INTRODUCTION:

Bioisosterism is a strategy of Medicinal Chemistry for the rational design of new drugs, applied with a lead compound (LC) as a special process of molecular modification¹. The LC should be of a completely well known chemical structure and possess an equally well known mechanism of action, if possible at the level of topographic interaction with the receptor, including knowledge of all of its pharmacophoric group.

Furthermore, the pathways of metabolic inactivation, as well as themain determining structural factors of the physicochemical properties which regulate the bioavailability, and its side effects, whether directly or not, should be known so as to allow for a broad prediction of the definition of the bioisosteric relation to be used².

Classification of Bioisosterism:

Classic and Non-classic:

In 1970, Alfred Burger classified and subdivided bioisoteres into two broad categories: Classic and Non- Classic Burger’s definition significantly broadened this concept, now denominating those atoms or molecular subunits or functional groups of the same valence and rings equivalents as classic bioisosteres, while non-classic bioisosteres were those which practically did not fit the definitions of the first class³.

Fig 1: Classic and Non-Classic bioisoteres

1. Classic bioisosteres:

1.1 Monovalent atoms or groups

1.2 Divalent atoms or groups

1.3 Trivalent atoms or groups

1.4 Tetrasubstituted atoms

1.5 Ring equivalents

2. Non-Classic bioisosteres:

2.1 Cyclic vs Noncyclic

2.2 Functional groups

2.3 Retroisosterism

Bioisosterism as a Strategy of Molecular Modification:

Among the most recent numerous examples used in the strategy of bioisosterism for designing new pharmacotherapeutically attractive substances^6-7,13, there is a significant predominance on non-classic bioisosterism, distributed in distinct therapeutic categories, be they selective receptor antagonist or agonist drugs, enzymatic inhibitors or anti-metabolites. The use of classic bioisosterism for the structural design of new drugs, while less numerous, has also been carried out successfully⁶. The correct use of bioisosterism demands physical, chemical, electronic and conformational parameters involved in the planned bioisosteric substitution, carefully analyzed so as to predict, although theoretically, any eventual alterations in terms of the pharmacodynamic and pharmacokinetic properties which the new bioisosteric substance presents. Thus being, any bioisosteric replacement should be rigorously preceded by careful analysis of the following parameters:

a) Size, volume and electronic distribution of the atoms or the considerations on the degree of hybridization, polarizability, bonding angles and inductive and mesomeric effects when fitting;

b) Degree of lipidic and aqueous solubility, so as to allow prediction of alteration of the physicochemical properties such as logP and pKa;

c) Chemical reactivity of the functional groups or bioisosteric structural subunits, mainly to predict significant alterations in the processes of biotransformation, including for the eventual alteration of the toxicity profile relative to the main metabolites;

d) Conformational factors, including the differential capacity formation of inter- or intramolecular hydrogen bonds.

Bioisosterism and alterations of physicochemical properties:

Some bioisosteric groups dramatically alter the physicochemical properties of substances and, therefore, their activities. This can be easily understood by comparing classic isosteres resulting from bioisosteric replacementbetween hydroxyl (–OH) and amine (–NH2), an example of classic bioisosterism of monovalent groups according to Grimm’s Rule. In this case, considering the bioisosteric replacement of aromatic amine present in aniline (18) by hydroxyl, we have phenol (17) (Scheme 3) resulting in a significant change in the acid-base properties of isosteres, with dramatic modification of the pKa of the compounds, which is responsible for the distinct pharmacokinetic profiles among the isosteres in question. Furthermore, in terms of molecular recognition of a given receptor site, we have a change form one positively charged function (-NH3⁺), originating from basic aromatic amine function (pKb = 9, 30) by another acid (pKa = 10,0) present in phenol, which may, quite probably, abolish the original activity [14]. Thus, in this example, we may predict that the use of bioisosterism, even the classic type, can promote severe alterations of molecular properties, as much in terms of lipidic-aqueous solubility as well as chemical reactivity, among others, which, broadly speaking, is not observed in the same homologue carbonic series. Otherwise, the system’s enzymatic capacity for hepatic detoxification of xenobiotics, involving the microsomal mixed function oxidase also called cytochrome P-450 system¹⁴, is distinct in the presence of these functional isosteric groups, which does not allow a simplistic comparison between the lead compound aniline (18) and the hydroxylated isostere (17) in terms of metabolism, altering, therefore, the pharmacokinetic phase as well as the pharmacodynamics of the isosteres⁴.

