Synthesis of furo-salicylanilides and their heterocyclic derivatives with anticipated molluscicidal activity

Article abstract of DOI:10.1002/ardp.200600020

The synthesis of new furo-salicylanilides and their heterocyclic derivatives is described. Twenty-three compounds were screened for their molluscicidal activity against Biomphalaria alexandrina snails, the intermediate host of Schistosoma mansoni. Five of

Full text of DOI:10.1002/ardp.200600020

448
Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Full Paper
Synthesis of Furo-salicylanilides and Their Heterocyclic
Derivatives with Anticipated Molluscicidal Activity
Ghaneya Sayed Hassan, Gehan Hegazy Hegazy, Hany Mohamed Safwat
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
The synthesis of new furo-salicylanilides and their heterocyclic derivatives is described. Twenty-
three compounds were screened for their molluscicidal activity against Biomphalaria alexandrina
snails, the intermediate host of Schistosoma mansoni. Five of the tested compounds showed no
activity, while eighteen compounds showed strong to moderate activity using bayluscide as a
reference.
Keywords: 1,4-Benzoxazepine-3,5-dione / 1,3-Benzoxazine-2,4-diones / Furo-salicylanilides / Molluscicidal activity /
Received: January 25, 2006; accepted: March 16, 2006
DOI 10.1002/ardp.200600020
Introduction
Schistosomiasis is one of the endemic diseases infesting
millions of people and animals in tropical and subtropi-
cal regions. Control lines involve hygienic measures, che-
motherapeutic treatment of human and animal hosts,
Figure 1. Chemical structures of bergapten and compound 1.
and stopping the life cycle of the parasite through killing
the snail hosts which harbor one of the stages of the hel-
minthes cycle in water, namely, cercaria. The latter starts
the life-cycle by penetrating human or animal skin. Preli-
minary field trials were carried out using a variety of
inorganic and organic materials [1–5]. The most success-
ful were copper sulfate and salicylanilides [6–11]. 5,29-
Dichloro-49-nitrosalicylanilide (bayluscide) is the most
commonly used molluscicide [9, 12].
Literature survey revealed that bergapten – a natural
linear furocoumarin – is active at concentrations as low
as 5 ppm where its effect is 100% mortality in experimen-
tal trials [13, 14]. Its structure displays a cyclic form of a
salicylic acid vinylogue. Simplification of the latter struc-
ture leads to a salicylic acid derivative: 6-hydroxy-4-meth-
oxybenzofuran-5-carboxylic acid 1 (Fig. 1). Since 1 is
obtained easily from visnagin by extracting khellin from
Ammi visnaga L. fruits [15]. It seemed of interest to use it
for monomer decoration and as a feasible starting mate-
rial. Interactive pharmacology revealed negligible activ-
ity contrary to what was anticipated as a salicylic acid
derivative. This directed us to try a linearly fused three-
cycle system incorporating the aniline moiety, which is
designed to carry different groups with (+ or –) M and
(+ or –) I effects, with impact for the electron density at
the nitrogen atom, including the pattern of bayluscide.
Two-ring systems were used as a substitute for the c-py-
rone ring of bergapten: an oxazine 5 and an oxazepine 8,
which were reported to exhibit good molluscicidal activ-
ity [8, 16].
Results
Chemistry
The course of the synthesis involved the formation of the
anilides 3. We tried reacting the ethyl ester of 1 with
different anilines which turned out to be unsuccessful.
Ester formation using ethyl ortho-formate instead of its
Correspondence: Gehan Hegazy Hegazy, Pharmaceutical Chemistry
Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
E-mail: gehan_hegazy@yahoo.com
Fax: +20 23 628-426
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Furo-salicylanilides with Molluscicidal Activity
449
Table 1. IR (KBr, cm– 1) spectra of compounds 1–8.
Table 2. 1H-NMR spectra of compounds 2–8.
Compound
2
1H-NMR d (ppm)
Compound
1
IR (cm– 1
)
(DMSO-d6): 4.28 (s, 6H, 2OCH3), 6.90 (d, 2H, C3-
furan H, J = 2 Hz), 7.45 (s, 2H, C7-ArH), 7.85 (d,
2H, C2-furan H, J = 2 Hz).
(CDCl3-D2O): 4.24 (s, 3H, OCH3), 6.50–7.76 (m,
8H, ArH & furan H), 10.10 (s, 1H, NH, exch.),
13.49 (s, 1H, OH exch.).
(CDCl3-D2O): 4.19 (s, 3H, OCH3), 6.85 (s, 1H, C7-
ArH), 7.26 (d, 1H, C3-furan H, J = 2 Hz), 7.36 (d,
2H, C2 & C6-ArH, J2-3 & 6-5 = 8.2 Hz), 7.58 (d, 2H, C3
& C5-ArH, J3-2 & 5-6 = 8.2 Hz), 7.87 (d, 1H, C2-furan
H, J = 2Hz), 10.33 (s, 1H, NH exch.), 13.40 (s, 1H,
OH exch.)
(DMSO-d6): 4.31 (s, 3H, OCH3), 6.81 (s, 1H, C7-
ArH), 7.29 (d, 1H, C3-furan H, J = 2 Hz), 7.40–7.58
(m, 3H, C4,C5 & C6-ArH), 7.82 (d, 1H, C2-furan H,
J = 2 Hz), 8.26 (d, 1H, C3-ArH), 10.68 (s, 1H, NH
exch.), 12.79 (s, 1H, OH exch.).
