Topliss scheme

Topliss Decision Tree Method. This method is quicker and easier to use than the Hansch method. The Topliss scheme is an empirical method in which each compound is tested before an analog is planned, and is compared in terms of its physical properties with analogs already planned. Like the Free-Wilson method, the Topliss decision tree is no longer extensively used. The 2D- and 3D-QSAR methods are gradually supplanting the ID methods. 

A Topliss scheme is a flow diagram which allows such a procedure to be followed. There are two Topliss schemes, one for aromatic substituents (Fig. 9.17) and one for aliphatic side-chain substituents (Fig. 9.18). The schemes were drawn up by considering the hydrophobicity and electronic factors of various substituents and are designed such that the optimum substituent can be found as efficiently as possible. However, they are not meant to be a replacement for a full Hansch analysis. Such an analysis... 

Fig. 9.18 Topliss scheme for aliphatic side chain substituents.

The Topliss scheme for aromatic substituents (Fig. 9.17) assumes that the lead compound has been tested for biological activity and contains a monosubstituted aromatic ring. The first analogue in the scheme is the 4-chloro derivative, since this derivative is usually easy to synthesize. The chloro substituent is more hydrophobic and electron withdrawing than hydrogen and therefore, tt and a are positive. 

Once the chloro analogue has been synthesized, the biological activity is measured. There are three possibilities. The analogue will have less activity (L), equal activity (E), or more activity (M). The type of activity observed will determine which branch of the Topliss scheme is followed next. 

The validity of the Topliss scheme was tested by looking at structure-activity results for various drugs which had been reported in the literature. For example, the biological activity of nineteen substituted benzenesulfonamides (Fig. 9.19) have been reported. The second most active compound was the nitro-substituted analogue which would have been the fifth compound synthesized if the Topliss scheme had been followed. 

Another example comes from the anti-inflammatory activities of substituted aryl-tetrazolylalkanoic acids (Fig. 9.20). Twenty-eight of these were synthesized. Using the Topliss scheme, three out of the four most active structures would have been synthesized from the first eight compounds synthesized. 

The Topliss scheme for aliphatic side-chains (Fig. 9.18) was set up following a similar rationale to the aromatic scheme, and is used in the same way for side-groups attached to a carbonyl, amino, amide, or similar functional group. The scheme only attempts to differentiate between the hydrophobic and electronic effects of substituents and not the steric properties. Thus, the substituents involved have been chosen to try and minimize any steric differences. It is assumed that the lead com-... 

The Topliss scheme has proved useful many times, but it will not work in every case, and it is not meant to be a replacement for more detailed QSAR studies. 

The right substituent choice minimahzes the number of test compounds that have to be synthesized to insnre a significant space volume. This point represents a 3D extension of the Craig plot discnssed by Craig" and by Anstel. In this context, the decision tree proposed by Topliss allows a fast identification of the snbstitnents associated with the highest potency. Application examples of the Topliss scheme are discussed by Martin and Dnnn. ... 

An alternative game plan could be to utilize the Topliss scheme as the initial approach to extract valuable information by the synthesis of a small number of compounds. 

The Topliss scheme is nothing but an organized flow diagram which categorically permits such a procedure to be adopted with a commendable success rate. 

In actual practice, however, there are two distinct Topliss Schemes, namely (a) For aromatic substituents and (Z>) For aliphatic side-chain substituents. It is pertinent to mention here that the said two schemes were so meticulously designed by taking into consideration both electronic and hydrophobicity features (i.e., substituents) with acommon objective to arrive at the optimum biological active substituents . 

It may be made abundantly clear and explicit that the Topliss Schemes are not a replacement for the Hansch analysis. Hence, the former may be made useful and efifective only when a good number of tailor-made structures have been designed and synthesized. 

A] Fig. 2.8 represents the Topliss Scheme for Aromatic substituents and has been based on the assumption that the lead compound essentially possesses a single monosubstituted aromatic ring and that it has already been screened for its desired biological activity. 

The various salient features with respect to the Topliss scheme for aromatic substituents are as described below ... 

The Topliss scheme has been thoroughly investigated, tested and above all validated by various researcher after evaluating their structure-activity relationships (SARs) for a host of drug substances . 

Substituted phenyltetrazolylalkanoic acid A total of 28 structural analogues of substituted phenyltetrazolylalkanoic acids were synthesized in the laboratory and screened duly for their anti-inflammatory activities. Nevertheless, if the whole exereise would have been based on the Topliss Scheme only the first eight compounds (out of 28) should have yielded three most aetive compounds as given below ... 

B] Fig. 2.9 designates the Topliss Scheme for the Aliphatic side-chains and adopted in the same vein and rationale as the aforementioned aromatic scheme (section A ). The present scheme is expanded exactly in the same fashion for the side functional moieties strategically linked to a variety of such functional groups as amine, amide or carbonyl. 

Fig. 2.9. Topliss Scheme for Aliphatic Side-chain Substituents.

Interestingly, the Topliss Scheme helps to make a elear cut distinction between the two pronounced physical characteristic features, namely electronie eifect, and hydrophobie effeet, eaused due to the various substituents and not the steric characteristie features. Perhaps that eould be the possible line of thought judiciously utilized in the selection of appropriate substituents so as to reduee any sterie differences. Let us have an assumption that the lead compound possesses a—CH3 funetional moiety. 

A real advance in design strategy resulted from the Topliss operational schemes [637, 638]. The Topliss scheme for aromatic substituents (Figure 39) starts from two analogs, e.g. a compound bearing an unsubstituted phenyl ring and the corre-... 

Figure 39 Topliss scheme for aromatic substitution (adapted from Scheme 1 of ref. [637] with permission from the American Chemical Society, Washington, DC, USA).

The different approaches proposed by Topliss should not be understood as rigid schemes they are strategies which have to be adjusted to each problem. A recent review [403] lists more than 50 references where the Topliss methods have been applied, mostly in medicinal chemistry. It was shown that optimum activity would have rapidly been reached in many series of compounds in accordance with the Topliss scheme [641] on the other hand, there are at least some examples where the Topliss method failed [403, 633]. 

FIGURE 8.2 A Topliss Tree for aliphatic side chain substitutions. The Topliss schemes were constructed by consideration of hydrophobic and electronic factors and are designed such that the optimum substituent maybe found as efficiently as possible. It is assumed that the methyl substituted compound has been made, tested, and compared to the unsubstituted compound. There are three possibilities the analogs will have less (L), equal (E), or more (M) activity and this determines which branch of the tree should be followed next. 

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