Scheme 1:

Non-classic bioisosterism:

Cyclic vs Non-Cyclic:

In the category of diuretic substances of the phenoxyacetic class, in which etacrinic acid 82 is the main representative, we have found innumerous examples of the use of non-classic bioisosterism in the discovery of new drugs. To develop new diuretic substances, with uric activity superior to 82, Hoffman and coworkers applied non-classic bioisosterism represented by ring-closing, or anelation, as a strategy to choose definitions of new lead compounds for diuretic drugs. These authors working at Merck, Sharp and Dohme Laboratories, proposed compound 84 as a bioisostere of 83. The structure of 84 was defined based on the anelation of the phenoxyacetic chain (a) of 83, which, in turn, arose by the replacement of the ethylenone function present in 82 by the thiophene nucleus of 83, including all four carbon atoms of the replacement of 82, there being a clear correspondence between the carbons with sp² hybridization in 82 and 84. This type of anelation in the ethylenone chain of 82 had been proposed previously by Thuillier, who described the synthesis of 83 as being an acid equivalent to etacrinic acid in terms of its diuretic properties, while with superior uric properties. In fact, this last compound represents one of the first examples of bioisosteres of 82, obtained by application of non-classic bioisosteric strategies. Compound 84, proposed and synthesized by Hoffman, presented a profile comparable to 83, its uric potential being even greater. Furthermore, the introduction of the thiophene ring in 83 to replace the ethylenone subunit of 82, eliminates Michael’s acceptor site present in the structure of etacrinic acid, responsible for the hepatotoxic effects of this drug. Still on the subject of diuretics related to etacrinic acid, Shutske and coworkers later developed the synthesis of new aryl-benzisoxazolyloxyacetic acids (e.g., 85), based on the probable bioisosteric relationship existing between the aryl-benzisoxazole unit and the 2-acyl-thiophenyl moiety present in acid 83. This illustrative example is sufficient to show the potential of the strategy of non-classic bioisosterism for designing molecular modifications in substances of pharmacological interest⁵.

Structural Analog:

A structural analog (analogue in Commonwealth English), also known as a chemical analog or simply an analog, is a compound having a structure similar to that of another compound, but differing from it in respect to a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analog can be imagined to be formed, at least theoretically, from the other compound. Structural analogs are often isoelectronic. Despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very different physical, chemical, biochemical, or pharmacological properties. In drug discovery either a large series of structural analogs of an initial lead compound are created and tested as part of a structure–activity relationship study⁵ or a database is screened for structural analogs of a lead compound. Chemical analogues of illegal drugs are developed and sold in order to circumvent laws. Such substances are often called designer drugs. Because of this, the United States passed the Federal Analogue Act in 1986. This bill banned the production of any chemical analogue of a Schedule I or Schedule II substance that has substantially similar pharmacological effects, with the intent of human consumption.

e.g. Neurotransmitter analog:

A neurotransmitter analog is a structural analogue of a neurotransmitter, typically a drug. Some examples include:

Catecholamine analogue

Serotonin analogue

GABA analogue

Rigid analogs:

Rigid analogs of acetylcholine offer an opportunity for selective actions at muscarinic receptor subtypes, since restricted conformational mobility alters the capacity of ligands to adapt to subtle differences in receptor structure. AF102B, a highly rigid analog of acetylcholine, is a centrally active M1 agonist and is evaluated in light of some currently available therapeutic strategies in Alzheimer's disease. AF102B, a highly rigid analog of acetylcholine, is a centrally active M1 agonist and is compared with some of old and new muscarinic agonists. AF102B is evaluated in light of some currently available therapeutic strategies in Alzheimer's disease⁶.

