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NPC Natural Product Communications

EDITOR-IN-CHIEF

DR. PAWAN K AGRAWAL Natural Product Inc. 7963, Anderson Park Lane, Westerville, Ohio 43081, USA agrawal@naturalproduct.us EDITORS

PROFESSOR ALESSANDRA BRACA Dipartimento di Chimica Bioorganicae Biofarmacia, Universita di Pisa, via Bonanno 33, 56126 Pisa, Italy braca@farm.unipi.it PROFESSOR DEAN GUO State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China gda5958@163.com

PROFESSOR YOSHIHIRO MIMAKI School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Horinouchi 1432-1, Hachioji, Tokyo 192-0392, Japan mimakiy@ps.toyaku.ac.jp PROFESSOR STEPHEN G. PYNE Department of Chemistry University of Wollongong Wollongong, New South Wales, 2522, Australia spyne@uow.edu.au PROFESSOR MANFRED G. REINECKE Department of Chemistry, Texas Christian University, Forts Worth, TX 76129, USA m.reinecke@tcu.edu PROFESSOR WILLIAM N. SETZER Department of Chemistry The University of Alabama in Huntsville Huntsville, AL 35809, USA wsetzer@chemistry.uah.edu PROFESSOR YASUHIRO TEZUKA Institute of Natural Medicine Institute of Natural Medicine, University of Toyama, 2630-Sugitani, Toyama 930-0194, Japan tezuka@inm.u-toyama.ac.jp PROFESSOR DAVID E. THURSTON Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK david.thurston@pharmacy.ac.uk

ADVISORY BOARD Prof. Berhanu M. Abegaz Gaborone, Botswana

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Prof. A.A. Leslie Gunatilaka Tucson, AZ, USA

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Prof. Winston F. Tinto Barbados, West Indies

Prof. Karen Valant-Vetschera Vienna, Austria

Prof. Peter G. Waterman Lismore, Australia

HONORARY EDITOR

PROFESSOR GERALD BLUNDEN The School of Pharmacy & Biomedical Sciences,

University of Portsmouth, Portsmouth, PO1 2DT U.K.

axuf64@dsl.pipex.com

Antifungal Activity of Plumericin and Isoplumericin

Dharmendra Singha, Umakant Sharmaa, Parveen Kumara, Yogesh K. Guptab, M. P. Dobhalb and Sarman Singha,* aDepartment of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi-110 029, India

bDepartment of Chemistry, University of Rajasthan, Jaipur-302 055, India

sarman_singh@yahoo.com

Received: June 13th, 2010; Accepted: August 6th, 2011

This study evaluated the in vitro antifungal activity of the chloroform extract of Plumeria bicolor and its phytoconstituents plumericin and isoplumericin against Candida species and Cryptococcus neoformans by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC). Plumericin’s consistently high activity against Candida albicans, C. krusei, C. glabrata, C. tropicalis and Cryptococcus neoformans was more potent than isoplumericin and the standard antifungal drug nystatin suggesting its potential as a drug candidate for candidiasis and cryptococcosis. Keywords: Candidiasis, Cryptococcosis, Plumeria bicolor, Plumericin, Isoplumericin. Acquired immunodeficiency syndrome (AIDS) increases the impact of life-threatening fungal infections in immuno-compromised patients in spite of new antifungal agents [1a]. Candidiasis, a fungal disease caused by various Candida species such as C. albicans, C. krusei, C. glabrata, and C. tropicalis, has a worldwide distribution [1b]. In India candidiasis appears in approximately 58% of AIDS patients as the first opportunistic infection [1c]. Cryptococcus neoformans is the second most common cause of opportunistic fungal infection in AIDS patients, but also causes disease in normal hosts [2]. Hence, there is an urgent need for new, inexpensive antifungal agents for which plant-derived natural products may offer potential leads [3a]. Recently, plant derived compounds showed anticandidal and anticryptococcal activities [3b]. Plumeria bicolor, commonly known as “Champa”, is a well-known Indian medicinal plant containing the iridoid, plumeiride, which is reported to have anticancerous [4a] and antispermatogenic activity [4b]. Plumericin (1) and isoplumericin (2) are iridoids reported to have algicidal [5a], anti-leishmanial [5b], molluscicidal [5c] and antifungal activity [6]. Testing of the antifungal activity of the chloroform extract of P. bicolor, as well as (1) and (2), against C. albicans, C. krusei, C. glabrata, C. tropicalis and C. neoformans revealed considerable activity as measured by the MIC and MFC values and compared to nystatin (Table 1). Plumericin showed the most potent anticandidal and anticryptococcal activity compared to the P. bicolor extract, isoplumericin and the standard drug nystatin. The strong activity might be explained by the presence of the α-methylene γ-lactone moiety, which is susceptible to Michael-type addition with biological nucleophiles [5c,7].

