الفهرس 
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Abstract
This thesis deals with the synthesis and biological evaluation of novel neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) analogues as potential
antibacterial agents. In the introductory chapter, the chemistry of cryptolepine and its
regioisomer neocryptolepine as well as the chemistry of α-aminophosphonates were
reviewed. In the results and discussion chapter, the preparation, reactions and in
vitro antibacterial activity were described.
N N
CH3
A B C
D
N N
CH3
N
CH3
N
I II
1
2
3
4 5 6
7
8
10 9
11
(Neocryptolepine) (Cryptolepine)
Cl N
N NH
CH3
H3C
H3C
(Chloroquine)
III
Fig. 1: Structures of Neocryptolepine I, Cryptolepine II, Chloroquine III.
Neocryptolepine analogues with substitution at 11th position were prepared from
methyl-1H-indole-3-carboxylate 1 and aniline derivatives 2a,-b. The intermediate
methyl 2-(phenylamino)-1H-indole-3-carboxylates 3a,b, were obtained by
chlorination with N-chlorosuccinimide in the presence of 1,4-dimethylpiperazine
followed by addition of the aniline derivatives 2a,b as trichloroacetate salt.
Compounds 3 were cyclized in boiling diphenyl ether to give 5,6-dihydro-11Hindolo[
2,3-b]quinolin-11-ones 4a,b which were dehydroxychlorinated with POCl3 to
yield 5a,b. N-Methylation of the quinoline ring of 5b with methyl iodide afforded
the corresponding 2,11-dichloroneocryptolepine 6b in good yield as depicted in
Scheme 1.
English summary
- ii - -
NH
O O HN
+
NH
O O
N
i ii
N NH
O
iii
N N
Cl
N N
Cl
iv
CH3
1 2a: R1 = H, R = CH3
b: R1 =Cl, R = H
3a: R1 = H , R = CH3
b: R1 = Cl, R = H
5a: R1 = H, R = CH3
b: R1 = Cl, R = H
4a: R1 = H, R = CH3
b: R1 = Cl, R = H
R
R
R
R
R1
R1
R1
Cl R1
6b
when
R1= Cl, R = H
Scheme 1: Synthesis of neocryptolepine analogues.
Reagents and conditions: (i) N-chlorosuccinimide, 1,4-dimethylpiperazine, CH2Cl2, 0ºC,
trichloroacetic acid, stirring 3h. (ii) diphenyl ether, reflux, 4hrs. (iii) POCl3, reflux 4hrs. (iv) MeI,
THF, reflux 18-24 hrs. b. NH4OH, CH2Cl2, room temperature.
Further amination of chlorosubstituted neocryptolepine 5a via SNAr reaction in DMF
with excess of the appropriate amines such as ethylene diamine 7a, hydrazine 7b and
1,3-diaminopropane 7c at high temperature afforded target compounds 8a-c
respectively in high yields as shown in Scheme 2.
N N + H2N NH2
N N
5a
( )n
7a: n = 2
b: n = 0
c: n = 3 8a: n = 2
b: n = 0
c: n = 3
Cl
CH3
CH3
HN
NH2
i
( )n
Scheme 2: Synthesis of amino-substituted neocryptolepines.
Reagents and conditions: i) DMF and reflux 3h.
English summary
- iii - -
Having made the aminoneocryptolepine derivatives 8a-c needed for further
synthesis of α-aminophosphonates 11a-d bearing neocryptolepine moiety, the
reaction of 8a-c with aldehydes 9a,b and phosphite 10 in one-pot three component
reaction under mild conditions in presence of zinc triflate as a Lewis acid catalyst
afforded multi-substituted α-aminophosphonates 11a-d in good yields according to
scheme 3.
N N
CH3
8
HN NH2
+ R1-CHO + P(OC6H5)3
N N
CH3
HN
NH
P
O
C6H5
C6H5
R1
9
10
8a: n = 2
b: n = 0
c: n = 3
9a: R2= 3-indolyl
b: R2=2-hydroxyphenyl
11a: n = 2, R1 = 3-indolyl
b: n = 2, R1 = 2-hydroxyphenyl
c: n = 0, R1 = 3-indolyl
d: n =3, R1 = 3-indolyl
( )n
i n
Scheme 3: Synthesis of α-aminophosphonates.
