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NATURAL QUINOLONE NATURAL QUINOLONE ANTIMICROBIAL AGENTS FROMANTIMICROBIAL AGENTS FROMANTIMICROBIAL AGENTS FROM ANTIMICROBIAL AGENTS FROM
MALAYSIAN RUTACEOUS SPECIESMALAYSIAN RUTACEOUS SPECIES
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
QUINOLINE ALKALOIDS OF QUINOLINE ALKALOIDS OF
• Quinoline alkaloids of the Rutaceae plant family
THE RUTACEAETHE RUTACEAE• Quinoline alkaloids of the Rutaceae plant family
- an anthranilic acid-derived alkaloids.
• Typical and unique chemical constituents of the Rutaceae plant family (Grundon,1988).
• Main classes :Simple Quinolines 2(1H)-quinolinonesp Q ( ) q
4(1H)-quinolinones dihydrofuroquinolinesfuroquinolines pyranoquinolinesfuroquinolines pyranoquinolines
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
• A considerable number of antimicrobial active• A considerable number of antimicrobial activequinoline alkaloids have been isolated from variousspecies of Rutaceae.
• The 4-oxygenated quinolone and 2-substituted 4-quinolone alkaloids which have similar basic structureto that of 4 quinolone antimicrobial agents have beento that of 4-quinolone antimicrobial agents have beenproved to be candidates for further study as potentialantimicrobial agents.
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Antimicrobial active quinoline alkaloids from Rutaceae speciesq p
OCH3
DubamineHapplophyllum sp
OCH3
OCH
GalipineG officinalis
N
O
OHapplophyllum spGrundon, 1988 N
OCH3
OCH3
G. officinalisHoughton et al., 1999
OO
N
CH3
(CH2)m (CH2)nCH3
Evocarpine, m = 7, n = 3 Evodia rutaecarpaRho et al., 1999 N
CH3
IsodictamnineDictamnus albusTowers et al., 1981
Quinoline alkaloids with DNA-binding activity (Hanawa et al., 2004)
N O
OCH3
HO N OH CO
OCH3
N OH CO
OCH3
H3COO
N O
OCH3
HO N OH3CO
OCH3
N OH3CONH
O
Haplopine Skimmianine Kokusaginine Haplopine
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
SELECTED RUTACEOUS SPECIESSELECTED RUTACEOUS SPECIES(1) Selected Rutaceae
species(1) Glycosmis pentaphylla(1) Glycosmis pentaphylla
(Retz.) DC./Nerapan
(2) Lunasia amara Blanco
(3) Ruta angustifolia (L.)Pers./ Aruda/Garuda
6
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Quinoline alkaloids of Glycosmis pentaphyllaAlkaloid Occurrence References2-(1H)-QuinolinonesGlycolone Leaves
Root barksBhattacharyya and Chowdhury, 1985Kumar et al., 1986
GlycophyloneGlycosolone
SeedsLeavesRoot barks
Bhattacharyya and Chowdhury, 1984Bhattacharyya and Chowdhury, 1985Das and Chowdhury, 1978
Homoglycosolone Root barks Kumar et al., 1986FuroquinolinesDictamnine Mester, 1973γ-FagarineKokusaginineSkimmianine
StemsLeavesStems
Mester, 1973Ito et al., 1999Chaterjee and Majumdar, 1954Ito et al 1999Stems Ito et al., 1999
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Quinoline alkaloids of Lunasia amara
Simple Quinolines4 Methoxy 2 phenyl quinoline
FuroquinolinesKokusagine
(Goodwin et al., 1959c; Hart and Price, 1966; Mester, 1983)
4-Methoxy-2-phenyl-quinolineGraveolinine
KokusagineSkimmianine
2(1H)-QuinolinonesL idi
DihydrofuroquinolinesL iLunacridine
LunidonineLunidine( ) H d l idi
LunacrineLunine(-)-O-Methylluninium ionLunasine(+)-Hydroxylunacridine
Hydroxylunidine
Lunasine(-)-HydroxylunacrineHydroxylunine
4(1H)-Quinolinones Pyranoquinolines( )1-Methyl-2-phenyl-4-quinolone5-Hydroxy-1-methyl-2-phenyl-4-quinoloneEduleineLunasia I
y q(-)-Lunacrinol
Lunasia ILunamarine
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Quinoline alkaloids of Ruta angustifoliaQuinoline alkaloids of Ruta angustifolia
Alkaloid Occurrence References4-(1H)-QuinolinoneGraveoline Aerial parts
RootsWh l l
Del Castillo et al., 1984Ulubelen and Terem, 1988V d d L k 1968Whole plants Vasudevan and Luckner, 1968
FuroquinolinesDictamnine Roots Vasudevan and Luckner, 1968Dictamnineγ-Fagarine
Roots Vasudevan and Luckner, 1968Kong et al., 1984
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Antimicrobial activity of quinolone antimicrobial agentsy q g
345
6
O OCOOH
OCOOHF
OF COOH
NH
2
36
7
8 1N
C2H5
H3C
NHN N NH3CN N
F
CH2F
H2C
4-quinolone Nalidixic acid Ciprofloxacin Fleroxacin4 quinolone Nalidixic acid Ciprofloxacin Fleroxacin
• Nucleic acid-targeted drugs. • The functional target is the enzyme DNA gyrase that exists only in bacteria (Shen, 1993; Kreuzer, 1998). • Inhibit the replication and transcription activities of bacterial cell’s genetic code (Hooper and Wolfsonbacterial cell s genetic code (Hooper and Wolfson, 1993).