O

O

O

H

OCH3O

H

H

H

O

(1R,5S,8S,9S,10S)-1 (1R,5S,8S,9S,10S)-2

1

3

4

5

6

7

89

10

1112

13 14

15

16

O

O

O

H

OCH3O

H

H

H

O

1

3

4

5

6

7

89

10

1112

13

14

15

16

Plumerecin (1) Isoplumerecin (2)

Figure 1: Absolute configurations of (1) and (2) [8].

Experimental

Plant material and Isolation of plumericin & isoplumericin: The stem bark of Plumeria bicolor was collected from the campus of University of Rajasthan, Jaipur and identified by their Department of Botany (RUBL-20603). Three kilograms of shade dried, powdered bark of P. bicolor was exhaustively extracted at 65°C with methanol for approximately 72 hours. The methanol extract was filtered and evaporated to dryness under reduced pressure in a rotary evaporator at 40°C. The concentrated mass was subsequently extracted with acetonitrile and chloroform. Removal of the chloroform by distillation at 70°C afforded ~30 g. residue. Half of the extract was used for the antifungal assay and half for isolation of compounds 1 and 2 by chromatography on Si-gel. Elution with 8:2 chloroform: methanol gave 900 mg plumericin (1) as white crystals mp 210-212°C [9] and 550 mg isoplumericin (2) white crystals mp 196-198°C [9]. NMR and MS values were in agreement with those reported earlier [9,10]. Microbial strains and growth condition: Four standard strains (Table 1) of Candida and one standard strain of Cryptococcus. The culture stock was maintained on Sabouraud’s Dextrose Agar (SDA) at 4°C. The organisms

NPC Natural Product Communications 2011 Vol. 6 No. 11

1567 - 1568

1568 Natural Product Communications Vol. 6 (11) 2011 Singh et al.

were sub-cultured on SDA and incubated at 37°C for 24-48 hours. The active cultures for experiment were prepared by streaking on SDA and incubated at 37°C for 24 hours. The suspension was adjusted to 70% transmittance by a spectrophotometer at 530 nm, which results in a suspension containing about 1 x 106 CFU/mL.

In vitro antifungal assay: The anti-candidal and anti-cryptococcal activities of P. bicolor extract, plumericin and isoplumericin were determined by measuring the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC) by the microbroth dilution method according to the CLSI, NCCLS M27-A2 guidelines [11]. Geometric dilutions ranging from 15.6 to 500 µg/mL of P. bicolor extract and from 0.1 to 10 µg/mL of both compounds were prepared in 96-well microtiter plates. The final concentration of each well was adjusted to 1×106 CFU/mL cells of C. albicans, C. krusei, C. glabrata, C. tropicalis and C. neoformans and incubated at 37°C for 24 hours (Candida species) or 48 hours (C. neoformans).

The MIC was defined as the lowest concentration of test sample that resulted in complete inhibition of visible growth. The microbial growth was indicated by the presence of a white pellet on the well bottom. Nystatin was used as a reference. The samples and reference were dissolved in DMSO at the same concentration (1%). Aliquots from each of the wells were sub-cultured on SDA plates and incubated for 24 hours (Candida species) and 48 hours (C. neoformans). MFC was determined as the lowest concentration of test samples at which the organisms showed no growth on further sub-culturing on SDA plates. All experiments were repeated three times and median values were calculated by statistical analysis.

Acknowledgments - This study was supported by a grant from Central Council for Research in Unani Medicine, Ministry of Health & Family Welfare, Government of India, to SS. The financial assistance in the form of research fellowship from Indian Council of Medical Research (ICMR), New Delhi, to US is also acknowledged.

Table 1: Antifungal activity of Plumeria bicolor extract and its isolated compounds against Candida species and C. neoformans.

Plumeria bicolor Plumericin Isoplumericin NystatinStrains MIC (µg/mL) MFC (µg/mL) MIC (µg/mL) MFC (µg/mL) MIC (µg/mL) MFC (µg/mL) MIC (µg/mL) MFC (µg/mL)

Candida albicans (ATCC 10231) 199 242 1.61 2.60 3.85 5.33 1.85 3.20Candida krusei (ATCC 14243) 56 77 0.32 0.46 0.47 0.80 1.33 2.10Candida glabrata (ATCC 15126) 204 247 2.00 2.71 3.98 5.75 2.10 3.35Candida tropicalis (ATCC 20336) 221 297 2.62 3.14 3.70 5.60 2.62 3.25Cryptococcus neoformans (ATCC 90112) 61 92 0.33 0.60 0.56 0.92 1.45 2.20

References

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[2] Satishchandra P, Mathew T, Gadre G, Nagarathna S, Chandramukhi A, Mahadevan A, Shankar SK. (2007) Cryptococcal meningitis: clinical, diagnostics and therapeutic overview. Neurology India, 55, 226-232.