Design of stereo isomer and geometric isomers:

Stereochemistry Isomerism and CONNECTIVITY-The term connectivity means all the atoms in a molecule are connected in the same sequence. For a molecule containing atoms A, B, and C; one connectivity is A-B-C while A-C-B is a different connectivity. Both have the same connectivity but the atoms have a different orientation in space. The same atoms or groups are connected to the central carbon atom. The connectivity is the same, but OH and H are oriented differently in space. To change the positions of H and OH, one would have to break the H-C and HO-C bonds and connect them in the reverse order. The two compounds differ in their connectivity: CO -C and CC -Ov Stereoisomers have the same connectivity but a different spatial orientation. Stereoisomers do not differ from each other as a result of rotation around single (sigma) bonds⁷.

They are different compounds:

The three main types of isomers are constitutional isomers, conformational isomers and stereoisomers.

Isomers are compounds that have the same formula but different structures.

Geometrical Isomerism o Isomerism: Different types of isomerism, their nomenclature and associated physico chemical properties.

· Structural isomerism: chain isomerism, positional isomerism, functional isomerism and metamerism, keto-enol tautomerism.

· Conformational isomerism: Conformations of ethane and butane. o Geometrical isomerism: Cis-trans isomers and E-Z isomers, physical and chemical properties, stability of cis and trans isomers⁸.

· Optical isomerism: Optical activity, specific rotation, asymmetric carbon, chirality, Fischer projection, enantiomerism, diastereomerism. o Specification of configuration: Absolute and relative configuration (D,L system and R,S system). Racemic mixture, racemization⁹.

· Methods of determination of configuration of geometrical isomers. o Stereo isomerism in biphenyl compounds (Atropisomerism) and conditions for optical activity.

· Stereospecific and stereoselective reactions.

Fragment-Based Drug Design:

The methodology consists of iterative design, synthesis, and X-ray crystallographic screening of three libraries of compounds. Target-specific compound design, by way of active site electron density in the presence of a bound fragment hit and the intentional lack of solution activity bias form the basis of our approach. We provide an example of this alternative fragment-based drug design (FBDD) method, detailing results from a campaign using ketohexokinase to generate a unique lead series with promising drug-like properties¹⁰.

3. Residence Time and Kinetic Selectivity in Fragment Evolution:

Residence time becomes a more and more appreciated optimization parameter in conventional and fragment-based lead discovery. The reporter displacement assay represents an ideal technology to support an entire fragment-based lead discovery program that is aiming at generating lead compounds with defined binding affinities and residence times. Usually, the first step of a fragment lead optimization program is to screen a fragment library for fragments that bind to the target, here exemplified for a fragment screen against p38α. In this screen, 1023 fragments were screened at a concentration of 2 mM against p38α using the reporter displacement technology¹¹. A reporter was used that addresses the ATP binding site and the back pocket region of p38α ensuring that only fragments were identified that bound to the binding site of interest, while fragments that bound nonspecifically to the protein surfaces did not contaminate the hit list¹².

Intermolecular or interatomic forces:

Fig 2: Variation of potential energy with interatomic force

Intermolecular or interatomic forces:

Consider two isolated hydrogen atoms moving towards each other as shown in Fig.

Fig 3: Electrical energy of electrical force

As they approach each other, the following interactions are observed.

1. Attractive force A between the nucleus of one atom and electron of the other. This attractive force tends to decrease the potential energy of the atomic system.

2. Repulsive force R between the nucleus of one atom and the nucleus of the other atom and electron of one atom with the electron of the other atom. These repulsive forces always tend to increase the energy of the atomic system.

There is a universal tendency of all systems to acquire a state of minimum potential energy. This stage of minimum potential energy corresponds to maximum stability. If the net effect of the forces of attraction and repulsion leads to decrease in the energy of the system, the two atoms come closer to each other and form a covalent bond by sharing of electrons. On the other hand, if the repulsive forces are more and there is increase in the energy of the system, the atoms will repel each other and do not form a bond^13-14.

CONCLUSION:

Novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues).

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Received on 30.01.2021 Modified on 11.02.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(2):134-138.

DOI: 10.52711/0975-4377.2021.00024