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By P.Divya External guide: Dr. G.Sudhakar Internal guide: Dr. T.

Saritha jyostna

CONTENTS

ABSTRACT CHAPTERS
INTRODUCTION LITERATURE REVIEW RESULTS AND DISCUSSIONS

REFERENCES

Fatty acids constitute the essential part of triglycerides and wax esters, which are the major components of fats and oils. Nevertheless, phospholipids and glycolipids have considerable importance that excites increasing regarding their promising biological activities. Thus in addition to the major polyunsaturated fatty acids (PUFA) such as eicosapentaenoic (EPA) and decosahexaenoic (DHA) acids, a great number of various fatty acids occur in marine organisms, example: saturated, mono- and di-unsaturated, branched, halogenated, hydroxylated, methoxylated, non-methylene interrupted etc. Fatty acids containing halogen

atoms covalently bonded to carbon and are deemed as naturally occurring. Most of the
naturally occurring halogenated fatty acids have anti-microbial properties. This important requirement prompts us for the synthesis of halogenated polyunsaturated fatty acid and its

derivatives in order to evaluate their pharmacological activities.

Halogenated fatty acids are one of the most interesting groups among the

naturally occurring halogen compounds which are produced by many different


organisms, including micro-organisms, algae, marine invertebrates, higher plants and some animals.

This review is intended as a comprehensive survey of fatty acids and/or their derivatives possessing carbon-halogen covalent bonds. Fatty acids constitute the

most abundant class of natural compounds and are included in the composition of
complex lipids. The fatty acids differ in the number of olefinic bonds, extent of branching, the length of the hydrocarbon chain and the number of functional groups.

Fluorinated secondary metabolites are rarely available in nature. Fluoroacetic acid was first isolated by Marais from South African plant Dichapetalum cymosum growing in the trausvaal region, in 1943. This plant is highly toxic to cattle and sheep.1 Peter et. al isolated fluorooleic acid (1) from the seed oil of D. toxicarum in 1959.2
O F OH

18-Flouro oleic acid

Chlorinated fatty acids have been found to be major constituents among organohalogen compounds in fish, molluses, and other invertebrates and seaweeds. 11-Cl-12-hydroxy stearic

acid (2) was isolated for the first time in gelly fish (Auritia aurita).3
OH COOH Cl

11-Cl, 12-OH-stearic acid f rom Auritia aurita

The first investigation of bromine in fatty acids was reported the 1970s in lipid extracts from marine animals.4 Most of the brominated fatty acids are found from marine sponges. Several brominated fatty acids, such as 3-bromo-2-nonaenoic acid (3) have been isolated from red marine algae.5
Br H 3C COOH

3-bromo-2-non aenoic acid

Natural iodinated fatty acids are much rarer than the chlorinated and brominated acids. Simple iodinated acetic, acrylic acids, and their ethyl esters have been isolated from red algae Asparagopsis toxiformis and Asparagopsis armata.1 Literature survey revealed the diversified biological significance of haloginated fatty acids. This aspect drawing the attention of many researchers towards exploiting the biological importance of various haloginated fatty acids and establishing the relationship between their biological and

pharmacological potency in relation to their structural features.

The

objective

of

present

work

entitled

Synthesis

and

pharmacological Evaluation of Halogenated polyunsaturated fatty acids


and their derivatives is primarily aimed to focus on the synthesis of novel fatty acids and study the effect of halogen and unsaturation on the

biological activity. The brominated fatty acids have been attracting the
interests of organic chemist and biochemists because of their unique chemical structures such as increased chain length, unusual unsaturated pattern, bromine and also because of their functions as secondary metabolites. These brominated fatty acids pocess different biological acivities. 7

Halogenated fatty acids are one of the most interesting groups among the naturally occurring halogen compounds. Halogenated natural products are abundant in nature, with over 4500 unique compounds isolated from terrestrial and marine sources. While the vast majority of these compounds contain Br, Cl, few contain both. Some of them are listed below.