(CDCl3-D2O): 4.30 (s, 3H, OCH3), 6.80 (s, 1H, C7-
ArH), 6.85 (d, 1H, C3-furan H, J = 2 Hz), 7.27 (d,
1H, C6-ArH, J6-5 = 8 Hz), 7.84 (d, 1H, C2-furan H, J
= 2Hz), 8.40 (d, 1H, C5-ArH, J5-6 = 8 Hz), 8.49 (s, 1H,
C3-ArH), 10.96 (s, 1H, NH exch.), 13.20 (s, 1H, OH
exch.).
(DMSO-d6): 4.28 (s, 3H, OCH3), 6.81 (s, 1H, C7-
ArH), 7.24 (d, 1H, C3-furan H, J = 2.2 Hz), 7.85 (d,
1H, C2-furan H, J = 2 Hz), 8.27 (d, 1H, C6-ArH,
J6-5 = 9 Hz), 8.41 (d, 1H, C5-ArH, J5-6 = 9 Hz), 8.57 (s,
1H, C3-ArH), 10.90 (s, 1H, NH exch.), 12.06 (s, 1H,
OH exch.).
(DMSO-d6): 4.06 (s, 3H, OCH3), 6.78 (s, 1H, C7-
ArH), 7.17 (d, 1H, C3-furan H, J = 1.8 Hz), 7.85 (d,
1H, C2-furan H, J = 1.8 Hz), 7.99 (d, 2H, C2 & C6-
ArH, J2-3 & 6-5 = 7.7 Hz), 8.32 (d, 2H, C3 & C5-ArH,
J3-2 & 5-6 = 7.7 Hz), 10.16 (s, 1H, NH exch.), 10.85 (s,
1H, OH exch.).
(CDCl3-D2O): 2.32 (s, 3H, CH3), 4.19 (s, 3H, OCH3),
6.56 (s, 1H, C7-ArH), 6.81 (d, 2H, C3 & C5 ArH,
1681 (C=O), 2962 (OH carboxylic), 3124 (OH phe-
nolic).
1765 (C=O).
3a
3b
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
1639 (C=O), 3150 (NH), 3324 (OH).
1635 (C=O), 3150 (NH), 3309 (OH).
1646 (C=O), 3140 (NH), 3300 (OH).
1637 (C=O), 3135 (NH), 3311 (OH).
1641 (C=O), 3150 (NH), 3264 (OH).
1650 (C=O), 3150 (NH), 3305 (OH).
1635 (C=O), 3150 (NH), 3324 (OH).
1640 (C=O), 3150 (NH), 3320-3350 (2 OH).
1644 (C=O), 3137 (NH), 3332 (OH).
1646 (C=O), 3150 (NH), 3350 (OH).
1140, 1200 (SO2), 1640 (C=O), 3200 (NH), 3300
(OH), 3400 & 3450 (NH & NH2).
1670, 1758 (2 C=O), 3200 (NH).
1658, 1758 (2 C=O), 3290 (NH).
1648, 1760 (2 C=O), 3284 (NH).
1675, 1750 (2 C=O), 3282 (NH).
1656, 1750 (2 C=O), 3200 (NH).
1623, 1750 (2 C=O), 3150 (NH).
1660, 1762 (2 C=O), 3180 (NH).
1658, 1720 (2 C=O), 3158 (NH), 3316 (OH).
1644, 1750 (2 C=O), 3200 (NH).
1650 (broad, 2 C=O).
1650 (broad, 2 C=O).
1641 (broad, 2 C=O).
1627 (broad, 2 C=O).
1623 (broad, 2 C=O).
1639 (broad, 2 C=O).
1662 (broad, 2 C=O).
1635, 1770 (2 C=O), 3324 (NH).
1639, 1780 (2 C=O), 3309 (NH).
1637, 1739 (2 C=O), 3353 (NH).
1639, 1712 (2 C=O), 3316 (NH).
1637, 1730 (2 C=O).
3c
3j
3k
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
6a
6b
7a
7b
8a
8b
3d
3e
3f
3g
J3-2 & 5-6 = 8.2 Hz), 7.09 (d, 1H, C3-furan H, J = 2.1
1639, 1735 (2 C=O).
Hz), 7.50 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 8.2 Hz),
7.66 (d, 1H, C2-furan H), 10.01 (s, 1H, NH exch.),
13.50 (s, 1H, OH exch.).
3h
3i
(DMSO-d6): 4.15 (s, 3H, OCH3), 6.72 (s, 1H, C7-
ArH), 6.80 (d, 1H, C3-furan H, J = 2 Hz), 7.12 (d,
2H, C2 & C6-ArH, J2-3 & 6-5 = 8 Hz), 7.49-7.86 (m, 3H,
C2-furan H,C3 & C5-ArH), 10.00 (s, 1H, NH exch.),
10.33 (s, 1H, OH exch.), 10.45 (s, 1H, OH exch.).
(CDCl3-D2O): 3.74 (s, 3H, OCH3), 4.10 (s, 3H,
OCH3), 6.77 (s, 1H, C7-ArH), 6.96 (d, 2H, C3 & C5-
ArH, J3-2 & 5-6 = 9 Hz), 7.13 (d, 1H, C3-furan H, J = 2
Hz), 7.68 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 9 Hz), 7.80
(d, 1H, C2-furan H, J = 2 Hz), 10.08 (s, 1H, NH
exch.), 10.91 (s, 1H, OH exch.).
