Phloroglucidic acid and derivatives as antibacterial agents

Details Phloroglucidic acid and derivatives as antibacterial agents Phloroglucidic acid and derivatives as antibacterial agents

1999-09-20

2001-09-11

Killos, Paul J. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S057000, C562S460000, C562S468000, C564S169000, C564S170000, C564S177000

Reexamination Certificate

active

06288265

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related generally to synthesis of novel phloroglucide derivatives and their pharmaceutical use, and more particularly to synthesis of novel phloroglucide derivatives which possess potent antibacterial activities. They include unsymmetrical phloroglucide analogs, phloroglucides attached to cephalosporins at the C-3′ position, and 7-(phloroglucidamido)cephalosporins.
BACKGROUND OF THE INVENTION
The presence of essential functional groups with a suitable spatial arrangement for chelation with metal ions of enzymes is a significant feature common to several classes of antibiotics [Moshfegh, A. et al.
Helv. Chim. Acta
1957, 40, 1157]. They include trisaspidinol [Widen, C.-J. et al.
Helv. Chim. Acta
1973, 56, 831], cryptosporin [Closse, A. et al.
Helv. Chim. Acta
1973, 56, 619], and tetracycline [Albert, A.
Nature
(
London
) 1953, 172, 201]. These compounds exhibit various degrees of activity against Gram-positive bacteria as well as other microorganisms. It was reported that the presence of halogen atoms in phloroglucide analogs is essential for their antibacterial activity [Hakimelahi, G. H. et al.
Helv. Chim. Acta
1981, 64, 599; Swiss Patent 003848, 1977; Swiss Patent 003849, 1977; Swiss Patent 007448, 1978. Moshfegh, A. A. et al.
Helv. Chim. Acta
1982, 65, 1221
; Helv. Chim. Acta
1982, 65, 1229
; Helv. Chim. Acta
1982, 65, 1264].
&bgr;-Lactam antibiotics exert certain biological activity by acylating serine residues of transpeptidases, in which the cross-linking of peptidoglycans does not take place [Waxman, D. J. et al.
J. Biol. Chem
. 1980, 255, 3964]. The ring opening of the &bgr;-lactam nucleus would occur when cephalosporins react with bacterial enzymes. Consequently, the substituent attached at the C-3′ position is liberated. When the eliminated species possesses antibacterial activity, cephalosporins would exhibit a dual mode of action [O'Callaghan, C. H. et al.
Antimicrob. Agents Chemother
. 1976, 10,245; Greenwood, D. et al.
Antimicrob. Agents Chemother
. 1976, 10, 249; Beskid, G. et al.
Chemotherapy
1990, 36, 109]. It was reported that attachment of antibacterial quinolones to the C-3′ position of cephalosporins gives a class of new compounds with a broadened spectrum of antibacterial activities [Albrecht, H. A. et al.
J. Med. Chem
. 1990, VI, 77
; J. Med. Chem
. 1991, 34, 669
; J. Med. Chem
. 1994, 37,400].
SUMMARY OF THE INVENTION
The present invention discloses a novel class of phloroglucide derivatives, including unsymmetrical phloroglucide analogs, phloroglucides attached to cephalosporins at the C-3′ position, and 7-(phloroglucidamido)cephalosporins as antibacterial agents. They exhibited more potent antimicrobial activity than the previous reported phloroglucide derivatives.
The characteristics of this invention is that cephalosporin 3′-phloroglucide esters, which were obtained by condensation of cephalosporin with bioactive phloroglucides, exhibited a dual mode of antibacterial activity in vitro. In comparison with traditional cephalosporins bearing an acetoxy unit at the C-3′ position, the bifunctional cephalosporins showed a broadened spectrum of activity.
Unlike cephalosporin 3′-phloroglucide esters, 7-(phloroglucidamido)cephalosporins were found resistant to &bgr;-lactamases from
Staphylococcus aureis
95 and
Pseudomonas aerziginosa
18S-H. These new compounds, however, showed notable activities against
Staphylococcus azireus
FDA 209P,
Staphylococcus aureus
95
, Candida albicans, Pseudomonas aerziginosa
1101-75, and
Pseudomonas aeruginosa
18S-H. In this invention, new phloroglucide derivatives are disclosed as potent antibacterial agents. They have a high potential in the development of new antibacterial drugs.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a novel phloroglucide derivative having the following formula:
