Synthesis and antifungal activity of new N-(1-phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides.

Article abstract of DOI:10.1016/S0014-827X(01)01190-9

N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides 6, with a Benodanil-like structure, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 5 with potassium iodide for 1 h in order to

Full text of DOI:10.1016/S0014-827X(01)01190-9

Il Farmaco 57 (2002) 183–187
www.elsevier.com/locate/farmac
Synthesis and antifungal activity of new
N-(1-phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and
N-(indazol-5-yl)-2-iodobenzamides
Demetrio Raffa a,*, Giuseppe Daidone a, Fabiana Plescia a, Domenico Schillaci a,
Benedetta Maggio a, Livio Torta b
a Dipartimento di Chimica e Tecnologie Farmaceutiche, Uni6ersita` degli Studi di Palermo, Via Archirafi, 32, 90123 Palermo, Italy
b Istituto di Patologia Vegetale, Uni6ersita` degli Studi di Palermo, Viale delle Scienze, 2, 90128 Palermo, Italy
Received 5 June 2001; accepted 22 October 2001
Abstract
N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-, N-(indazol-3-yl)- and N-(indazol-5-yl)-2-iodobenzamides 6, with a Benodanil-like struc-
ture, were synthesized by refluxing in acetic acid the corresponding benzotriazinones 5 with potassium iodide for 1 h in order to
study the role on the antifungal activity of the N-substitution with an aromatic heterocyclic system on benzamide moiety. Among
the tested iododerivatives, compounds 6d,f,g,h possess interesting activities toward some phytopathogenic fungal strains. © 2002
´
Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-2-iodobenzamides; N-(Indazol-3-yl)-2-iodobenzamides; N-(Indazol-5-yl)-2-iodobenzamides; Anti-
fungal activity
dermal alternariosis, occurring during an immunosup-
pressive therapy, are reported [8].
1. Introduction
Among the iododerivative III and IV, N-(3-
Benodanil, namely N-phenyl-2-iodobenzamide (I),
active principle of Carilus® (BASF) [1,5], is one of the
most significant fungicide anilides structurally con-
nected with the wide class of fungicide carboxamides
known as cis-crotoanilides (II). It exhibits a spectrum
of antifungal activities primarily including smuts (Usti-
laginales), rusts (Uredinales), and rots caused by Rhi-
zoctonia solani [1–5].
methylisoxazol-5-yl)-4-chloro-2-iodobenzamide (IIIa)
and N-(5-methylisoxazol-3-yl)-2-iodobenzamide (IVa)
possess interesting activities against the aforesaid fungal
strains in several cases similar to that of Benodanil I
taken as reference drug [6].
On the basis of such results, we synthesized new
N-(heteroaryl)-2-iodobenzamides in order to study the
role of the N-substitution with an aromatic heterocyclic
system on benzamide moiety.
In particular, owing to their antimicrobial activity
reported in literature [9–11], the pyrazolyl and inda-
zolyl moiety were selected as heterocyclic systems for
new N-(heteroaryl)-2-iodobenzamides.
Previously [6], we had investigated the synthesis of
N-isoxazolyl-2-iodobenzamides III and IV with a
benodanil-like structure, which showed interesting anti-
fungal activity against Phytophtora citricola saw.,
Botrytis cinerea Pers., Rhizoctonia sp., and Alternaria
sp. Particularly, Alternaria sp., besides being a very
common phytotoxic fungi, can also play a considerable
role in human pathology, especially in patients with
immunological deficiency. Its pathogenic role in hu-
mans is mainly expressed by asthma [7], even if cases of
2. Chemistry
N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-2-iodobenza-
mides 6a–c, N-(indazol-5-yl)-2-iodobenzamides 6d–f
and N-(indazol-3-yl)-2-iodobenzamides 6g,h were ob-
tained by a previously described method (Scheme 1) [6].
* Corresponding author.
E-mail address: demraffa@unipa.it (D. Raffa).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(01)01190-9