(CDCl3-D2O): 3.77 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 4.22 (s, 3H, OCH3), 6.57 (m, 1H, C3-ArH),
6.70 (d, 1H, C5-ArH, J5-6 = 8 Hz), 6.79 (s, 1H, C7-
ArH), 6.82 (d, 1H, C3-furan H, J = 2 Hz), 7.80 (d,
1H, C2-furan H, J = 2 Hz), 8.00 (d, 1H, C6-ArH,
methyl analogue failed. This ester was previously
obtained through interaction of a silver salt of 1 with
ethyl iodide [14], or 1 with ethyl chloroformate [16]. Reac-
tion of 1 with thionyl chloride, followed by removal of
excess reagent and in situ addition of the corresponding
aniline led to a dimer 2, as shown by its mass spectrum:
M+ m/z 380.0 and the absence of both of NH and OH in IR
and 1H-NMR spectra (Tables 1 and 2). Therefore, an effort
has been made to react 1 with the corresponding aniline,
phosphorous trichloride in chlorobenzene [17, 18]. This
method proved superior to the aforementioned methods
as it provided the required anilides 3 in an excellent yield
(90–100%). IR spectra of the anilides 3 showed the amide
C=O, NH, and OH frequencies. 1H-NMR spectra of 3
showed characteristic singlets exchangeable with D2O
(NH & OH). Iron III chloride gave a violet color with 3.
3j
J6-5 = 8 Hz), 11.00 (s, 1H, NH exch.), 13.70 (s, 1H,
OH exch.).
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450
G. S. Hassan et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Table 2. Continued ...
Table 2. Continued ...
Compound
3k
1H-NMR d (ppm)
Compound
5b
1H-NMR d (ppm)
(DMSO-d6): 4.03 (s, 3H, OCH3), 5.30 (brs, 2H, NH2
exch.), 6.75 (s, 1H, C7-ArH), 7.01 (d, 1H, C3-furan
H, J = 2 Hz), 7.49 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 7.8
Hz), 7.79 (d,1H,C2-furan H, J = 2 Hz), 8.05 (d, 2H,
C3 & C5-ArH, J3-2 & 5-6 = 7.8 Hz), 9.58 (s, 1H, NH
exch.).
(CDCl3-D2O): 1.26 (t, 3H, CH2-CH3), 4.23 (s, 3H,
OCH3), 4.26 (brs, 2H, CH2-CH3), 6.84 (s, 1H, C7-
ArH), 6.97 (d, 1H, C3-furan H, J = 2 Hz), 7.00–7.54
(m, 5H, ArH), 7.64 (d, 1H, C2-furan H, J = 2 Hz),
10.60 (s, 1H, NH exch.).
(DMSO-d6): 1.21 (t, 3H, CH2-CH3), 4.00 (m, 2H, CH2-
CH3), 4.16 (s, 3H, OCH3), 6.67 (s, 1H, C7-ArH), 6.95
(d, 1H, C3-furan H, J = 2 Hz), 7.11–7.76 (m, 4H,
ArH), 7.82 (d, 1H, C2-furan H, J = 2 Hz), 10.87 (s,
1H, NH exch.).
(DMSO-d6): 1.25 (t, 3H, CH2-CH3), 3.40 (brs, 2H,
CH2-CH3), 4.04 (s, 3H, OCH3), 6.67 (s, 1H, C7-ArH),
6.90 (d, 1H, C3-furan H, J = 2 Hz), 7.11–7.76 (m,
4H, ArH), 7.85 (d, 1H, C2-furan H, J = 2 Hz), 10.29
(s, 1H, NH exch.).
(DMSO-d6): 1.25 (t, 3H, CH2-CH3), 3.45 (brs, 2H,
CH2-CH3), 4.18 (s, 3H, OCH3), 6.64 (s, 1H, C7-ArH),
6.94 (d, 1H, C3-furan H, J: 2 Hz), 7.48 (d, 1H, C6-
ArH, J6-5 = 9 Hz), 7.75 (d, 1H, C2-furan H, J = 2 Hz),
8.10 (d, 1H, C5-ArH, J5-6 = 9 Hz), 8.39 (s, 1H, C3-
ArH), 11.45 (s, 1H, NH exch.).
(DMSO-d6): 1.20 (t, 3H, CH2-CH3), 3.60 (brs, 2H,
CH2-CH3), 4.15 (s, 3H, OCH3), 6.58 (s, 1H, C7-ArH),
6.89 (d, 1H, C3-furan H, J = 2 Hz), 7.80 (d, 1H, C2-
furan H, J = 2 Hz), 8.18 (d, 1H, C6-ArH, J6-5 = 9 Hz),
8.29 (d, 1H, C5-ArH, J5-6 = 8 Hz), 8.67 (s, 1H, C3-
ArH), 11.81 (s, 1H, NH exch.).
(DMSO-d6): 4.17 (s, 3H, OCH3), 6.76 (s, 1H, C7-
ArH), 6.96 (d, 1H, C3-furan H, J = 2 Hz), 7.51 (d,
2H, C3 & C5-ArH, J3-2 & 5-6 = 9 Hz), 7.69 (d, 1H, C2-
furan H, J = 2 Hz), 7.79 (d, 2H, C2 & C6-ArH,
J2-3 & 6-5 = 9 Hz).
