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The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counterparts, has drawn attention to develop novel antibacterial agents to overcome drug resistance and especially multidrug resistance. In this review, we focus on the recent achievements on the development of inhibitors of bacterial enzymes peptide deformylase (PDF), metallo-β-lactamase (MBL), methionine aminopeptidase (MetAP) and UDP-3-O-acyl- N-acetylglucosamine deacetylase (LpxC). The state of the art of the design and investigation of inhibitors of bacterial metalloenzymes is presented, and challenges are outlined and discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The facultative intracellular pathogen and zoonotic agent Brucella sp. possesses two carbonic anhydrases (CAs, EC 4.2.1.1), termed bsCA I and bsCA II (in Brucella suis), belonging to the β-class of these metalloproteins. These zinc enzymes, present in many other pathogenic bacteria, have been considered recently as potential antibacterial targets. The catalytic activity of bsCA II is higher than that of bsCA I (for the conversion of CO(2) to bicarbonate). Both enzymes were inhibited by the well-studied inhibitor acetazolamide, a sulfonamide drug. A library of 41 sulfonamides and one sulfamate, among which 12 clinically tested drugs, was used for inhibition studies with bsCA I and II. These compounds were generally much more potent inhibitors of bsCA I (K(Is) of 17-75 nM) than of bsCAII (K(I)s of 84-923nM). However, certain glycosidic sulfonamide derivatives exhibited the same strong inhibitory activity on both bsCA I and bsCA II (K(Is) of 8.9-20 nM). Furthermore, at least one of these glycosylsulfonamides showed a significant inhibition of B. suis growth after 8-11 days of culture in minimal medium. In conclusion, as β-CAs of Brucella are susceptible to inhibition by a wide range of aromatic and heteroaromatic sulfonamides, they may represent novel targets for the development of clinically useful antibacterial agents.

Of the thirteen active carbonic anhydrase (CA) isozymes, the transmembrane isoform CA IX has been shown to be linked with carcinogenesis. CA IX presents an ectopic expression in a multitude of carcinomas derived from cervix, uteri, kidney, lung, oesophagus, breast, colon, etc., contrasting with its restricted expression in normal tissues, namely in the epithelia of the gastrointestinal tract. It has been demonstrated that this membrane-bound CA is strongly overexpressed in hypoxic tumors, participating in tumor cell environment acidosis and contributing to malignant progression and poor treatment outcome. Targeting CA IX could thus be an important means of controlling cancer disease. Modulation of extracellular tumor pH via inhibition of CA IX activity represents a promising approach to novel anticancer therapies. Much attention has recently been paid to the CA IX inhibitors drug design, and efforts have been made to obtain isozyme IX inhibitors, with putative applications as antitumor drugs/diagnostic agents. This review will focus on the different CA IX inhibitors described in the literature which could represent excellent potential as candidate therapeutic agents in cancer chemotherapy.

Zinc ion plays a crucial role in the protein's functions and is linked to a variety of physiological processes. It constitutes an essential component of numerous enzymes especially carbonic anhydrase (CAs, EC 4.2.1.1), a pharmaceutically-important metalloprotein which catalyses efficiently the reversible hydration of carbon dioxide to bicarbonate with discharge of a proton. The potential therapeutic applications of selective carbonic anhydrase inhibitors has become an important challenge over the last few years, as some isoforms of this enzyme on the 16 described in higher vertebrates have been found to be involved in important pathologies such as cancer, obesity and ophthalmologic diseases. Coordination of the inhibitor with the zinc ion present in the active site is an important determinant which has to be taken into consideration for the design of isozyme-specific and organ-selective inhibitors. Besides the well known sulfonamide function, others zinc binding groups have been described constituting a new platform for the development of novel pharmacological agents. In this review, recent studies on the discovery of new zinc binding function will be discussed.

Three series of derived compounds of N, Aryl-N',Sulfamoyloxazolidin-2-ones were synthesized starting from chloro-sulfonylisocyanate (CSI) by carbomoylation, sulfamoylation and intramolecular cyclization reactions followed by methylation and heterocyclic reopening reactions. This later is based on a new hydrolysis method which uses a solid support, in order to obtain the correspondent amino-alcohols, which allowed isolating a new amino-alcohol ester. Measurements of the hydro-solubility by determination partition coefficient (log p) in water/octanol system were carried out by spectrophotometry. The antibacterial activities in vitro of some synthesized compounds were evaluated on a "Staphylococus aureus" strain in a Mûller-Hintone medium, showing good activity for some of them. All the synthesized compounds are characterized by IR, (1)H NMR and mass spectroscopy (ESI-MS).

The carbonic anhydrases (CAs, EC 4.2.1.1) are zinc containing metalloenzymes which catalyse efficiently the reversible hydration of carbon dioxide to bicarbonate with discharge of a proton, playing important physiological and physiopathological functions. To date, 16 different carbonic anhydrase isoforms have been described in higher vertebrates, including humans, and some of them have been considered as important targets for inhibitors with therapeutic applications. The catalytic and structural role of zinc in these enzyme are understood in great detail, and this provided molecular basis for the design of potent inhibitors, some of which possessing important clinical applications mainly as topically acting anti-glaucoma drugs, anticancer or antiobesity agents. The metal binding function is a critically important factor in the development of isozyme-specific and organ-selective inhibitors. Discovery of compounds that possess zinc binding function different from that of the classical one (sulfonamide type) is in constant progress and can offer opportunities for developing novel pharmacological agents. In the present review we will discuss the different zinc binding function reported in the literature up to now in the design of carbonic anhydrase inhibitors.

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc enzymes which catalyze a very simple physiological reaction, the interconversion between carbon dioxide and the bicarbonate ion, and are involved in physiological and pathological processes. The different isozymes have been considered as important targets for inhibitors with clinical applications. Several sulfonamide carbonic anhydrase inhibitors (CAIs) were used for decades as diuretics, anti-glaucoma, anti-epileptic, anti-ulcer agents, or as drugs for treating other neurological/neuromuscular disorders, whereas presently several such agents still find wide applications in therapy, mainly as topically acting anti-glaucoma drugs, anti-cancer, or anti-obesity agents. Although sulfonamides were considered the moiety par excellence to coordinate the catalytic zinc and for designing potent CAIs, in recent years related functional groups such as sulfamate, sulfamide and others have proven to be successful in the design of selective CAIs. The present review will deal with these different zinc binding functions recently reported in literature.