[3] (a) Lachoria L, Jain PC, Agrawal SC. (1999) Activity of some plant extracts against dermatophytes. Hindustan Antibiotics Bulletin, 41, 17-21; (b) Rates SMK. (2001) Plants as source of drugs. Toxicon, 39, 603-613.

[4] (a) Dobhal MP, Li G, Gryshuk A, Graham A, Bhatanager AK, Khaja SD, Joshi YC, Pandey RK. (2004) Structural modifications of plumieride isolated from Plumeria bicolor and the effect of these modifications on in vitro anticancer activity. Journal of Organic Chemistry, 69, 6165-6172; (b) Gupta RS, Bhatnager AK, Joshi YC, Sharma R, Sharma A. (2004) Effects of Plumieride, an iridoid on spermatogenesis in male albino rats. Phytomedicine, 11, 169–174.

[5] (a) Coppen JJW. (1983) Iridoids with algicidal properties from Allamanda. Phytochemistry, 22, 179-182; (b) Castillo D, Arevalo J, Herrera F, Ruiz C, Rojas R, Rengifo E, Vaisberg A, Lock O, Lemesre JL, Gornitzka H, Sauvain M. (2007) Spirolactone iridoids might be responsible for the anti-leishmanial activity of a Peruvian traditional remedy made with Himatanthus sucuuba (Apocynaceae). Journal of Ethnopharmacology, 112, 410-414; (c) Kupchan SM, Giacobbe TJ, Krull JS, Thomas AM, Eakin MA, Fessler DC. (1970) Reaction of endocyclic α, β-unsaturated lactones with thiols. Journal of Organic Chemistry, 35, 3539-3543.

[6] Wood CA, Lee K, Vaisberg AJ, Kingston DGI, Neto CC, Hammond GB. (2001) A bioactive spirolactone iridoid and triterpenoids from Himatanthus sucuuba. Chemical & Pharmaceutical Bulletin, 49, 1477-1478.

[7] Montero-Torres A, Vega MC, Marrero-Ponce Y, Rolon M, Gomez-Barrio A, Escario JA, Aran VJ, Martínez-Fernández AR, Meneses-Marcel A. (2005) A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds. Bioorganic & Medicinal Chemistry, 13, 6264-6275.

[8] Stephens PJ, Pan JJ, Devlin FJ, Krohn K, Kurtan T. (2007) Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism, and optical rotation: the iridoids plumericin and isoplumericin. Journal of Organic Chemistry, 72, 3521-3536.

[9] Abdel-Kader MS, Wisse J, Evans R, van der Werff H, Kingston DGI. (1997) Bioactive iridoids and a new lignan from Allamanda cathartica and Himatanthus fallax from the Suriname rainforest. Journal of Natural Products, 60, 1294-1297.

[9] Abdel-Kader MS, Wisse J, Evans R, van der Werff H, Kingston DGI. (1997) Bioactive iridoids and a new lignan from Allamanda cathartica and Himatanthus fallax from the Suriname rainforest. Journal of Natural Products, 60, 1294-1297.

[10] De Sá Barretoa A, De Carvalhoa MG, De Almeida Nerya I, Gonzaga L, Kaplan MAC. (1998) Chemical Constituents from Himatanthus articulata. Journal of Brazilian Chemical Society, 9, 430-434.

[11] National Committee for Clinical Laboratory Standards. (2002) Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard NCCLS document M27-A2. National Committee for Clinical Laboratory Standards, Wayne, PA.

Natural Product Communications Vol. 6 (11) 2011 Published online (www.naturalproduct.us)

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Natural Product Communications 2011

Volume 6, Number 11

Contents

Original Paper Page

Antifungal Activity of Plumericin and Isoplumericin Dharmendra Singh, Umakant Sharma, Parveen Kumar, Yogesh K. Gupta, M. P. Dobhal and Sarman Singh 1567

A New Diacylated Labdane Diterpenoid from Andrographis wightiana Jalli Madhu Sudhana, Rachakunta Munikishore , Mopuru Vijayabhaskar Reddy, Duvvuru Gunasekar, Alain Blond

and Bernard Bodo 1569

Triterpenoid Acids and Lactones from the Leaves of Fadogia tetraquetra var. tetraquetra (Rubiaceae) Dulcie A. Mulholland, Abdelhafeez M.A. Mohammed, Philip H. Coombes, Shafiul Haque, Leena L. Pohjala, Päivi S.M. Tammela and Neil R. Crouch 1573