5c
(DMSO-d6): 4.02 (s, 3H, OCH3), 6.72 (s, 1H, C7-
ArH), 6.73 (d, 1H, C3-furan H, J = 2 Hz), 7.09
(d, 2H, C5 & C6-ArH, J5-6 = 8Hz), 7.88 (m, 2H,
C3-ArH & C2-furan H).
(DMSO-d6): 4.19 (s, 3H, OCH3), 6.70 (d, 1H, C3-fur-
an H, J = 2 Hz), 6.93 (d, 1H, C6-ArH, J6-5 = 8Hz),
7.07 (s, 1H, C7-ArH), 7.67 (d, 1H, C2-furan H, J = 2
Hz), 7.87 (d, 1H, C5-ArH, J5-6 = 8Hz), 8.00 (s, 1H,
C3-ArH).
(DMSO-d6): 4.05 (s, 3H, OCH3), 6.78 (s, 1H, C7-
ArH), 7.08 (d, 1H, C3-furan H, J = 2 Hz), 7.50 (d,
2H, C2 & C6-ArH, J2-3 & 6-5 = 9 Hz), 7.77 (d, 1H, C2-
furan H, J = 2 Hz), 8.04 (d, 2H, C3 & C5-ArH,
4a
4b
4c
4d
5d
5e
5f
J3-2 & 5-6 = 9 Hz).
(DMSO-d6): 2.17 (s, 3H, CH3), 4.04 (s, 3H, OCH3),
6.72 (s, 1H, C7-ArH), 7.02 (d, 1H, C3-furan H, J = 2
Hz), 7.11 (d, 2H, C3 & C5-ArH, J3-2 & 5-6 = 8 Hz), 7.49
(d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 8 Hz), 7.69 (d, 1H,
C2-furan H, J = 2 Hz).
(CDCl3-D2O): 3.74 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 4.16 (s, 3H, OCH3), 6.60 (s, 1H, C7-ArH),
6.70 (m, 1H, C3-ArH), 6.75 (d, 1H, C5-ArH, J5-6 = 8
Hz), 6.82 (d, 1H, C3-furan H, J = 2 Hz), 7.67 (d, 1H,
C2-furan H, J = 2 Hz), 8.06 (d, 1H, C6-ArH).
(CDCl3-D2O): 3.92 (s, 3H, OCH3), 4.22 (s, 2H,CH2),
6.82 (s, 1H, C7-ArH), 7.10 (d, 1H, C3-furan H, J = 2
Hz), 7.27–7.45 (m, 5H, ArH), 7.57 (d, 1H, C2-fur-
an H, J = 2 Hz), 10.87 (s, 1H, NH exch.).
CDCl3-D2O): 3.84 (s, 3H, OCH3), 4.30 (s, 2H, CH2),
6.86 (s, 1H, C7-ArH), 6.95 (d, 1H, C3-furan H, J = 2
Hz), 7.41 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 8 Hz), 7.58
(d, 1H, C2-furan H, J = 2 Hz), 7.66 (d, 2H, C3 & C5-
ArH, J3-2 & 5-6 = 8 Hz), 10.43 (s, 1H, NH exch.).
(DMSO-d6): 1.22 (t, 3H, CH2-CH3), 3.86 (brs, 2H,
CH2-CH3), 4.15 (s, 3H, OCH3), 5.50 (s, 2H, OCH2-
COO), 6.99 (s, 1H, C7-ArH), 7.10 (d, 1H, C3-furan
H, J = 2 Hz), 7.42–7.64 (m, 5H, ArH), 7.67 (d, 1H,
C2-furan H, J = 2 Hz), 10.00 (s, 1H, NH exch.).
(DMSO-d6): 1.24 (t, 3H, CH2-CH3), 3.94 (s, 3H,
OCH3), 4.20 (q, 2H, CH2-CH3), 5.40 (s, 2H, OCH2-
COO), 6.99 (d, 1H, C3-furan H, J = 2 Hz), 7.10 (s,
1H, C7-ArH), 7.49 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 8
Hz), 7.67 (d, 2H, C3 & C5-ArH, J3-2 & 5-6 = 8 Hz), 7.81
(d, 1H, C2-furan H, J = 2 Hz), 10.10 (s, 1H, NH
exch.).
5g
4e
4f
6a
6b
(DMSO-d6): 1.21 (t, 3H, CH2-CH3), 3.34 (brs, 2H,
CH2-CH3), 4.15 (s, 3H, OCH3), 6.63 (s, 1H, C7-ArH),
7.13 (d, 1H, C3-furan H, J = 2 Hz), 7.82 (d, 1H, C2-
furan H, J = 2 Hz), 8.07 (d, 2H, C2 & C6-ArH,
J2-3 & 6-5 = 8 Hz), 8.42 (d, 2H, C3 & C5-ArH, J3-2 & 5-6
=
8 Hz), 11.40 (s, 1H, NH exch.).
7a
7b
4g
4h
(DMSO-d6): 1.21 (t, 3H, CH2-CH3), 2.19 (s, 3H, CH3),
4.00 (s, 3H, OCH3), 4.26 (m, 2H, CH2-CH3), 6.75 (s,
1H, C7-ArH), 6.96 (d, 1H, C3-furan H, J = 2 Hz),
7.14–7.72 (m, 4H, ArH), 7.90 (d, 1H, C2-furan H,
J = 2.2 Hz), 10.15 (s, 1H, NH exch.).