Naturally occurring halogenated fatty acids, esters and their importance:

Masashi Taniguichi and coworkers isolated a brominated unsaturated fatty acid (4), and its ester (5) from unidentified marine sponge collected in Papua New Guinea. Considering the components this sponge might belong to the genus Xestospongia and they exhibit anti fungal activity against Auritima salina, (5) anti bacterial activity against methicillin resistant Staphylococcus aureus, Streptococcus mutants.7
Br O
H 3CO Br O

HO

Tadenz F. Molinskiand coworkers isolated brominated ene-yne 2, 5-disubstituted tetrahydrofurans named as mutafuran (8) from Bahamian sponge Xestospongia muta. It possess anti fungal activity against the pathogenic fungus Cryptococcus neoformans, an opportunistic fungus commonly linked to the pathologies of HIV patients.13
O H3CO O Br

Thomas Williamson, William H. Gerwick and coworkers isolated new chlorinated toxins Taveuniamides (9), (10) from a marine Cyanobacteria Lyngbya majuscula

Schizothrix sp collected from the Taveuni, Yanuca islands in Fiji. Which possess brine
shrimp toxicity.15
O Cl OCH3 NH O Cl Cl OCH3
Cl Cl O OCH3 NH O OCH 3 Cl Cl

Taveuniamide A

Taveuniamide D

Junichi Tanaka, Satoe Aratale, Agus Trianto and coworkers isolated a new polyunsaturated brominated fatty acid (12) possessing acetylenic bonds from the Indonesian sponge Haliclona sp. It is showing moderate cytotoxic activity.19
Br

COOH

Nobuhiro Fusetani, Hong-yu Li and coworkers isolated brominated triacetylenic, diacetylenic fatty acids (17), (18) respectively from Petrosia volcano Hashino (Japan sea).

It was found to possess anti fungal activity against pathogenic fungus Mortierella
ramannianus.22
COOR Br R = H, CH3 COOR Br R = H, CH3

D. John Faulkner, Christine E. Salomon and coworkers isolated new aza cyclopropane derivatives (E) S- antazirine (21), (Z) S- antazirine (22) from the marine in human tumor cell lines.16
Br Br N COOMe H

Br Br

N H

COOMe

Ashok D. Patil and coworkers isolated straight chain unsaturated, polyacetylenic, brominated acid (24) from marine sponge Xestospongia muta collected in Colombus island, Bahamas. It possess HIV protease enzyme inhibitory activity. Which results immature viral replication.12 and thereby stops the viral division.
COOH Br

The above entire literature revealed that the naturally occurring halogenated fatty acids exhibit variety of pharmacological properties. Our present interest is to synthesize halogenated polyunsaturated fatty acids and their derivatives in order to evaluate their pharmacological activities and their by contribute significantly to the structure activity relationship in these group of compounds.

Synthetic approaches for halogenated fatty acids:

Only a few synthetic approaches are available in the literature, among them the following two are important.

Sudhakars approach:
Sudhakar and coworkers25 first synthesized the motualevic acids A-E in 2010. The synthesis starts from a key intermediate (29), which in turn can be synthesized from a

commercially available1, 10-decanediol.

Treatment of (29) with KCN in the presence of catalytic amount of 18-crown-6 in acetonitrile at room temperature gave cyanide moiety that was treated with DIBAL-H at -78oC to provide aldehyde (30) in 75% yield over two steps. Two carbon Wittig olefination was carried out in CH2Cl2 at room temperature to get , -unsaturated ester (31) exclusively as the (E)-isomer in 80% yield. Deprotection of the THP ether moiety (31) with catalytic

amount of PTSA in MeOH resulted in a primary hydroxyl functional group that was oxidized
using Swern oxidation reaction conditions to get aldehyde (32) in 88% overall yield. The aldehyde (33) was converted to gem-dibromoalkene (33) by CoreyFuchs reaction in 86% yield. The ester hydrolysis using LiOH in THF/MeOH/H2O system resulted in the desired motualevic acid E (34) with 72% yield. The motualevic acid E was coupled with glycine methyl ester hydrochloride using EDCI, HOBt as coupling reagents in the presence of Et3N in CH2Cl2 to give methyl ester of motualevic acid A. The ester hydrolysis using LiOH in

THF/MeOH/H2O system resulted in the desired motualevic acid A (35).