184
D. Raffa et al. / Il Farmaco 57 (2002) 183–187
Scheme 1.
All new products were characterized on the basis of
previously synthesized compounds IIIa and IVa [6]
emphasize the positive role of the introduction in the 3
position of the indazolyl moiety with respect to the
references.
elemental analysis, infrared (IR) and nuclear magnetic
resonance (1H NMR) spectra.
3. Biological results and discussion
4. Experimental
2-Iodobenzamides IIIa, IVa, 6a–h and Benodanil I,
included in all tests as positive control, were screened
for antifungal activity at 100 mg/ml against the follo-
wing isolates of phytopathogenic fungi: P. citrophthora,
B. cinerea, R. solani and Alternaria sp. (Table 1); com-
pounds 6d, 6f–h which showed the best activities in the
above preliminary screening, were tested again at lower
concentrations of 50, 25, 12.5, and 6.2 mg/ml (Table 2).
In particular, against P. citrophthora compounds
6d,f–h were more active than Benodanil I at 50 mg/ml
concentration, and, except for compound 6d, they exhi-
bited good activities at lower concentrations in which
Benodanil I resulted inactive.
2-Iododerivatives 6 did not show noteworthy antifun-
gal activity against all the other isolates of phytopatho-
genic fungi, having activities lower than the reference
drug Benodanil I.
Moreover they were also evaluated for their antifun-
gal activity against human pathogenic yeasts, like Can-
dida albicans ATCC10231 and Candida tropicalis
ATCC 13803, but no compounds resulted active at the
screening concentration of 100 mg/ml.
4.1. Chemistry
Melting points were determined on a Bu¨chi–Tottoli
apparatus and are uncorrected; IR spectra were
recorded with a Jasco IR-810 spectrophotometer as
1
Nujol mull supported on NaCl disk; H NMR spectra
were obtained in CDCl3 or DMSO-d6 using a Bru¨ker
AC-E 250 MHz spectrometer (TMS as the internal
standard). Elemental analyses (C, H, N), performed by
Table 1
Inhibitory effects of compounds IIIa, IVa, 6a–h and Benodanil I at
100 mg/ml on radial growth of some phytopathogenic fungal strains
Comp.
% Inhibition
P.
B. cinerea
R. solani
Alternaria
sp.
citrophthora
IIIa
30
58.5
44.3
ns
12.8
ns
54
13.7
49
52
43
IVa
6a
6b
52.5
ns a
ns
27.8
14.7
12.6
ns
ns
14.2
19
17.3
11.7
79.4
17.7
10.5
28.2
11.3
35.8
ns
36.8
38.3
36.2
56.9
6c
6d
6e
10.2
44.8
ns
Data reported in Tables 1 and 2 showed that
iodobenzamides 6, bearing in the position 3 the inda-
zolyl moiety, possess interesting activities towards some
phytopathogenic fungal strains, especially against P.
citrophthora; no significant activities were shown if the
3 position was substituted with the pyrazolyl moiety.
A comparison of the antifungal activities against P.
citrophthora between compounds 6, Benodanil I and the
6f
6g
6h
53.8
42.1
45.6
16.5
50.4
19.5
64.5
Benodanil
a ns: not significant i.e. below 10% of inhibition; values are the
mean of at least three determinations.