Isolation of Friedelin from Black Condensate of Cork Ricardo A. Pires, Ivo Aroso, Susana P. Silva, João F. Mano and Rui L. Reis 1577

Novel Microbial Transformation of Resibufogenin by Absidia coerules Jian Zheng, Dong-hai Su, Dong-sheng Zhang, Xiu-Lan Xin, Jun-ying Liu, Yan Tian, Qing Wei and Xun Cui 1581

Antidiabetic Activity of Terminalia sericea Constituents Nolitha Nkobole, Peter James Houghton, Ahmed Hussein and Namrita Lall 1585

X-ray Crystallographic Study of Ranaconitine Yang Li, Jun-hui Zhou, Gui-jun Han, Min-juan Wang, Wen-ji Sun and Ye Zhao 1589

Obscurine: a New Cyclostachine Acid Derivative from Beilschmiedia obscura Bruno Ndjakou Lenta, Jean Rodolphe Chouna, Pepin Alango Nkeng-Efouet, Samuel Fon Kimbu, Etienne Tsamo and Norbert Sewald 1591

Alkaloids from Papaver coreanum Dong-Ung Lee, Jong Hee Park, Ludger Wessjohann and Jürgen Schmidt 1593

Isolation, Structure Elucidation, and Biological Activity of a New Alkaloid from Zanthoxylum rhetsa Karsten Krohn, Stephan Cludius-Brandt, Barbara Schulz, Mambatta Sreelekha and Pottachola Mohamed Shafi 1595

Amplexicine, an Antioxidant Flavan-3-ol from Polygonum amplexicaule Mudasir A. Tantry and Aziz A. Rahman 1597

A New Flavonoid Glycoside from Vaccaria hispanica Haijiang Zhang, Kuiwu Wang, Jie Wu, Yao Chen and Peipei He 1599

Flavonoids from Algerian Endemic Centaurea microcarpa and their Chemotaxonomical Significance Souheila Louaar, Amel Achouri, Mostefa Lefahal, Hocine Laouer, Kamel Medjroubi, Helmut Duddeck and Salah Akkal 1603

On-line (HPLC-NMR) and Off-line Phytochemical Profiling of the Australian Plant, Lasiopetalum macrophyllum Michael Timmers and Sylvia Urban 1605

Chemical Fingerprint Analysis of Phenolics of Albiziachinensis Based on Ultra-Performance LC-Electrospray Ionization-Quadrupole Time-of-Flight Mass Spectrometry and Antioxidant Activity Abha Chaudhary, Pushpinder Kaur, Neeraj Kumar, Bikram Singh, Shiv Awasthi and Brij Lal 1617

Application to Classification of Mulberry Leaves using Multivariate Analysis of Proton NMR Metabolomic Data Eriko Fukuda, Motoyuki Yoshida, Masaki Baba, Yoshihiro Uesawa, Ryuichiro Suzuki, Osamu Kamo, Koji Tsubono, Kazunori Arifuku, Kazuhisa Yatsunami and Yoshihito Okada 1621

Phenolic Constituents of Knautia arvensis Aerial Parts Jaroslaw Moldoch, Barbara Szajwaj, Milena Masullo, Lukasz Pecio, Wieslaw Oleszek, Sonia Piacente and Anna Stochmal 1627

New Acylated Anthocyanins and Other Flavonoids from the Red Flowers of Clematis Cultivars Masanori Hashimoto, Toshisada Suzuki and Tsukasa Iwashina 1631

Prenylated Isoflavonoids from Rhynchosia edulis Ifedayo V. Ogungbe, Gabrielle M. Hill, Rebecca A. Crouch, Bernhard Vogler, Meenakshi Nagarkoti, William A. Haber and William N. Setzer 1637

Antiparasitic and Antimicrobial Isoflavanquinones from Abrus schimperi Aziz A. Rahman, Volodymyr Samoylenko, Surendra K. Jain, Babu L. Tekwani, Shabana I. Khan, Melissa R. Jacob, Jacob O. Midiwo, John P. Hester, Larry A. Walker and Ilias Muhammad 1645

Two New Rotenoids from Boerhavia repens Mamona Nazir, Muhammad Saleem, Naheed Riaz, Maria Hafeez, Misbah Sultan, Abdul Jabbar and Muhammad Shaiq Ali 1651

A Comparison of the Diastereoisomers, Silybin A and Silybin B, on the Induction of Apoptosis in K562 cells Jiyong Zhang, Qiuying Luan, Yanze Liu, David Y-W Lee and Zhao Wang 1653

(Continued inside back cover)