HO

OH 8

THPO
31

8 Br

THPO
32

8 CHO

THPO

OEt
8 33

OHC
7 34

OEt O

Br
e

Br OEt
f

Br
35

OH Br
7

Motualevic acid E 36

Br
g

Br

H N 7 O

O OH

Motualevic acid A 37

Reagents and conditions: (a) (i) HBr, toluene, reflux, 16 h; (ii) DHP, PPTS, CH2Cl2, 16 h, 73% over two steps; (b) (i) KCN, 18-crown-6, CH3CN, 50 h; (ii) DIBALH, CH2Cl2, 78oC, 2 h, 75% over two steps; (c) Ph3P=CHCO2Et, CH2Cl2, overnight, 80%; (d) (i) PTSA, MeOH, 0oC to rt, 4 h; (ii) (COCl) 2, DMSO, Et3N, CH2Cl2, -78oC, 0. 5 h, 88% over two steps; (E) CBr4, Ph3P, CH2Cl2, 1 h, 86%; (f) LiOH, THF/MeOH/H2O (3:1:1), overnight,

72%.(g) (i) EDCI, HOBT, CH3O2CCH2NH2 HCl, Et3N, CH2Cl2, 0oC to rt, 3 h; (i)
LiOH, THF/MeOH/H2O (3:1:1), 2 h, 76% over two steps

In the present investigation, we have followed Sudhakars approach to synthesize

halogenated poly-unsaturated fatty acid and its derivatives and evaluate their
pharmacological properties.

PRESENT WORK:

The present work is mainly aimed at synthesizing novel halogenated polyunsaturated fatty acids and their derivatives and their biological evaluation for antibacterial and antifungal activity.

The synthesis of title compounds which comprises of two parts


Synthesis of (2E,4E)-15, 15-dibromopentadeca-2, 4,14-trienoic acid (10a)
Coupling reaction of trienoic acid (10a) with various methyl esters of aminoacids.

To know the effect of halogen and un-saturation on microbial activity, synthesis is carried on brominated polyunsaturated fatty acid and their derivatives. The synthesis starts from commercially available 1, 10 decanediol. Where one hydroxyl group was protected with THP by using DHP, PPTS to give mono protected compound 1a. Another hydroxyl group was oxidized using swern oxidation reaction conditions to get aldehyde 2a. Then two carbons Wittig olefination was carried out to get , unsaturated ester 3a. Then the ester was reduced to alcohol 4a using DIBAL-H. Then oxidation was carried out using PCC to get aldehyde 5a. Then two carbon witting olefination was carried out to get another , unsaturated ester 6a. Then the deprotection of THP moiety by using PTSA to give primary hydroxyl compound 7a. The resultant primary hydroxyl functional group was oxidized using PCC to get aldehyde 8a. Then the aldehyde was converted to gem-dibromoalkens 9a by Corey-Fuches reaction. Then ester hydrolysis using LiOH in THF/MeOH/H2Osystem

resulted desired acid 10a.

HO

OH

DHP, PPTS DCM O O 1a DMSO, (COCl)2 Et 3 N, DCM OH

O 3a DIBAL-H Toluene O

OEt

Ph 3P=CH-COOEt DCM O O 2a O H

O 4a

OH

PCC DCM O O 5a Ph 3P=CH-COOEt O

HO 7a PCC O H 8a DCM O

OEt

DCM PTSA M eOH O O O 6a OEt

OEt O

Ph 3P, CBr 4 DCM

Br Br 9a O

OEt

LiOH THF:MeOH:H 2O 3:1:1 Br OH Br 10a O

Scheme-1

Reacting the , unsaturated acid 10 with various methyl ester aminoacids in the presence of peptide coupling reagents EDCI, HOBt, Et3N in DCM, and followed by their hydrolysis using LiOH.H2O to their to corresponding acids total eight different derivatives have been prepared and presented in table