Where Q is halogen; X is CH
2
or C═O; Y is hydroxyl, methoxy, NH(CH
3
) or cephalosporin having formulas as follows:
wherein Me is methyl, Ph is phenyl, Ac is acetoxy,
or pharmaceutically acceptable salts thereof.
Preferably, X of the phloroglucide derivative of formula (I) is CH
2
.
Preferably, Y of the phloroglucide derivative of formula (I) is
The present invention may provide a method for the use of antibacterial drugs. In the preferred embodiments of the present invention, the following compounds (II) to (XI) were synthesized. The compounds (II) to (VII) are unsymmetrical phloroglucides, and the compounds (VIII) to (XI) are cephalosporin-phloroglucide derivatives.
Compound (II) having one carboxylic acid unit at the C-3′ position exhibited more potent antimicrobial activity than that of the model phloroglucide (XXI). When the methylene bridges in phloroglucide (II) were converted to carbonyl functionalities as in the phenolic keto acid (III), its antimicrobial property decreased. In comparison with dicarboxylic acid derivative (XV), mono-carboxylic acid (III) however exhibited greater potency. Phenolic keto acid (III), however, showed a lower efficacy than phenolic acid (II) and phenol (XII) against pathogenic microorganisms.
In comparison with the reference cephalosporins (XV) and (XVI), cephemphloroglucidic esters (VIII) and (IX) possessed a broadened spectrum of antibacterial activity in vitro. On the other hand, (VIII) and (IX) showed greater antibacterial activity than the corresponding phloroglucides (II) and (III) against
S. aureus
FDA 209P, yet less activity against other pathogenic microorganisms. Nevertheless, the activity added to the spectrum of the parent cephalosporin parallels the activity of the phloroglucidc component in each assay.
The antibacterial activity of simple esters (IV) and (V) as well as the corresponding amides (VI) and (VII) exhibited lower efficacy than phloroglucides (II) and (III) as well as the bifunctional cephalosporins (VIII) and (IX). Compounds (VIII) and (IX) are dual-action antibiotics; their biological activities came from both phloroglucide and cephalosporin moieties. This pattern of activity reveals that the corresponding phloroglucides (II) and (III) were released in situ from bifunctional cephalosporins (VIII) and (IX), respectively.
On the other hand, 7-(phloroglucidarnido)cephalosporins (X) and (XI) are not expected to exhibit a dual mode of action, yet they showed notable antibacterial activity. Compound (X) exhibited potent phloroglucide-like antibacterial activity.
Results from the biological assay, cephalosporin-phloroglucide esters (VIII) and (IX) underwent hydrolysis to liberate their phloroglucidc components, as evidenced by their notable values or minimum protective concentration (MPC) against the &bgr;-lactamases of
S. aureus
95 and
Ps. aeruginosa
18S-H. Therefore, cephemphloroglucidic esters (VIII) and (IX) exhibited phloroglucide-like antibacterial activity. Recreance cephalosporins (XV) and (XVI) were also susceptible to hydrolysis by &bgr;-lactamases. As a result, they did not show significant activity against &bgr;-lactamase producing microorganisms (i.e.,
S. aureus
95). 7-(Phloroglucidamido)cephalosporins (X) and (XI) did not exhibit notable &bgr;-lactamase inhibitory property. Thus their pronounced antimicrobial activity is mainly due to their stability towards &bgr;-lactamases.
The invention will be further illustrated by the following examples which are only meant to illustrate the invention, but not to limit it. The reaction routes for synthesizing the title compounds of the Preparation Examples 1-5, 6-9, and 10-13 are shown in the Schemes 1, 2, and 3, respectively.
Reagents: (a) NaOH, THF; (b) AlCl
3
; (c) 1. NaOI, 2. HCl; (d) Zn, KOH(aq); (e) 1. Ac
2
O, 2. CrO
3
, 3. NaOH, 4. HCl.
Reagents: (a) NaHCO
3
, DMF; (b) CF
3
CO
2
H, CH
2
Cl
2
.
Reagents: (a) 1. Me
3
SiNHSiMe
3
, (NH
4
)
2
SO
4
(cat.), 2. EEDQ, THF; (b) CF
3
CO
2
H, CH
2
Cl
2
.


REFERENCES:
Helv. Chim Acta (1981) 64(2) 599-609 Chem Abst 95: 132400.*
J. Med. C

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