D. Raffa et al. / Il Farmaco 57 (2002) 183–187
185
Table 2
ml), 0.05 mol of the proper 2-nitrobenzoyl chloride
2a–c was added dropwise.
Inhibitory effects of compounds IIIa, IVa, 6d, 6f, 6g, 6h and
Benodanil I at 50, 25, 12.5, 6.2 mg/ml on radial growth of selected
phytopathogenic fungal strains
The reaction mixture was left under magnetic stirrer
overnight then poured in crushed ice. The solid which
separated was filtered off and crystallized to give 3.
The physical and spectroscopical data of compounds
3 are reported in Table 3.
Comp.
Concentration %Inhibition
(mg/ml)
P.
B. cinerea Alternaria
citrophthora
sp.
4.1.3. N-(1-Phenyl-4carbetoxypyrazol-5-yl)- and
N-(indazol-5-yl)-5-R1-4-R2-2-aminobenzamides
4,b,c,e,f
IIIa
IVa
6d
50
25
12.5
6.2
50
25
39.5
16.9
ns
ns
11.8
ns
ns
ns
34
ns
ns
ns
45.2
25.8
ns
31.2
29.4
11.2
ns
ns
ns
ns
ns
ns
ns
ns
ns
29.5
ns
ns
12.5
ns a
ns
30
ns
ns
ns
18.4
ns
ns
4.8 mmol of the proper 2-nitrobenzamide 3 were
added to a cold (bath ice, 0–5 °C) magnetically stirred
suspension of stannous chloride dihydrate (1.8 mmol,
3.6 g) in concentrated HCl (25 ml) at such a rate so that
the temperature was maintained below 10 °C (ꢀ1 h).
After the complete addition, the mixture was left under
magnetic stirrer for 24 h then diluted with cold water
(500 ml). Aqueous sodium hydroxyde (40%) was added
till the solution became alkaline and the solid which
separated was collected and crystallized to give 4.
The physical and spectroscopical data of compounds
4 are reported in Table 3.
25
12.5
6.2
50
25
12.5
6.2
50
ns
40
40
23
6f
25
12.5
6.2
50
25
12.5
6.2
ns
ns
ns
6g
25.1
11.6
ns
34.8
21.3
ns
40.5
34.2
ns
4.1.4. N-(1-Phenyl-4-carbetoxypyrazol-5-yl)- and
N-(indazol-5-yl)-5-R1-4-R2-1,2,3-benzotriazin-4(3H)-
ones 5a–c,e,f
To a cold (ice bath 0–5 °C) magnetically stirred
solution of 2-aminobenzamides 4 in 2 M HCl (30 ml),
5.6 mmol of potassium nitrite in a little amount of
water was added dropwise.
The solution was left 1 h under magnetic stirrer then
poured in cold water. The solid which separated was
collected and crystallized to give 5.
ns
ns
ns
6h
50
25
12.5
6.2
31.9
22.8
ns
ns
11.6
ns
nt b
nt
nt
34.2
ns
ns
nt
ns
Benodanil 50
25
56.8
42.2
27.2
ns
39.5
15.8
ns
12.5
6.2
ns
ns
ns
a ns: not significant i.e. below 10% of inhibition.
b nt: not tested; values are the mean of at least three determina-
tions.
The physical and spectroscopical data of compounds
5 are reported in Table 3.
4.1.5. N-(1-Phenyl-4-carbetoxypyrazol-5-yl)-,
N-(indazol-3-yl)- and N-(indazol-5-yl)-5-R1-4-R2-
2-iodobenzamides 6a–h
A solution of 3.3 mmol of the proper benzotriazi-
nones 5a–c,d [14], e,f,g [15], h [15] in glacial acetic acid
(54 ml) was refluxed for 1 h with 6.6 mmol of potas-
sium iodide.
After this time, 500 ml of water were added and the
precipitate which separated out was collected and crys-
tallized to give 6.
Dipartimento di Scienze Farmaceutiche-Universita` di
Catania, were within 90.4% of theoretical values.
5-Aminoindazole and compound 2a are commercially
available.
3-Aminoindazole [12], 5-amino-4-carbetoxy-1-phen-
ylpyrazole [13] and compounds 5d [14], 5g [15], and 5h
[15] were obtained by methods previously described.
4.1.1. 2-Nitrobenzoylchlorides 2b–c
Substituted 2-nitrobenzoylchlorides 2b,c were ob-
tained by refluxing for 5 h the opportune 2-nitrobenzoic
acid derivatives 1b,c (0.04 mol) with thionyl chloride
(28.9 ml) [16].
The physical and spectroscopical data of compounds
6 are reported in Table 3.
4.2. Biology
4.1.2. N-(Indazol-5-yl)-5-R1-4-R2-2-nitrobenzamides
3e–f
To a cold (ice bath 0–5 °C) magnetic stirred solution
The in vitro antifungal activity against isolates of
planta pathogenic fungi was evaluated by an agar dilu-
tion method using potato dextrose agar (Oxoid) [17]. A
suitable volume of solution of the test compounds
of 5-aminoindazole(0.05 mol, 6.65 g) in pyridine (16