Br Br 10a O

OH

EDCI, HOBt Et3N, DCM

Br Br 11a-h O

R-methly esters of amino acids

Scheme-2

COMPOUND

11a
*

O H N O CH3

11b
*

O H N OH

11c
*

O H N O CH3

11d
*

O H N OH

11e 11f 11g 11h

O H N * O CH 3

O H N * OH

O H N * O CH 3

O H N * OH

All the compounds are purified by column chromatography and

characterized by the analytical and spectral (1H NMR, IR, Mass) data. The compounds are evaluated for antibacterial and antifungal activity by serial dilution and cup-plate method respectively.

The antibacterial, antifungal assay revealed that the activity of

synthesized compounds have significant antifungal activity.

S.NO

Sample structure

Molecular Formula

Molecular weight

Reaction time

%Yield

Melting point(oC)

Br

OH

1
Br

Br

C15H22Br2O2

394
CH3

4hrs

80

Liquid

O H N O

2
Br

Br

C18H27Br2NO 3

465
O H N OH

5hrs

77

70-720C

Br

C17H25Br 2NO3

3
O Br H N O Br O CH3

451
C19H29Br2NO 3

4hrs

80

Liquid

4
O Br H N OH

479
C18H27Br 2NO3

5hrs

77

Liquid

Br

465
O

4hrs

85

Liquid

Br

H N O

CH3

C22H35Br2NO3

Br

521

1hr

79

Liquid

O Br H N OH Br O

C21H33Br 2NO3

7
O Br H N O CH3

507
C22H35Br 2NO 3

2hrs

88

Liquid

8
Br

Br

521
O H N OH

1hr

85

Liquid

C21H33Br 2NO3

Br

507

2hrs

85

Liquid

To obtain biologically active halogenated polyunsaturated fatty acid and their

derivatives a synthesis of a series of compounds have been conceived. The structures of all
the synthesized compounds are established by spectral methods as discussed below.

Spectral interpretation of 10-((tetrahydro-2H-pyran-2-yl)oxy) decan-1-ol (1a):

4.55 (t, J = 3.0 Hz, 1H, O-CH-O), 3.75 (dt, J = 3.0 Hz, 6.7 Hz, 2H, O-CH2 ), 3.60 (t, J = 6.7 Hz, 2H, CH2-OH), 3.40 (dt, J = 3.7 Hz, 6.7 Hz, 2H, tetrahydropyran O-CH2), 1.62-1.47 (m, 6H, tetrahydropyran methylene protons), 1.39-1.26 (m, 16H, aliphatic protons).

Spectral interpretation of 10-((tetrahydro-2H-pyran-2-yl)oxy)decanal (2a):

9.74 (t, J = 1.5 Hz, 1H, CHO), 4.54 (t, J = 3.0 Hz, 1H, O-CH-O), 3.74 (dt, J = 3.0 Hz, 6.7 Hz, 2H, O-CH2), 3.39 (dt, J = 3.7 Hz, 6.7 Hz, 2H, tetrahydropyran O-CH2), 2.35 (dt, J = 1.5 Hz, 7.5 Hz, 2H, CHO-CH2), 1.68-1.47 (m, 6H, tetrahydropyran methylene protons), 1.40-1.24 (m, 16H, aliphatic protons).

Spectral interpretation of (E)-ethyl-12-((tetrahydro-2H-pyran-2-yl)oxy) dodeca-2-enoate (3a):

6.90 (dt, J = 6.9, 15.6 Hz, 1H, =CH), 5.76 (d, J = 15.6 Hz, 1H, =CH), 4.54 (t, J = 3.2 Hz, 1H, O-CH-O), 4.16 (q, J = 7.1 Hz, 2H, COOCH2), 3.74 (dt, J = 3.2, 6.7 Hz, 2H, tetrahydropyran O-CH2), 3.39 (dt, J = 4.3, 6.4 Hz, 2H, O-CH2), 2.19 (q, J = 6.9 Hz, 2H, allylic protons), 1.73-1.41 (m, 6H, tetrahydropyran methylene protons), 1.38-1.22 (m, 16H, aliphatic protons).

