Bio-isosterism

The constant endeavour toward newer and more potent biologically active compound has paved the way for research into more specific, more effective, structurally similar compounds either possessing same or opposite activity. 

Langmuir suggested that any two ions or molecules possessing essentially an identical number and arrangement of electrons must exhibit similar characteristics and all such pairs he named as isosteres  

Isosterism is of vital importance to a medicinal chemist beeause the biological characteristics of isosteres appear to be similar more frequently than their physical or chemical characteristics. 

Keeping in view the munerous advantageous applications of isosterism in resolving biological problems effectively, Friedman proposed the following definition of bio-isosterism —the phenomenon by which componnds usually fit the broadest definition of isosteres and possess the same type of biological activity. 

For instance, among antihistaminics it is always preferable to have small compact substituents on the terminal nitrogen. 

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Also the bio-isosteric potential of the pyridazine system hitherto remained largely unexplored, despite the fact that several examples discussed in this review indicate that the replacement of aromatic moieties in bio-ac-tive compounds by the highly polar pyridazine nucleus may well improve the pharmacodynamic and/or the pharmacokinetic profile of a drug molecule. 

Several DHAP aldolases having different stereospecificities were tested for their acceptance of this phosphonomethyl substrate mimic as the aldol donor, individual enzymes belonging to both Glass 1 and 11 types were found to catalyze the stereoselective addition of 14 to various aldehydes, providing bio-isosteric non-hydrolyzable analogues of sugar 1-phosphates in high yields (for example, 16/17 Scheme 2.2.5.7) [25, 26]. 

Scheme 2.2.5.6 Comparison of GPO-catalyzed enzymatic synthesis with a new chemical synthesis of phosphonate analogue 14, which is bio-isosteric with 1.

Shi, X. Mazandarani, H. Coupet, J. Marquis, K. Brennan, J. A. Andree, T. H. New generation dopaminergic agents. 7. Heterocyclic bio-isosteres that exploit the 3-OH-phenoxyethyl-amine D2 template. Bioorg. Med. Chem. Lett. 1999, 9, 2593-2598. 

Fluoroquinolones have proved to be one of the most successful classes of antibacterial agents both economically and clinically [59] and, as such, 2-pyridones, as bio-isosteres of quinolones, provide a valuable source of potential new therapeutic agents [60],... 

Chemically stable analogues of acyclovir (26) have been synthesised in an attempt to attain appreciable activity against herpes virus type-1 while allowing their cellular internalisation and bypassing the intracellular activation of acyclovir to its triphosphate derivative required for activity. These compounds are bio-isosteres of acyclovir monophosphate and diphosphate, but are devoid of any appreciable antiviral activity on both HSV-1 and HIV-1. 

In a series of substituted 2-arylpyrrolidines in which the substituted aryl group is a bio-isosteric replacement for the pyridine ring of nicotine, it was found that the isoxazole derivative (69) is a potent cholinergic channel activator (116). 

Similarly, Carroll et al. (176)reported that the 1,2,4-oxadiazoles (e.g., 37) that are bio-isosteres of ester groups, are potent cocaine analogs. Compound (37) had low nanomolar affinity for the dopamine uptake transporter with greater than 100-fold selectivity for the dopamine transporter over the norepinephrine and serotonin transporters. 

For a long time, fluorine has been considered as a bio-isostere of hydrogen, which is no more true. Indeed, fluorine is very different from hydrogen, with a van der Waals radius comparable to that of oxygen, it induces an increase in lipophilicity and its electronegativity is the highest in the periodic classification. 

With respect to pharmacokinetics it is obvious that biotransformation of natural or only slightly modified natural oligonucleotides - mainly by action of nucleases - is a major obstacle towards application of such compounds. It is not surprising that first of all a variety of modifications of the labile phosphodiester bond has been developed, with phosphorothioate and methylphosphonate groups being hitherto the most successful approaches (see section 6). This report will also include structures such as peptide nucleic acids (PNAs), which are promising bio-isosteres of natural lead structures (see section 10.1). 

Various pharmaceuticals and biocides are derived from benzo[Z ]thiophene, and it is found to be bio-isosteric with naphthalene and indole. Mobam 1 [4-(V-methylcarbamoyl)benzo[6]thiophene] is an insecticide which is as effective as carbaryl 2. Both compounds inhibit the enzyme acetylcholinesterase. 

Another particularly impressive example of ring bio-isosterism is found in the development of the antiulcer H2-receptor histamine antagonists in which the initial imidazole ring was changed to various other equivalents ... 

In the recent past, receptors and drug-reeeptor interaetions theories have highlighted the importance of physical and chemical characteristics with regard to drug action. Such salient features may include partition coefficients, solubility, degree of ionization, isosterism and bio-isosterism, surface activity, thermodynamic activity, intramolecular and intermolecular forces, redox potentials, stereochemisty and interatomic distances between various funetional groups. 

A plethora of physical properties play an important role in modifying the biological activities of a good number of medicinal compoimds. A few such properties are features governing drug action at active site, factors governing ability of drugs to reach active site, dissociation constants, isosterism and bio-isosterism. 

Give a eomprehensive accoimt of the importanee of Isosterism and Bio-isosterism in drug design. 

The design of enzyme inhibitors has included random screening of synthetic chemical agents, natural products, and combinatorial libraries followed by molecular optimization or structure-activity relationships of so-called lead structures as well as bio-isosteric analogues of the enzyme substrates themselves. Drugs (e.g., finasteride) also have been developed for one indication but, based on observed side effects, have lead to other uses. 

Arecoline is of historical interest, because its structure, like those of many other early medicinal agents, viras determined and confirmed by a 19th-century German pharmacist, E. Jahns (2). Xanomeline may be viewed as a nonclassical bio-isostere of the ester moiety of arecoline. It is a muscarinic M1/M4 agonist that is showing promise in clinical trials for the treatment of Alzheimer s disease (35). Although it is not tolerated at orally effective doses, transdermal delivery systems are showing promise. 

Ticarcillin. Ticarcillin is a sulfur-based bio-isostere of carbenicillin that cannot decarboxylate as the carboxyl group of carbenicillin does (Table 38.5). This agent is somewhat more potent against pseudomonads compared with indanyl carbenicillin. 

The group of agents generally known as allyl amines[34] strictly includes only naftifine and terbinafine, but because butenafine and tolnaftate function by the same mechanism of action, they are included in this class and are shown in Figure 40.8. One can, of course, consider the benzyl group of butenafine to be bio-isosteric with the allyl group of naftifine and terbinafine. 

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