Antibacterial prodrug

Fig. 33.21 Bioactivation of the antibacterial prodrug of an impermeant inhibitor of 3-deoxy-D-manno-2-octulosonate cytidylyl-transferase. ...

Far et al. have prepared a set of 13 bisphosphonated antibacterial prodrugs of the general formula (247) for prevention of osteomyelitis infection located in bone, based on eight different linkers tethered to the free amino functionality on fluoroquinolone antibiotics. Syntheses employed tetra-ethylbisphosphonate and tetraethyl 1,1-ethenylbisphosphonate as the Michael acceptor of amine group. 

One of the problems with cycloserine (57) as an antibacterial agent is its tendency to dimenze In an attempt to overcome this, the prodrug penti/idone (59) has been prepared The primary amino group essential for the dimenzation reacnon is reversibly blocked to prevent this Penti/idone is synthesized conveniently from cycloserine (57) by merely mixing it with acetyl acetone (58) and storing for two days to achieve the dehydration The resulting pentizidone apparently requires enzymic assistance to release cycloserine in vivo [20]... 

Use antibacterial, semisynthetic p-lactam antibiotic, derivative of ampicillin (prodrug for ora application)... 

A potentially interesting application of (acyloxy)methyl ester prodrugs can be found in delivery through skin of antibacterial agents. Nalidixic acid (8.53, R = H), a topoisomerase II inhibitor, showed promising activity in the treatment of antiproliferative skin disorders, notably psoriasis. To improve the... 

K. Tougou, A. Nakamura, S. Watanabe, Y. Okuyama, A. Morino, Paraoxonase Has a Major Role in the Hydrolysis of Prulifloxacin (NM441), a Prodrug of a New Antibacterial Agent , Drug Metab. Dispos. 1998, 26, 355-359. 

Sulfasalazine is a prodrug of which 70% is converted by colon bacteria to two active metabolites, sulfapyri-dine and 5-aminosalicylic acid (mesalamine). Sulfa-pyridine has antibacterial activities, and 5-aminosali-... 

Penam Sulfone p-Lactamase Inhibitors. Natural product discoveries stimulated the rational design of /i-lactainase inhibitors based on the readily accessible penicillin nucleus. An early success was peni-cillanic acid sulfone, (2(5)-ru)-3,3-dimethyl-7-oxo-4,4-dioxide-4-thia-l-azabicyclo [3.2.0]heptane-2-carboxylic acid (sulbactam) (R = R1 = H,R2 = R = CH3), CsHnNOjS. The synthesis, microbiology, and clinical use of sulbactam have been reviewed. Sulbactam, with minor exceptions, is a weak antibacterial, but is a potent irreversible inactivator of many /3 lactamases, including penases and Richmond Sykes type 11, III, IV. V, and VI (Bactcroides) /3-lactamases. Sulbactam is better than clavulanic acid against type I Cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sul-fones have been reported to be /3-lactamase inhibitors. 

Mycophenolic acid (MPA) was isolated from cultures of Penicillium spp. in 1896 and was purified in 1913. Initially the compound was studied for its antifungal and antibacterial effects and later for its antitumor effects. Many years later, its immunosuppressive activities were recognized and after further developmental work, an ester prodrug mycophenolate mofetil was developed, which was approved by the United States Food and Drug Administration for the prevention of acute renal allograft rejection in 1995 and for heart transplant recipients in 1998. Mycophenolate mofetil is a cytotoxic agent now used for immunosuppressive therapy and is the mofetil ester of MPA, which is the active immunosuppressive agent. 

Continuing research on sulfamidochrysoidine revealed that sulfanilamide (1.21), a metabolite of sulfamidochrysoidine, was the active antibacterial compound (Figure 1.9). Compounds that are chemically altered in the body to form the biologically active drug are called prodrugs.1... 

Recently, prodrugs have been constmcted in which amoxicillin (antibacterial agent) and clavulanic acid or cephalosporin 1-oxide (/3-lactamase inhibitors) are covalently linked. All these compounds show better antibacterial activity than Augmentin , comparable anti-/3-lactamase activity, and better solubility properties <2002BMC3489>. 

In this context, phenacetin can be thought of as a prodrug, that is, an inactive or less active precursor of a more active drug form. The classic example of a prodrug is prontosil, which was the first antibacterial sulfonamide, introduced in 1935 by Gerhard Domagk. However, within a year it was discovered that prontosil itself was inactive. The actual active substance was found to be sulfanilamide, which was formed from prontosil by bacterially mediated fission of the parent compound in the gut (see Chapter 10 for additional coverage). 

Diamba HM et al (2009) Towards calixarene-based prodrugs drug release and antibacterial behaviour of a water-soluble nalidixic acid/calix[4]arene ester adduct. Bioorg Med Chem Lett 19 2679-2682... 

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