Spectral interpretation of (E)-12-((tetrahydro-2H-pyran-2-yl)oxy) dodeca-2-en-1-ol (4a)

` 5.70-5.52 (m, 2H, =CH), 4.55 (t, J = 3.0 Hz, 1H, O-CH-O), 4.03 (d, J = 4.5 Hz, 2H, CH2-OH), 3.81 (dt, J = 3.0, 11.3 Hz, 1H, tetrahydropyran O-CH2), 3.68 (dd, J = 6.7 Hz, 16.6 Hz, 1H, tetrahydropyran O-CH2 ) 3.5-3.42 (m, 1H, O-CH2), 3.32 (dd, J = 6.7 Hz, 15.8 Hz, 1H, O-CH2) 2.07-1.98 (m,2H, allylic protons), 1.9-1.75(m, 1H, aliphatic protons), 1.69-1.46 (m, 6H, tetrahydropyran methylene protons), 1.38-1.22 (m, 16H, aliphatic protons).

Spectral interpretation of (E)-12-((tetrahydro-2H-pyran-2-yl)oxy) dodeca-2-enal (5a):

9.4(d, J = 7.9 Hz, CHO), 6.85-6.71 (m, 1H, =CH), 6.09(q, J = 7.9 Hz, 1H, =CH) 4.54 (t, J = 3.0 Hz, 1H, O-CH-O), 3.85-3.76 (m, 1H, tetrahydropyran O-CH2), 3.68 (dd, J = 6.7 Hz, 13.5 Hz, 1H, tetrahydropyran O-CH2 ) 3.5-3.41 (m, 1H, O-CH2), 3.32 (dd, J = 6.6 Hz, 16.0 Hz, 1H, O-CH2) 2.30-2.28 (m,2H, allylic protons), 1.69-1.46 (m, 6H, tetrahydropyran methylene protons), 1.37-1.23 (m, 12H, aliphatic protons).

Spectral interpretation of (2E,4E)-ethyl-14-((tetrahydro-2H-pyran-2-yl)oxy) tetradeca-2,4-dienoate (6a):

7.19 (dd, J = 9.8 Hz, 15.1 Hz, 1H, =CH), 6.20-6.02 (m, 2H, =CH), 5.73(d, J = 15.8 Hz, 1H, =CH) 4.54 (t, J = 3.0 Hz, 1H, O-CH-O), 4.13 (q, J = 7.5 Hz, 2H, COOCH2), 3.86-3.76 (m, 1H, tetrahydropyran O-CH2), 3.72-3.63 (m, 1H, tetrahydropyran O-CH2) 3.5-3.41 (m, 1H, O-CH2), 3.32 (dd, J = 6.7 Hz, 15.8 Hz, 1H, O-CH2) 2.16 (q, J = 6.7 Hz, 2H, allylic protons), 1.63-1.47 (m, 3H, aliphatic protons), 1.37-1.21 (m, 17H, aliphatic protons).

Spectral interpretation of (2E,4E)-ethyl-14-hydroxytetradeca-2,4-dienoate (7a):

7.18 (dd, J = 9.8 Hz, 14.8 Hz, 1H, =CH), 6.16-6.02 (m, 2H, =CH), 5.71(d, J = 14.8, 1H, =CH), 4.15 (q, J = 6.9 Hz, 2H, COOCH2), 3.57 (t, J = 6.9 Hz, 2H, CH2-OH), 2.19-2.11 (m, 2H, allylic protons), 1.55-1.48 (m, 3H, O-CH2-CH3), 1.44-1.37(m, 2H, aliphatic protons), 1.34-1.24(m, 16H, aliphatic protons).

