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749
present at the arylhydrazone unit, phenyl (W=H, 8a–
d), 4-dimethylaminophenyl (W=N(CH3)2, 8e–h) and
furyl (X=O, 8i–l) residues. Bioisosteric thienyl series
(X=S, 8m–p) were also designed in order to investi-
gate the role of lipophilicity increase in the bio-evalua-
tion of these new derivatives, considering the important
lipophilic contribution of the thienyl ring [10] (Fig. 1).
2. Chemistry
The new substituted arylidene 3-phenyl-1,2,4-oxadia-
zole-5-carbohydrazide (8a–p) derivatives were synthe-
sized using the route illustrated in Scheme 1.
The key synthetic intermediates for the target com-
pounds 8a–p were the corresponding hydrazides 11a–d,
which by condensation with the appropriate aromatic
aldehydes, i.e. benzaldehyde, 4-dimethylaminobenzalde-
hyde, furfural or thiophene 2-carboxaldehyde, at reflux
in ethanol, produced the new desired arylidene 3-
phenyl-1,2,4,-oxadiazole-5-carbohydrazide (8a–p) de-
rivatives [6,7].
Scheme 1. (a) i- NH2OH · HCl, Na2CO3, methanol, water, reflux, 4 h,
70–80%; ii- ClCOCOOCH3, THF, reflux, 2.5 h, 42–52%. (b) 80% aq.
NH2NH2 · H2O, ethanol, r.t., 1 h, 80–90%. (c) Benzaldehyde or
4-N,N-dimethylaminobenzaldehyde or furfuraldehyde or thiophene
2-carboxaldehyde, H2SO4 (cat.), ethanol, water, reflux, 2.5 h.
The initial synthetic step, illustrated in Scheme 1, was
the construction of the 1,2,4-oxadiazole system present
in the methyl 3-aryl-1,2,4-oxadiazole-5-carboxylate
derivatives 9a–d, chosen as a precursor for the hy-
drazides 11a–d. This was performed by exploring the
classical methodology to access the 1,2,4-oxadiazole
system [11], by treatment of the appropriate benzoni-
trile 12a–d with hydroxylamine in ethanol at reflux
[12]. This procedure produced the substituted benzami-
doxime precursor derivatives 10a–d, which were next
treated, in situ, with methyl oxalylchloride in tetrahy-
drofuran, at reflux, to furnish, in yields varying between
42 and 52%, the desired 1,2,4-oxadiazole-5-carboxylate
(9a–d) derivatives (Table 1). These derivatives were
then treated with hydrazine hydrate in ethanol [6,7] to
give the hydrazides 11a–d in 80–90% yield (Table 1).
After purification by recrystallization from an
ethanol/water mixture, the target compounds 8a–p
were obtained in good yields, as crystalline derivatives
ries 5 the acyl functions have two aromatic CH at the
ortho position, whereas this new series 8 possess two
distinct aromatic heteroatoms, e.g. O and N (Fig. 1).
Due to this distinct neighborhood around the acyl
function, we decided to investigate by molecular me-
chanics, using the AM1 method, the relative stability of
the two possible S-cis versus S-trans conformations
(vide conformers A, C versus B, D (Table 5)) in this
series of derivatives. This conformational study was
also undertaken in order to identify any possible
‘pseudo-ortho-effect’ caused by the distinct heteroatoms
in the heterocyclic ring favoring one of the possible
conformations. For instance, we can anticipate that the
masked amide function present in the NAH functional-
ity of 8 could be involved in an intramolecular H-bond-
ing, due to its ꢀNH-donor character. This structural
feature could be responsible for an eventual favored
stability between the two mentioned acyl conformations
(Table 5).
The nature of the para-substituent Y present in the
phenyl group at C-3 of 1,2,4-oxadiazole ring (i.e. H,
CH3, OCH3, NO2) in the derivatives 8a–p, was defined
in order to introduce in this new series of compounds a
variation in sp-Hammett values [ranging from −0.21
(OCH3) to +0.78 (NO2)] which could be used to
investigate any electronic contribution by this structural
sub-unit on the analgesic activity. Additionally, consid-
ering the SAR of previously related acylhydrazone se-
ries 2, 5, 6 and 7, the new envisaged derivatives should
1
(Tables 2 and 3). The H NMR spectra in DMSO-d6 of
8a–p (Table 4) showed a broad singlet varying between
l 12.50 to 13.00 ppm similar to NꢀH hydrogen, ex-
changeable with D2O, indicating that the hydrazone
form (H) is preferred over the possible tautomeric
diazo form (D) [13,14] (Scheme 2).
The careful analysis of the 1H NMR spectra of
1,2,4-oxadiazole carbohydrazone derivatives, 8b and 8c,
showed the presence of two components in each. These
were assigned as (E)-8 and (Z)-8 diastereomers and
downfield shifts of CHꢁN hydrogen indicated that the
(E)-isomer was the major one in the mixture [15–17]
(Table 4). For all remaining compounds only the (E)-
diastereomer was detected.
Leite, Lucia Fernanda C.C.