(DMSO-d6): 1.28 (t, 3H, CH2-CH3), 4.01 (s, 3H,
OCH3), 4.26 (q, 2H,CH2-CH3), 6.63 (s, 1H, C7-ArH),
6.80 (d, 2H, C3 & C5-ArH, J3-2 & 5-6 = 8.4 Hz), 6.92
(d, 1H, C3-furan H, J = 2 Hz), 7.45 (d, 2H, C2 & C6-
ArH, J2-3 & 6-5 = 8.4 Hz), 7.78 (d, 1H, C2-furan H, J = 2
Hz), 10.02 (s, 1H, NH exch.), 10.66 (s, 1H, OH
exch.).
(DMSO-d6): 1.20 (t, 3H, CH2-CH3), 3.40 (q, 2H, CH2-
CH3), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.30
(s, 3H, OCH3), 6.66 (m, 1H, C5-ArH), 6.80 (s, 1H,
C7-ArH), 6.95 (d, 1H, C3-furan H, J = 2 Hz), 7.24
(s, 1H, C3-ArH), 7.86 (d, 1H, C2-furan H, J = 2 Hz),
8.04 (d, 1H, C6-ArH, J6-5 = 9 Hz), 11.00 (s, 1H, NH
exch.).
(DMSO-d6): 4.08 (s, 3H, OCH3), 6.68 (s, 1H, C7-
ArH), 6.98 (d, 1H, C3-furan H, J = 2 Hz), 7.00–7.76
(m, 5H, ArH), 7.82 (d, 1H, C2-furan H, J = 2 Hz).
8a
8b
(DMSO-d6): 4.00 (s, 3H, OCH3), 5.33 (s, 2H, CH2),
6.96 (s, 1H, C7-ArH), 7.10 (d, 1H, C3-furan H, J = 2
Hz), 7.36–7.65 (m, 5H, ArH), 7.77 (d, 1H, C2-fur-
an H, J = 2 Hz).
(DMSO-d6): 4.05 (s, 3H, OCH3), 5.30 (s, 2H, CH2),
6.75 (s, 1H, C7-ArH), 7.17 (d, 1H, C3-furan H, J = 2
Hz), 7.44 (d, 2H, C2 & C6-ArH, J2-3 & 6-5 = 8 Hz), 7.75
(d, 2H, C3 & C5-ArH, J3-2 & 5-6 = 9 Hz), 7.95 (d, 1H,
C2-furan H, J = 2 Hz).
4i
5a
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Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Furo-salicylanilides with Molluscicidal Activity
451
Scheme 1. Synthesis route of compounds 2–5.
Reaction of the resulting anilides 3 with ethyl chlorofor- ethyl O-acetate derivatives 7 were obtained, respectively
mate yielded the open structures: ethyl O-formate 4 (Scheme 2). Several trials were carried out to cyclize 6 to
(Scheme 1). For ethyl O-formates 4 the two C=O and NH 1,4-benzoxazepine-2,5-diones 9, using triethylamine/dry
absorption bands are very characteristic, while OH disap- benzene at room temperature, reflux, with anhydrous
1
peared in the IR and H-NMR spectra. Compound 4 was potassium carbonate/dry acetone with or without potas-
cyclized using ethanolic sodium ethoxide to give 1,3-ben- sium iodide or using ethanolic sodium ethoxide. All
zoxazine-2,4-dione derivatives 5 (Scheme 1). For 5, two these trials gave the unchanged anilides 3. 1,4-Benzoxaze-
C=O absorption bands were observed while both amide pine-3,5-diones 8 – isosters of 9 – were only obtained via
NH and OH bands had disappeared in IR and1H-NMR spec- cyclization of 7 using ethanolic sodium ethoxide
tra. Iron III chloride gave a negative result both with 4 (Scheme 2). A further confirmation for structures 3–8
1
and 5. When 3 was treated with chloroacetyl chloride or comes from mass spectra, IR, H-NMR, physical proper-
ethyl chloroacetate, O-chloroacetyl derivatives 6 and ties, and microanalysis data.
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452
G. S. Hassan et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Scheme 2. Synthesis route of compounds 6–8.
Pharmacology
mortality at 10 ppm, 100–60% mortality at 2 ppm) with
the advantage of having lower molar concentration. Rigi-
Molluscicidal activity screening
dification of the structure as 1,3-benzoxazines
5
The toxicity of the products towards Biomphalaria alexan-
drina snails, the intermediate host of Schistosoma man-
soni, which affects the intestinal system in man, was car-
ried out according to the standard method [3, 19, 20].
decreased the activity and 1,4-benzoxazepines 8 abol-
ished the activity. The most active compound was 4d; its
activity is comparable to that of bayluscide. Further, it
had a knocking-down effect on the snails due to bleeding
action.