186
D. Raffa et al. / Il Farmaco 57 (2002) 183–187
Table 3
Physical and spectroscopic data for compounds 3e,f, 4b,c,e,f, 5a–c,e,f and 6a–h
Comp. m.p. (°) (ethanol) Formula
Yields (%)
74
IR (nujol) (cm−1
)
1H NMR a (l)
3e
3f
289–290
298–299
108–110
C
14H9N4O3Cl
14H9N4O3Cl
3360–3040 (NH), 1640 (CO).
3320–3060 (NH), 1650 (CO).
7.40–8.21 (a set of signals, 7H, aromatic
protons); 10.64 (s, 1H, exchangeable NH);
12.97 (s, 1H, exchangeable NH).
7.52–8.23 (a set of signals, 7H, aromatic
protons); 10.74 (s, 1H, exchangeable NH);
13.08 (s, 1H, exchangeable NH).
1.16 (t, 3H, CH3); 4.17 (q, 2H, CH2);
6.56–7.73 (a set of signals, 10H, aromatic
protons and exchangeable NH2); 8.14 (s,
1H, pyrazole H-3); 10.32 (s, 1H,
exchangeable NH).
C
79
4b
C19H17N4O3Cl 54
3480–3100 (NH and NH2),1720
(CO), 1660 (CO).
4c
118–120
C19H17N4O3Cl 64
3520–3220 (NH and NH2), 1705
(CO), 1650 (CO).
1.72 (t, 3H, CH3); 4.18 (q, 2H, CH2);
6.77–7.71 (a set of signals, 10H, aromatic
protons and exchangeable NH2); 8.14 (s,
1H, pyrazole H-3); 10.37 (s, 1H,
exchangeable NH).
4e
4f
284–286
220–222
C14H11N4OCl
C14H11N4OCl
C19H15N5O3
28
46
87
3520–3240 (NH and NH2), 1640
(CO).
6.59 (s, 2H, exchangeable NH2); 6.81–8.14
(a set of signals, 7H, aromatic protons);
10.10 (s, 1H, exchangeable NH); 12.99 (s,
1H, exchangeable NH).
6.48 (s, 2H, exchangeable NH2); 6.77–8.16
(a set of signals, 7H, aromatic protons);
10.13 (s, 1H, exchangeable NH); 13.01 (s,
1H, exchangeable NH).
1.04 (t, 3H, CH3); 4.15 (q, 2H, CH2);
7.35–8.30 (a set of signals, 10H, aromatic
protons).
1.11 (t, 3H, CH3); 4.18 (q, 2H, CH2);
7.38–8.33 (a set of signals, 9H, aromatic
protons).
3500–3140 (NH and NH2), 1635
(CO).
5a
5b
5c
190–191
115–117
100–101
1730–1700 (CO).
1710 (CO).
C19H14N5O3Cl 96
C19H14N5O3Cl 62
1730–1770 (CO).
1.10 (t, 3H, CH3); 4.17 (q, 2H, CH2);
7.36–8.32 (a set of signals, 9H, aromatic
protons).
5e
5f
258–260
234–236
180–182
C14H8N5OCl
C14H8N5OCl
C19H16N3O3I
86
64
94
1700 (CO).
7.56–8.41 (a set of signals, 7H, aromatic
protons); 13.40 (s, 1H, exchangeable NH).
7.55–8.34 (a set of signals, 7H, aromatic
protons); 13.35 (s, 1H, exchangeable NH).
3210–3010 (NH), 1700 (CO).
6a
3260–3080 (NH), 1720 (CO), 1675 1.36 (t, 3H, CH3); 4.32 (q, 2H, CH2);
(CO).
7.10–8.02 (a set of signals, 10H, aromatic
protons); 8.63 (s, 1H, exchangeable NH).
6b
6c
6d
6e
6f
189–190
208–209
298–299
301–302
209–210
215–217
230–231
C
C
C
C
C
C
C
19H15N3O3ClI 75
19H15N3O3ClI 80
3260–3080 (NH), 1720 (CO), 1675 1.37 (t, 3H, CH3); 4.32 (q, 2H, CH2);
(CO).
7.34–8.01 (a set of signals, 9H, aromatic
protons); 8.66 (s, 1H, exchangeable NH).
3290–3100 (NH), 1720 (CO), 1675 1.37 (t, 3H, CH3); 4.33 (q, 2H, CH2);
(CO).
7.11–8.04 (a set of signals, 9H, aromatic
protons); 8.59 (s, 1H, exchangeable NH).
6.66–7.79 (a set of signals, 8H, aromatic
protons); 9.69 (s, 1H, exchangeable NH);
12.16 (s, 1H, exchangeable NH).
14H10N3OI
68
81
79
85
92
3320–3080 (NH); 1655 (CO).
14H9N3OClI
14H9N3OClI
14H9N3OClI
14H9N3OClI
3300–3100 (NH); 1645 (CO).
3300–3080 (NH); 1650 (CO).
3400–3100 (NH); 1660 (CO).
3380–3220 (NH); 1660 (CO).
7.52–8.25 (a set of signals, 7H, aromatic
protons); 10.46 (s, 1H, exchangeable NH);
13.05 (s, 1H, exchangeable NH).
7.29–8.24 (a set of signals, 7H, aromatic
protons); 10.49 (s, 1H, exchangeable NH);
13.04 (s, 1H, exchangeable NH).
7.08–8.05 (a set of signals, 7H, aromatic
protons); 10.89 (s, 1H, exchangeable NH);
12.80 (s, 1H, exchangeable NH).
7.11–7.98 (a set of signals, 7H, aromatic
protons); 10.94 (s, 1H, exchangeable NH);
12.81 (s, 1H, exchangeable NH).
6g
6h
a CDCl3 for compounds 3f, 5a–c,and 6a–c. DMSO-d6 for compounds 3e, 4b–f, 5e,f and 6d–h.

D. Raffa et al. / Il Farmaco 57 (2002) 183–187
187
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