Synthesis and in vitro antifungal properties of 4-aryl-4-N-arylamine-1- butenes and related compounds

Article abstract of DOI:10.3390/50300428

A new series of 4-aryl and 4-alkyl-4-N-arylamine-1-butenes (homoallylamines) were synthesized and some of them transformed to 4-aryl or alkylquinolines. All of them showed strong antifungal activities against human pathogenic fungi in vitro, being Epiderm

Full text of DOI:10.3390/50300428

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Molecules 2000, 5
Synthesis and In Vitro Antigungal Properties of 4-Aryl-4-N-
arylamine-1-butenes and Related Compounds
V. Kouznetsov1, J. Urbina1, A. Palma1, S. López2, C. Devia3, R. Enriz3 and S. Zacchino2
1Quím. Org. Fina, Fac. Quím., Univ. Ind. de Santander, A.A. 678, Bucaramanga, Colombia
2Farmacognosia, Fac.Cs. Bioq. y Farm., Univ.Nac de Rosario, Suipacha 531, (2000)-Rosario
E-mail:szaabgil@citynet.net.ar
3Quím.Gral, Fac. de Quím., Bioq. y Farm., Chacabuco y Pedernera, (5700)-San Luis, Argentina
Abstract: A new series of 4-aryl and 4-alkyl-4-N-arylamine-1-butenes (homoallylamines)
were synthesized and some of them transformed to 4-aryl or alkylquinolines. All of them
showed strong antifungal activities against human pathogenic fungi in vitro, being Epider-
mophyton floccosum the most susceptible species.
Introduction
As part of our project devoted to the search for antifungal agents [1-3], we synthesized a series of
new 4-aryl- or 4-alkyl-N-arylamine-1-butenes and transformed some of them into biologically impor-
tant 2-substituted 4-methyl-tetrahydroquinolines and quinolines [4]. We evaluated them for antifungal
properties with agar dilution assays and studied their structure-activities relationships (SAR).
Experimental
Chemistry. Homoallylamines 12-22 were prepared via the addition of Grignard reagent to aldimines
1-11. Electrophilic cyclization of two of them, compounds 12 and 13 under acidic conditions, led to
tetrahydroquinolines 23 and 24, which were oxidised to quinolines 25 and 26 with DDQ (Scheme 1)
Microorganisms. We used standardized human pathogenic fungi from CEREMIC or ATCC. at con-
centrations up to 50 µg/mL [1,2].
Antifungal evaluation.The dilution agar method was used according with reported procedures [1,2].
Results and Discussion
All compounds tested showed antifungal properties against dermatophytes (3.12<MIC<50 µg/mL),
in particular against Epidermophyton floccosum, similar to those obtained with Amphotericin or Keto-
conazole (Table 1). Substituents on benzene rings A or B increased four times the activity respective
the non-substituted analogs. The change of an OMe from position 4 to 2 in rings A or B increased the
activity twice.

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Molecules 2000, 5
Scheme 1
CH3
R1
R1
R1
b
a
N
N
H
R3
N
H
R3
R3
R2
R2
R2
1-9
23, 24
12-20
c
CH3
c
R1
R1
R1
a
N
N
N
R3
H
R2
10, 11
21, 22
25, 26
a)Allyl bromide+Mg/Et2O, 1OoC; b)H2SO4 75% W/V; c)DDQ/Bz,
Table I. MIC values (µg/mL) of homoallylamines, tetrahydroquinolines and quinolines acting against
dermatophytes.
CH3
N
CH3
R1
R1
R1
R1
A
N
N
N
H
H
B
R3
H
R3
R3
R2
R2
R2
C
D
E
F
Compd Typ
e
R1
H
CH3
OCH3
F
Cl
Br
H
Cl
H
H
CH3
H
CH3
H
R2
R3
M.
c.a
30
30
30
M.g
.
30
T.
T. r.d E. f e
b
m.c
C
C
C
C
C
C
C
C
C
D
D
E
E
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
-
30
30 12.5
12
13
14
15
16
17
18
19
20
21
22
23
24
>50 >50 >50 3.12
>50 30 30 3.12
>50 >50 >50 >50 30
>50 >50 >50 >50 30
>50 >50 >50 >50 30
30
>50 >50 >50 >50 >50
30 >50 >50 >50 3.12
OCH3
N(CH3)2
>50 >50 >50 3.12
H
-
-
H
H
H
H
>50 >50 >50 >50 >50
>50 >50 >50 >50 >50
-
H
H
H
H
50
50
25
25
25
25
25
25 12.5
25 12.5
25 12.5
12.5 12.5
12.5 12.5
25
>50 6.25 6.25
15 6.25 12.5
25
F
CH3
0.75 12.5
26
Amp.f
Ket.g
25
15
0.3
25
aMicrosporum canis C 112. Microsporum gypseum C 115.cTrichophyton mentagrophytes ATCC
b
d
e
f
9972. Trichophyton rubrum C 113. Epidermophyton floccosum C 114. Amp.= amphotericin B.
gKet.=ketoconazole.

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Molecules 2000, 5
References and Notes
1. Zacchino, S.; Rodríguez, G.; Pezzenati, G.; Orellana, G.; Enriz, D.; González Sierra, M. J. Nat.
Prod. 1997, 60, 659-662.
2. Zacchino, S.; Santecchia, C.; López, S.; Gattuso, S.; Muñoz, J.; Cruañes, A.; Vivot, E.; Salinas,
A.; Ruiz, R.; Ruiz, S. Phytomedicine 1998, 5, 389-395.
3. Rodríguez, A,; Giannini, F.; Baldoni, H.; Suvire, F.; Zacchino, S.; Sosa, C.; Enriz, R.; Csazar, P.;
Czismadia, I. J. of Molecular Structure (TEOCHEM) 1999, 463, 283-303.
4
Kuznetsov, V.; Andreeva, E.; Prostakov, N. Khim. Farm. Zh.1995, 29, 61-62; (1996) Chem. Abst.
124, 48.290. This work is part of: Urbina et al., Inhibitors of the fungal wall. Synthesis of 4-aryl-
4-N-arylamine-1-butenes and related compounds with inhibitory activities on β(1-3) glucan and
chitin synthases, Bioorganic & Med. Chem., in press