The applied method suffers from dealing with insolu-
ble or weakly soluble compounds i.e., the results
obtained with compounds 3e, 3f, 6b, and 8b are rather
dubious. Because they precipitate upon dilution with
water, this may imply that they are very potent, since the
amount left, which is truly in solution, is smaller than
the nominal concentration (compound 6b). Unfortu-
nately, this is the only available method. Taking salicyla-
nilide structure as a template, the results in Table 3 indi-
cate that lipophilicity is a prerequisite for activity as
investigated by bayluscide (log P = 4.73) and the top
active compounds 4b and 4d–f. Further, the soft part of
the mollusk is highly lipophilic (high concentration of
Discussion
Depending on the pharmacological responses obtained
from testing twenty-three compounds (Table 3). Five of
the tested compounds showed no activity, while eighteen
compounds showed moderate activity except 4-chloro,
2,4-dichloro, 2-chloro-4-nitro, and 4-nitro anilides
showed strong activity. Although, benzofuran salicylic
acid derivative 1 showed no molluscicidal activity, most
of salicylanilide derivatives 3, O-chloroacetyl derivatives
6, and ethyl O-acetate ester derivatives 7 showed moder-
ate activity. Further, some of ethyl O-formate ester deriv-
atives 4 displayed an activity similar to bayluscide (100%
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Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Furo-salicylanilides with Molluscicidal Activity
453
Table 3. Molluscicidal activity of synthesized compounds.
Compound
No.
Partit.
coeff.
(logP)
% Mortality at concentration
(ppm)
Molar concentration (M610– 3
)
Solvents/Remarks
Equivalent to (in ppm)
10
2
1
10
2
1
Control
Bayluscide
1
–
0
100
0
0
100
0
0
0
0
0
0
0
0
0
0
0
90
0
100
60
100
0
80
0
0
0
100
0
0
0
0
0
0
0
0
0
0
0
0
0
20
30
20
0
20
0
0
0
0
0
–
30.5
–
–
6.1
–
–
–
–
–
–
–
–
–
–
–
5.1
–
4.7
4.6
5.0
–
5.8
–
–
–
3.0
–
–
–
–
–
–
–
–
–
–
–
–
–
2.4
2.3
2.5
–
acetone or DMSO
acetone
DMSO
4.73
2.16
1.84
2.83
2.43
3.35
2.90
2.29
2.30
1.09
1.56
0.65
2.80
2.36
3.21
2.74
2.25
0.24
3.37
3.77
3.30
3.02
2.87
1.84
3a
3b
3c
3d
3e
3f
3g
3h
3j
3k
4b
4c
4d
4e
4f
10
40
20
40
40
0
30
20
10
20
100
50
100
100
100
0
35.3
31.5
31.5
28.4
27.6
–
33.6
33.4
29.2
27.6
25.7
25.7
23.6
23.0
25.0
–
DMSO
acetone
acetone
acetone
*
*
DMSO
DMSO
DMSO
DMSO
acetone
acetone
acetone/bleeding
DMSO
acetone
DMSO
acetone
acetone
insoluble in DMSO
*
4I
5b
5c
5d
6b
7b
8b
80
40
0
80
40
0
29.1
26.4
–
25.4
24.8
–
–
–
–
–
–
–
10
0
0
5.0
–
–
DMSO
insoluble in DMSO
* Dissolved in DMSO and precipitated when diluted with water.
sterols). The observation that blockade of the phenolic
OH either by cyclization or ester formation leads to
decrease in the activity, with the exception of the ethyl O-
formate which leads to enhancement of activity is in
accordance with the suggestion that these compounds
act by chelating a metal necessary for vital processes in
the mollusk's body. In this vein, the ethyl O-formate ester
serves as a prodrug that enhances absorption via
increased lipophilicity. Concerning the pattern of substi-
tution on both moieties – salicylic acid and aniline – the
salicylic acid part may carry groups other than the chloro
Experimental
Chemistry
All melting points were determined by the open capillary
method using Gallenkamp melting point apparatus (MFB-595-
010M, England) and were uncorrected. Microanalyses were car-
ried out at the Microanalytical Center at Cairo University and
are within l0.4% of the theoretical values. IR spectra were deter-
mined using potassium bromide discs on Shimadzu Infrared
Spectrometer IR 435 (Shimadzu, Kyoto, Japan), FT-IR 1650 (Per-
kin Elmer), and Genesis II FTIRTM Spectrometer (Mottson, Madi-
son, WI, USA). 1H-NMR Spectra were determined using Joel NMR
and Varian Gemini 200 MHz Spectrometer (Jeol, Tokyo, Japan)
(recalled for bayluscide) as shown by the high activity of and Varian Mercury VX-300 MHz NMR Spectrometer (Oxford,
England). Chemical shifts (d) are given in parts per million (ppm)
compounds 4b and 4d–f which carry furan and methoxy
downfield from TMS as the internal standard. Mass spectra were
functions. In the aniline moiety, 2,4-dichloro derivative
recorded using Hewlett Packard Varian (Varian, Palo Alto, CA,
is superior to the 2-chloro-4-nitro pattern of bayluscide.
USA) and Shimadzu Gas Chromatograph Mass spectrometer-QP
In general, the substituents must have electron-with-
drawing effect (-I) regardless of the sign of mesomeric
effect (M). Both, lipophilicity (partition coefficient more
than two) and electronic properities (electron withdraw-
ing as chloro and/or nitro) are important determinants
of the described biological activity.
1000 EX (Shimadzu, Japan). Partition coefficient and nomencla-
ture are according to the Acdlabs free ware version 8 on Acdlabs.-
com using Chem Sketch and Ilab add on software 2005. Progress
of the reaction was monitored by TLC using pre-coated alumi-
num/silica gel sheets Merck 60 F254 (Merck, Darmstadt, Germany)
using ethyl acetate/carbon tetrachloride (1:9) as eluent; spots
were visualized by UV lamp.