Reagents and conditions: CH2Cl2, room temperature, stirring 2hrs, Zn(OTf)2, where OTf=
CF3SO3.
Moreover, the use of different commercially available Lewis acids catalysts in the
synthesis of α-aminophosphonates 11 under atmospheric conditions at room
temperature were also studied. Among catalytic compounds, zinc triflate was found
to be the catalyst of choice with good catalytic efficiency for the one-pot three
components synthesis of 11 due to the high yields and short reaction time.
Furthermore, the amount of catalyst needed to afford α-aminophosphonates in a
reasonable reaction time was 10 mol%. We also screened different solvents to
investigate the solvent effect in order to increase the yield and reduce the reaction
English summary
- iv - -
time, we found that dichloromethane (CH2C12) or acetonitrile (CH3CN) was the best
solvent due to its polarity which results in a favorable interaction with the charged
transition state to lower the activation energy.
A mechanism for α-aminophosphonates formation was proposed (see results and
discussion section). We were further interested in exploring the incorporation of
novel chemical functionality into neocryptolepine core structure such azido group to
get new entities with potentially synergic biological activities. Therefore, 11-
azidoneocryptolepine analogues 14a-c were prepared by the nucleophilic
substitution reaction of chlorine at C-11 position neocryptolepines 5 with sodium
azide in aqueous dioxane as depicted in Scheme 4.
N N
NaN3
N N
+
R4
5a: R5 = CH3 , R4 = H
5b: R5 =H , R4 = Cl
6a: R5 = CH3, R4 = Cl
R4
14a: R5 = CH3 , R4 = H
b: R5 = CH3 , R4 = Cl
c: R5 = H , R4 = Cl
i
R5
Cl N3
R5
Scheme 4:Synthesis of azido neocryptolepines.
Reagents and conditions: (i) dioxane/water, reflux, 2-6h.
The formation of azide products 14 has been proved by their 1,3-dipolar
cycloaddition reaction with thiocarbonyl-based 1,3-dipolarophile with electron
depleted thiocarbonyl group such as C-sulfonyldithioformates 17a,b. The required
C-sulfonylated thiocarbonyl compounds 17a,b, were easily accessible in good yields
from the reaction of chlorodithioformates 15 with arylsulfinate anions 16a,b in
presence of tetrabutyl ammonium hydrogen sulphate (TBAHS) as a phase transfer
catalyst, as depicted in Scheme 5.
English summary
- v - -
S C
S
S
17a: R6 = 4-ClC6H4
b: R6 = 4-CH3C6H4
Cl
Cl
Cl Cl
Cl
S C
S
Cl
Cl
Cl
Cl Cl
Cl
+ R6SO2 Na
15
i
R6
16a: R6 = 4-ClC6H4
b: R6 = 4-CH3C6H4
O
O
b: R6 =4- CH3C6H4
N N
14a
ii
18a: R6 = 4-ClC6H4
N
N
S
N
S
O
O
R6
SC6Cl5
N
N
H3C
N3
CH3
Scheme 5: Synthesis and cycloaddition of C-sulfonyldithioformates
Reagents and conditions: (i) Benzen/water stirring at room temperature in presence of
TBAHS= tetra butyl ammonium hydrogen sulphate. (ii) Dichloromethane, room temperature,
stirring 2 dayes
All the newly synthesized compounds were characterized by elemental analysis, IR,
1H-NMR, and MS spectral analysis and they showed analyses consistent with their
structures.
Antibacterial activity:
The newly synthesized compounds 8a,b, 11a,c, 14a and 18a,b were tested in vitro
for their antibacterial activity against four human bacterial pathogens, Escherichia
coli (gram -ve bacteria), Bacillus subtilis (gram +ve bacteria), Staphylococcus
aureus (Gram +ve bacteria) and Klebsiela Spp (gram –ve bacteria) by the agar well.
.