Spectral interpretation of (2E,4E)-ethyl-14-oxotetradeca-2,4-dienoate (8a):

9.74(s, 1H, CHO), 7.20 (dd, J = 9.8 Hz, 15.4 Hz, 1H, =CH), 6.20-6.01 (m, 2H, =CH), 5.73(d, J = 15.2, 1H, =CH), 4.17 (dd, J = 7.1 Hz, 14.1 Hz, 2H, COOCH2), 2.40 (dt, J = 1.5 Hz, 14.5 Hz, 2H, COCH2), 2.16 (q, J = 6.6 Hz, 2H, allylic protons), 1.67-1.54 (m, 3H, O-CH2-CH3), 1.47-1.23(m, 13H, aliphatic protons).

Spectral interpretation of (2E,4E)-ethyl-15,15-dibromopentadeca-2,4,14-trienoate (9a):

7.20 (dd, J = 9.8 Hz, 15.1 Hz, 1H, =CH), 6.35 (t, J = 7.5 Hz, 1H, =CH), 6.20-5.97 (m, 2H, =CH), 5.74 (d, J = 15.1 Hz, 1H, =CH ), 4.17(dd, J = 6.7 Hz, 14.3 Hz, 2H, CO2CH2), 2.21-2.03 (m, 4H, allylic protons), 1.74-1.38 (m, 3H, aliphatic protons), 1.35-1.22 (m, 13H, aliphatic protons).

Spectral interpretation of (2E,4E)-15,15-dibromopentadeca-2,4,14-trienoic acid (10a):

7.37-7.21 (m, 1H, =CH), 6.35 (t, J = 7.3 Hz, 1H, =CH), 6.20-6.08 (m, 2H, =CH), 5.76 (d, J = 15.2 Hz, 1H, =CH ), 2.18 (q, J =6.2 Hz, 2H, allylic protons), 2.09 (q, J =7.1 Hz, 2H, allylic protons) 1.48-1.36 (m, 5H, aliphatic protons), 1.35-1.23 (m, 12H, aliphatic protons).

The base peak at m/z 417 [M+Na]+ in its ESI mass spectrum (Fig. 4.1.10.2). The 1:2:1 isotopic distribution at m/z 415, 417, 419 secured the presence of two bromine atoms, the corresponding [M+1]+at m/z 395 further confirms the structure.

The characteristic absorption band at 1250, 142, 164, 1701 cm-1 assigns to C-O (acid), C=C, C=C- (Br) 2, C=O (acid) group representative spectrum in (Fig. 4.1.10.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)acetate (11a):

7.25-7.09 (m, 1H, =CH), 6.35 (t, J = 7.3 Hz, 1H, =CH), 6.08 (m, 2H, =CH), 5.8 (s, 1H, NH ), 5.78 (d, J = 14.7 Hz, 1H, =CH ), 4.10 (d, J = 4.9 Hz, 2H, N-CH2), 3.78 (s, 3H, 0-CH3), 2.20-2.02 (m, 4H, allylic protons) 1.47-1.37 (m, 3H, aliphatic protons), 1.32-1.24 (m, 10H, aliphatic protons).

The base peak at m/z 488 [M+Na]+ in its ESI mass spectrum (Fig. 4.1.11.2). The 1:2:1 isotopic distribution at m/z 486, 488, 490 secured the presence of two bromine atoms, the corresponding [M+1]+ at m/z 466 further confirms the structure.

The characteristic absorption band at 1654, 1744, 3307 cm-1 assigns to C=O (amide), C=O (ester), N-H group representative spectrum in (Fig. 4.1.11.3).

Spectral interpretation of 2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)acetic acid (11b):

7.18-7.05 (m, 1H, =CH), 6.35 (t, J = 7.1 Hz, 1H, =CH), 6.17-5.98 (m, 2H, =CH), 5.9 (d, J = 14.9 Hz, 1H, =CH ), 4.01 (s, 1H, N-CH2), 3.66 (s, 1H, N-CH2), 2.17-2.03 (m, 4H, allylic protons), 1.47-1.21 (m, 16H, aliphatic protons).

The base peak at m/z 474 [M+Na]+ in its ESI mass spectrum (Fig. 4.1.12.2). The 1:2:1 isotopic distribution at m/z 472, 474, 476 secured the presence of two bromine atoms confirms the structure.