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454
G. S. Hassan et al.
Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Table 4. Physical properties and microanalytical data of the
synthesized compounds 3–8.
Bis(4-methoxy benzofuran-5-carboxylate) 2
A mixture of 1 (2.08 g, 0.01 mol) and thionyl chloride (5 mL) was
refluxed in boiling water bath for 30 min while stirring. Excess
thionyl chloride was distilled and the residue was treated with
the appropriate aniline (0.01 mol) in dry benzene. The reaction
mixture was stirred at room temperature for further 15 min.
Excess solvent was distilled under vacuum and the residue was
poured into ice/water. A resinous product was triturated with
petroleum ether till solidification and crystallized from acetone.
Yield 85%, m.p. 1588C. Reaction of I with aniline m/z (%): 380 [M+]
(12.60) and with p-chloroaniline m/z (%): 380 [M+] (2.00). Anal.
Calcd. for C20H12O8: C, 63.12; H, 3.16. Found: C, 62.97; H, 3.30%.
No R1
R2
Mol. Formula Yield M.P.
Microanalyses
(M. Wt.)
(%) (8C)
Calcd.% Found%
3a
H
H
C16H13NO4
(283.27)
95 134 C 67.83 67.47
H 4.62
N 4.94
4.94
4.95
3b Cl
H
C16H12ClNO4 100 154 C 60.47 60.73
(317.76)
H 3.80
N 4.40
3.52
4.04
3c
H
Cl
Cl
C16H12ClNO4
(317.76)
95 143 C 60.47 60.70
H 3.80
N 4.40
3.90
4.38
N-Aryl-6-hydroxy-4-methoxy-1-benzofuran-5-
carboxamide 3a–k
3d Cl
C16H11Cl2NO4
(352.25)
95 164 C 54.55 54.60
H 3.14
N 3.97
3.20
3.95
A suspension of furo-salicylic acid derivative 1 (4.16 g, 0.02 mol),
the appropriate aniline (0.02 mol), and phosphorus trichloride
(1.38 g, 0.01 mol.) in chlorobenzene (100 mL) was heated under
reflux for 3 h. The reaction mixture was filtered while hot and
the product allowed to crystallize upon cooling. The product
was crystallized from ethanol, except 3e and 3j from DMF/water
(Table 4). 3b m/z (%): 317.05 [M+] (16.68).
3e NO2 Cl
C16H11ClN2O6 100 204 C 52.97 53.00
(362.76)
H 3.05
N 7.72
3.10
7.62
3f NO2
3g CH3
3h OH
H
H
H
H
C16H12N2O6
(328.26)
95 232 C 58.53 58.62
H 3.68
N 8.53
3.99
8.65
C17H15NO4
(297.30)
90 122 C 68.67 69.02
H 5.08
N 4.71
4.85
4.75
N-Aryl-6-hydroxy-4-methoxy-N-propionyl-1-benzofuran-
5-carboxamide 4a–i
C16H13NO5
(299.27)
90 228 C 64.20 64.33
Ethyl chloroformate (1.08 g, 0.01 mol) was added dropwise to a
stirred solution of the furo-salicylanilide derivatives 3 (0.01 mol)
in dry pyridine (10 mL) at 08C. The mixture was heated in a
steam bath for 1h and poured into cold dilute hydrochloric acid
(50 mL). After standing for 24 h, the product was filtered off,
washed well with water, dried, and crystallized from ethanol,
except 4e and 4j from DMF/water (Table 4). 4a m/z (%): 353.30
[M+] (1).
H 4.37
N 4.68
3.94
4.51
3i OCH3
C17H15NO5
(313.30)
95 111 C 65.16 65.34
H 4.82
N 4.47
4.49
4.44
3j OCH3 OCH3 C18H17NO6
100 178 C 62.96 63.00
(343.32)
H 4.98
N 4.08
5.35
4.10
3k SO2N- H
C16H14N2O6S
(362.29)
90 210 C 53.04 53.10
H2
H 3.89
N 7.73
4.00
7.68
3-Aryl-5-methoxy-2H-furo [3,2-g][1,3]benzoxazine-
2,4(3H)-dione 5a–g
A mixture of 4 (0.01 mol.) and sodium metal (0.23 g, 0.01 mol.)
was refluxed with super dry ethanol (25 mL) for 24 h. The reac-
tion mixture was then treated with cold water, acidified with
acetic acid, and left in the ice chest. The solid was washed with
water and crystallized from DMF/water (Table 4).
4a
H
H
C19H17NO6
(355.34)
70 194 C 64.21 64.40
H 4.82
N 3.94
4.42
3.92
4b Cl
H
C19H16ClNO6
(389.83)
80 200 C 58.54 58.61
H 4.14
N 3.59
3.99
3.65
4c
H
Cl
Cl
C19H16ClNO6
(389.83)
70 154 C 58.54 58.20
H 4.14
N 3.59
4.45
3.63
4d Cl
C19H15Cl2NO6
(424.32)
90 174 C 53.78 53.90
(5-Arylamino carbonyl-4-methoxy-1-benzofuran-
6-yloxy)acetylchloride 6a, b
Chloroacetyl chloride (1.13 g, 0.01 mol) was added dropwise to a
stirred solution of 3 (0.01 mol) in dry pyridine (10 mL), left at
room temperature for 30 min and poured into ice/water. The
product was filtered, washed with water, and crystallized from
ethanol (Table 4). 6b m/z (%): 394 [M+] (2.70).