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
METHODSMETHODSMETHODSMETHODS
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
BIOASSAYBIOASSAY--GUIDED ISOLATION OF GUIDED ISOLATION OF ANTIMICROBIAL ACTIVEANTIMICROBIAL ACTIVE ALKALOIDSALKALOIDSANTIMICROBIAL ACTIVE ANTIMICROBIAL ACTIVE ALKALOIDSALKALOIDS
Extraction Crude extracts
Bioactivity screeningInactive extracts
Active extractsFractionation
TLC analysis
F1F2F2F3F4F5
Bioautographicscreening
Active fractions
Isolation &Purification
Antimicrobial active
alkaloidsF5
Inactive fractions Spectroscopic
identificationNatural Medicinal Products Centre
Kulliyyah of PharmacyInternational Islamic University Malaysia
ANTIMICROBIAL STUDYANTIMICROBIAL STUDY
(b) Chequerboard AssayA ti i bi l C bi ti Eff t
(a) Broth Microdilution Assay for - MIC & MBC
- Antimicrobial Combination Effects
*
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
RESULTS & OBSERVATIONSRESULTS & OBSERVATIONSRESULTS & OBSERVATIONSRESULTS & OBSERVATIONS
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
AAntimicrobialntimicrobial active alkaloid from active alkaloid from R. R. angustifoliaangustifoliaC. albicans
O
45
NO
1
2
364a
7
8
8a
1'5'
6'
AAntimicrobialntimicrobial active alkaloid ofactive alkaloid of GG pentaphyllapentaphylla
S. aureusO
CH3 2'
3'4'
O
45
S. aureusAAntimicrobialntimicrobial active alkaloid of active alkaloid of G. G. pentaphyllapentaphylla
N
N
CH21
2
34
6
7
8 1"
5"6"4a
8a
4"1'
CH3
1
2" 3"
E. coli ArborineNatural Medicinal Products Centre
Kulliyyah of PharmacyInternational Islamic University Malaysia
Antimicrobial Antimicrobial activity of alkaloiactivity of alkaloidsds
Microorganism MIC/MBC/MFC of Rutaceous alkaloidsLunidonine Graveoline ArborineLunidonine Graveoline Arborine
E. coli ATCC 35213 - 250/250 125/125S. aureus ATCC 25923 125/125 125/250 250/250C. albicans ATCC 90028 - 500/500 NR
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
Synergism antimicrobial Synergism antimicrobial effectseffects
CombinationMIC (μg/ml)
FIC FICICombinedeffect
alone combined
E. coli ATCC 35213
alone combined
Ampicillin 3.91 0.98 0.25 0.38 Synergy
Arborine 125 15.63 0.13
Ampicillin 3.91 0.98 0.25 0.38 Synergy
Graveoline 250 31.25 0.13
Ampicillin 3.91 0.98 0.25 0.38 Synergy
Quinoline 250 31.25 0.13
Ampicillin 3.91 0.98 0.25 0.38 Synergy
Odds, 2003
p y gy
Quinaldine 250 31.25 0.13
Odds, 2003
FICI <0.5 – Synergy
0.5<FICI>4.0 – No interaction
FICI>4.0 - AntagonismNatural Medicinal Products Centre
Kulliyyah of PharmacyInternational Islamic University Malaysia
g
CONCLUSIONSCONCLUSIONS• 3 alkaloids which were firstly detected to have
antimicrobial properties have been isolated from Lantimicrobial properties have been isolated from L.amara, R. angustifolia and G. pentaphylla, identifiedas lunidonine, graveoline and arborine, respectively., g , p y
• The alkaloids especially graveoline and arborine,which produce effect against Gram-negative bacteriawhich produce effect against Gram-negative bacteriamay be suitable candidates for use in combinationantimicrobial therapy.py
INTERNATIONAL ISLAMIC UNIVERSITY MALAYSIANatural Medicinal Products Centre
Kulliyyah of PharmacyInternational Islamic University Malaysia
ACKNOWLEDGEMENTACKNOWLEDGEMENTACKNOWLEDGEMENTACKNOWLEDGEMENTPROF DR MUHAMAD BIN ZAKARIAPROF. DR MUHAMAD BIN ZAKARIA
UNIVERSITY OF MALAYAINTERNATIONAL ISLAMIC UNIVERSITYINTERNATIONAL ISLAMIC UNIVERSITY
MALAYSIAMOHE (FRGS GRANT)MOHE (FRGS GRANT)
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia
THANK YOUTHANK YOUTHANK YOUTHANK YOU
Natural Medicinal Products CentreKulliyyah of Pharmacy
International Islamic University Malaysia