The characteristic absorption band at 1653, 3350 cm-1 assigns to C=O (amide), C=O (acid), N-H group representative spectrum in (Fig. 4.1.12.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14trienamido)propanoate (11c):

7.15 (dd, J = 9.4Hz, 14.9Hz, 1H, =CH), 6.35 (t, J = 7.11 Hz, 1H, =CH), 6.16-5.98 (m, 3H, =CH , NH), 5.76 (d, J = 14.9 Hz, 1H, =CH ), 4.70-4.56 (m, 1H, N-CH), 3.76 (s, 3H, 0-CH3), 2.21-2.0 (m, 5H, allylic protons), 1.51-1.20 (m, 11H, aliphatic protons).

The base peak at m/z 480 [M+1]+ in its ESI mass spectrum (Fig. 4.1.13.2). The 1:2:1 isotopic distribution at m/z 478, 480, 482 secured the presence of two bromine atoms, the corresponding [M+Na]+ at m/z 502 further confirms the structure.

The characteristic absorption band at 1660, 1740, 3299 cm-1 assigns to C=O (amide), C=O (ester), N-H group representative spectrum in (Fig. 4.1.13.3).

Spectral interpretation of 2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido) propanoic acid (11d):

7.15 (dd, J = 9 Hz, 15.1 Hz, 1H, =CH), 6.68 (bs, 1H, NH), 6.35 (t, J = 6.7 Hz, 1H, =CH), 6.09 (d, J = 7.5 Hz, 2H, =CH ), 5.81 (d, J = 14.3 Hz, 1H, =CH ), 4.64-4.52 (m, 1H, N-CH) 2.20-2.0 (m, 4H, allylic protons), 1.50-1.36 (m, 7H,aliphatic protons), 1.34-1.21 (m, 11H, aliphatic protons).

The base peak at m/z 466 [M+1]+ in its ESI mass spectrum (Fig. 4.1.14.2). The 1:2:1 isotopic distribution at m/z 464, 466, 468 secured the presence of two bromine atoms confirms the structure.

The characteristic absorption band at 1627, 1727, 3307 cm-1 assigns to C=O (amide), C=O (acid), N-H group representative spectrum in (Fig. 4.1.14.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)-4methylpentanoate (11e):

7.14 (dd, J = 9.8Hz, 15.1Mz, 1H, =CH), 6.35 (t, J = 7.5 Hz, 1H, =CH), 6.08 (m, 2H, =CH), 5.93 (d, J = 8.3, 1H, NH ), 5.75 (d, J = 15.1 Hz, 1H, =CH ), 4.71 (m, 1H, N-CH), 3.78 (s, 3H, 0-CH3), 2.20-2.08 (m, 4H, allylic protons), 1.42 (m, 2H, aliphatic protons) 1.29 (m, 7H, aliphatic protons), 0.95 (dd, J = 7.5Mz, 6.0Mz, 7H, aliphatic protons)

The base peak at m/z 522 [M+1]+ in its ESI mass spectrum (Fig. 4.1.15.2). The 1:2:1 isotopic distribution at m/z 520, 522, 524 secured the presence of two bromine atoms, the corresponding [M+Na]+ at m/z 544 further confirms the structure.

The characteristic absorption band at 1659, 1746, 3282 cm-1 assigns to C=O (amide), C=O (ester), N-H group representative spectrum in (Fig. 4.1.15.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)-4methylpentanoic acid (11f):

7.17 (m, 1H, =CH), 6.35 (t, J = 6.9 Hz, 1H, =CH), 6.26 (s, 1H, NH), 6.14-6.04 (m, 2H, =CH ), 5.80 (d, J = 14.8 Hz, 1H, =CH ), 2.19-2.05 (m, 4H, allylic protons), 1.42 (m, 4H,aliphatic protons) 1.30 (m, 15H, aliphatic protons), 0.96 (s, 8H, aliphatic protons)

The base peak at m/z 530 [M+Na]+ in its ESI mass spectrum (Fig. 4.1.16.2). The 1:2:1 isotopic distribution at m/z 528, 530, 532 secured the presence of two bromine atoms, the corresponding [M+1]+ at m/z 508 further confirms the structure.