H 3.56
N 3.30
3.60
3.45
4e NO2 Cl
C19H15ClN2O8
(434.83)
90 132 C 52.48 52.48
H 3.48
N 6.44
3.45
6.78
4f NO2
4g CH3
4h OH
H
H
H
C19H16N2O8
(400.34)
60 190 C 57.00 57.00
H 4.02
N 7.00
4.00
7.05
C20H19NO6
(369.36)
70 162 C 65.03 65.14
Ethyl (5-arylamino carbonyl-4-methoxy-1-benzofuran-
6-yloxy)acetate 7a, b
Ethyl chloroacetate (1.23 g, 0.01 mol) was added dropwise to a
stirred solution of 3 (0.01 mol) in dry pyridine (10 mL) and
refluxed for 3 h. The reaction mixture was cooled and poured
into ice/water. The product was filtered, washed with water, and
crystallized from ethanol (Table 4).
H 5.19
N 3.79
5.30
3.85
C19H17NO7
(371.34)
60 120 C 61.46 61.40
H 4.58
N 3.77
4.84
3.78
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Arch. Pharm. Chem. Life Sci. 2006, 339, 448–455
Table 4. Continued ...
Furo-salicylanilides with Molluscicidal Activity
455
left for further 24 h, after which the results were recorded by
counting the number of the killed snails and the%-mortality was
calculated. Control experiments were carried out using (1 mL) of
acetone or dimethylsulfoxide added to 1 L of water. 5,29-
Dichloro-49-nitrosalicyl anilide (bayluscide) was used as the refer-
ence molluscicidal agent [9, 12].
No R1
R2
Mol. Formula Yield M.P.
(M. Wt.) (%) (8C)
Microanalyses
Calcd.% Found%
4i OCH3 OCH3 C21H21NO8
70 152 C 60.72 61.07
(415.39)
H 5.06
N 3.37
4.68
3.42
The authors wish to thank Dr. Nancy A. Shafik, Pesticides
Department, National Research Center, Dokki, Cairo, Egypt for
carrying out the pharmacological screening.
5a
H
H
C17H11NO5
(309.27)
70 320 C 66.02 65.72
H 3.58
N 4.53
3.72
4.53
5b Cl
5c Cl
H
C17H10ClNO5 75 212 C 59.39 59.22
(343.76)
H 2.93
N 4.08
3.26
4.18
Cl
C17H9Cl2NO5 80 298 C 53.98 54.21
References
(378.28)
H 2.40
N 3.70
2.50
3.62
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5d NO2 Cl
C17H9ClN2O7 50 310 C 52.52 52.90
veria, Biorg. Med. Chem. 2004, 12, 865–869.
(388.76)
H 2.33
N 7.21
2.77
7.29
[2] D. Sukumaran, B. D. Parashar, A. K. Gupta, K. Jeevarat-
nam, S. Prakash, Mem. Inst. Oswaldo Cruz 2004, 99, 205–
210.
5e NO2
5f CH3
H
H
C17H10N2O7
(354.27)
60 320 C 57.63 57.24
H 2.83
N 7.91
2.98
7.89
[3] A. S. Girgis, Pharmazie 2000, 55, 426–428.
C18H13NO5
(323.29)
70 204 C 66.87 66.94
[4] G. Dreyfuss, P. Vignoles, D. Romdelaud, Vet Res. 1996, 27,
H 4.05
N 4.33
4.36
4.38
599–605.
5g OCH3 OCH3 C19H15NO7
80 235 C 61.79 61.56
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(369.32)
H 4.09
N 3.79
4.34
3.85
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6a
H
H
H
H
H
H
H
C18H14ClNO5 90 121 C 60.08 60.01
(359.80)
H 3.92
N 3.89
4.07
3.95
[7] A. Tanveer, K. Salahuddin, J. Zool. 2001, 16, 91–100.
6b Cl
C18H13Cl2NO5 90 142 C 54.83 54.85
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H 3.32
N 3.55
3.27
3.53
301–312.
7a
H
C20H19NO6
( 369.36 )
70 198 C 65.03 65.24
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2002, 97, 743–745.
H 5.19
N 3.79
5.29
3.81
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7b Cl
C20H18ClNO6 80 210 C 59.48 59.70
H 4.49
N 3.47
4.50
3.55
(403.85)
[11] M. T. Clark, R. A. Coburn, R. T. Evans, R. J. Jenco, J. Med.
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8a
8b
H
H
C18H13NO5
(323.29)
60 238 C 66.87 66.90
H 4.05
N 4.33
3.90
4.29
[12] K. El-Refaie, R. El-Sayed, Macromol Bioscie 2004, 4, 119–
C18H12ClNO5 65 330 C 60.42 60.30
128.
(357.78)
H 3.38
N 3.92
3.50
3.88
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4-Aryl-6-methoxy furo [3,2-h][1,4]-benzoxazepine-
3,5(2H,4H)-dione 8a, b
Apply the same procedure as for preparing 5, but starting with
7. The product was crystallized from acetic acid/water (Table 4).
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Molluscicidal activity screening
A solution having 10 ppm was prepared by dissolving (0.1 g) of
the tested compound in 10 mL of acetone or dimethylsulfoxide.
1 mL of this solution was diluted with water to a final volume of
1 L. Ten snails were used for each experiment. After an exposure
period of 24 h, the snails were transferred into fresh water and
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