to develop novel and potentantileishmanial agents. But the major disadvantage of this group ofcompounds is their cytotoxicity. The exact mechanism of action ofmanzamine alkaloids for their antileishmanial activity is not un-derstood clearly. Structure activity relationship (SAR) study ofmanzamine alkaloids for their antileishmanial is very much useful

Fig. 6. Semi-synthetic derivatives of manzamine A.


Fig. 7. Favorable positions on manzamine A.


to understand the importance of each moiety and effect of differentsubstituent on different positions of these complex alkaloids.Extensive SAR studies unquestionably will play a significant role inthe development of novel manzamine derivatives having potentantileishmanial activity with better therapeutic profiles.

3.4.1. Substitution on pentacyclic ringPotent antileishmanial activity of ircinal A (IC50 ¼ 4.2 mg/mL)

and ircinol A (IC50 ¼ 0.9 mg/mL) indicates the significance of pen-tacyclic ring in antileishmanial potency of manzamines. Sub-stituents on pentacyclic ring of manzamines have greatly affectedthe antileishmanial potency as well as cytotoxicity. Hydroxyl groupon position 12 is essential for antileishmanial activity. Modificationof this hydroxyl group into ether and ester resulted in drasticreduction of antileishmanial potency of manzamines. Reduction ofdouble bond at position 32, completely abolished the anti-leishmanial potency but introduction of keto group at position 31with reduction of double bond at position 32 affects anti-leishmanial activity marginally with complete loss of cytotoxicity.Substitutions on pyrrole ring as well as pyrrole ring opening led toextreme reduction in antileishmanial potency of manzamines.

3.4.2. Substitution on b-carboline ringSubstitution of hydroxyl group on b-carboline ring at position 6

and 8 resulted in marginal decrease in antileishmanial potency ofmanzamines without showing any effect on their cytotoxicity.Further substitutions on hydroxyl at position 8, leads to increase inantileishmanial potency of manzamines with significant decreasein their cytotoxicity. Manzamine A-N-oxide retained its anti-leishmanial potency without reduction in cytotoxicity (Fig. 7).

4. Conclusion

Leishmaniasis is one of the most neglected parasitic diseases.Developed resistance to first line antileishmanial drugs and toxiceffects of available second line antileishmanial agents increases thedemand for novel antileishmanial agents with better pharmacoki-netic profile. Manzamines with excellent antileishmanial activityare one of the important structural leads for the development ofnovel antileishmanial agents. Structure activity relationship studiesof manzamines are useful to develop novel manzamines havingpotent antileishmanial activity with better therapeutic profiles.Substitutions on b-carboline nucleus marginally affect the anti-leishmanial potency with significant effect on cytotoxicity. Penta-cyclic ircinal ring is mainly responsible for antileishmanial activityand substitutions on pentacyclic ring greatly affect the anti-leishmanial potency of manzamines. Hydroxyl group at position 12


is essential for antileishmanial activity and reduction of doublebond at position 32 results in complete loss of antileishmanial ac-tivity. Introduction of keto group at position 31 greatly enhancedthe antileishmanial potency of manzamines without any cytotox-icity. Substitutions on this keto functional group needs to beinvestigated, it may lead to further increase in antileishmanialpotency of manzamines.

5. Future perspective

Undoubtedly, manzamines are one of the important structuraltargets to develop potent and novel antileishmanial agents. Un-fortunately, manzamines and semi-synthetic manzamine de-rivatives are not explored much for their antileishmanial activity.Structure activity relationship study of manzamines will be usefulto develop potent antileishmanial agents with better therapeuticprofiles. Pentacyclic ircinal ring and its substitutions are playingvital role in antileishmanial activity. Semi-synthetic manzaminederivatives with substitution on ircinal ring without disturbinghydroxyl group at position 12 have to be explored for their anti-leishmanial activity. Reduction of C-32 double bond resulted incomplete abolition of antileishmanial activity, but introduction ofketo group at position 31 with reduced C-32 double bond enhancedthe antileishmanial potency greatly. Hence, selective introductionof keto group at position 31 without disturbing double bond mayincrease the antileishmanial potency of manzamines. Selectiveintroduction of keto group and further modification of this ketogroup also needs to be explored for antileishmanial potency.

Confliction of interest

None.

Acknowledgments

We acknowledge BITS-Pilani for support of this work. One of theauthors Ashok P acknowledges the financial support from Councilof Scientific and Industrial Research, New Delhi in the form of Se-nior Research Fellowship.

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manzamine alkaloids as antileishmanial agents: a review

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