The characteristic absorption band at 1624, 1717, 3292 cm-1 assigns to C=O (amide), C=O (acid), N-H group representative spectrum in (Fig. 4.1.16.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)-3methylpentanoate (11g):


Br Br O H N O O CH3

7.0

6.5

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

7.15 (dd, J = 9.8Hz, 15.1Mz, 1H, =CH), 6.35 (t, J = 7.5 Hz, 1H, =CH), 6.11-6.03 (m, 2H, =CH), 5.95 (d, J = 8.3, 1H, NH ), 5.77 (d, J = 15.1 Hz, 1H, =CH ), 4.67 (q, J = 4.5 Hz, 1H, N-CH), 3.74 (s, 3H, 0-CH3), 2.19-2.04 (m, 4H, allylic protons), 1.471.38 (m, 4H, aliphatic protons) 1.33-1.26 (m, 7H, aliphatic protons), 0.97-0.88 (q, J = 6.7Mz, 6H, aliphatic protons)

The base peak at m/z 522 [M+1]+ in its ESI mass spectrum (Fig. 4.1.17.2). The 1:2:1 isotopic distribution at m/z 520, 522, 524 secured the presence of two bromine atoms, the corresponding [M+Na]+ at m/z 544 further confirms the structure.

The characteristic absorption band at 1663, 1741, 3294 cm-1 assigns to C=O (amide), C=O (ester), N-H group representative spectrum in (Fig. 4.1.17.3).

Spectral interpretation of Methyl-2-((2E,4E)-15,15-dibromopentadeca-2,4,14-trienamido)-3-methylpentanoic acid (11h):

7.22-7.11 (m, 1H, =CH), 6.36 (t, J = 7.5 Hz, 1H, =CH), 6.13-6.04 (m, 2H, =CH ), 5.82 (d, J = 15.1 Hz, 1H, =CH ), 4.57(m, 1H, N-CH), 2.19-2.03 (m, 4H, allylic protons), 1.47-1.36 (m, 3H, aliphatic protons) 1.35-1.20 (m, 15H, aliphatic protons), 0.98-0.80 (m, 9H, aliphatic protons)

The base peak at m/z 530 [M+Na]+ in its ESI mass spectrum (Fig. 4.1.18.2). The 1:2:1 isotopic distribution at m/z 528, 530, 532 secured the presence of two bromine atoms, the corresponding [M+1]+ at m/z 507 further confirms the structure.

The characteristic absorption band at 1657, 1721, 3328 cm-1 assigns to C=O (amide), C=O (acid), N-H group representative spectrum in (Fig. 4.1.18.3).

All the synthesized compounds (10a, 11a-11h) are evaluated for antibacterial activity against three-gram positive and three-gram negative bacteria by serial dilution method, and antifungal activity against five fungal organisms by cup plate method.

The minimum inhibitory concentration (MIC) is taken as a parameter of antibacterial activity. The MIC of test compound is compared to that of the standard drug i.e. penicillin & streptomycin.

The area of Zone of Inhibition (ZOI) is taken as a parameter of antifungal activity. The ZOI of the compound is compared to that of the standard drug i.e. Amphotericin-B.

The work is still under progress for antibacterial activity and we are waiting for the results.

COMPOUND

C.albicans
100g 150g

C.rugosa
100g 150g

S.cerevisiae
100g 150g

A.niger
100g 150g

A.flavus
100g 150g

10a
11a

10

14

19
9

12

11

11b
11c 11d 11e 11f 11g 11h
Amphotericin-B
(50g)

14
10 8 16 12 12 11

18
18 20 16 16 14 11 13 10 13 9 13 10 9 13

23.5

21

22

25

24

The compounds when screened at 100g/ml and 150g/ml show different ZOI against four fungal organisms

All the compounds 10a, 11a, 11b, 11c, 11d, 11e, 11f, 11g and 11h has significant activity against C.rugosa, moderate activity against S.cerevisiae and A.niger at 150g/ml.

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