Antibacterial activity, QSAR

A QSAR seeks to relate quantitative properties (descriptors) of a compound with other properties such as drug-like activity or toxicity. The essential assumption of QSAR is that quantities that can be conveniently measured or calculated for a compound can be used to accurately predict another property of interest (e.g., antibacterial activity) in a nontrivial way. QSAR has become an integral part of screening programs in pharmaceutical drug-discovery pipelines of small compounds and more recently in toxicological studies (69). However, the use of QSAR modeling applied to the search for antimicrobial peptides is relatively recent. Advances in this area are reviewed in brief here. 

There are two separate but interrelated aspects to QSAR modeling of antibacterial peptides the choice of QSAR descriptors and the choice of numerical analysis techniques used to relate these values to antibacterial activity. A simple example of a QSAR descriptor is the total charge of a peptide. A large number of QSAR descriptors is available for small compounds in the literature and from commercial software products that may be considered. A smaller subset is used in QSAR studies of antibacterial peptides and may be separated into two categories descriptors based on empirical values and calculated descriptors. An example of an empirical value is HPLC retention time, which is a surrogate measure of solubility or hydrophilicity/hydrophobicity. An example of a calculated descriptor is total peptide charge at pH 7. 

There are several limitations of existing QSAR modeling of antibacterial activity. The primary limitation concerns the size of the data sets. Despite the... 

Previously, inductive QSAR descriptors have been successfully applied to a number of molecular modeling studies, including quantification of antibacterial activity of organic compounds (89), calculation of partial charges in small molecules and proteins (81), and in comparative docking analysis as well as in in silico lead discovery (82). Inductive QSAR descriptors have been used... 

Cherkasov, A. (2005) Inductive QSAR descriptors. Distinguishing compounds with antibacterial activity by artificial neural networks. Ini. J. Mol. Sci. 6, 63-86. 

Aptula, A.O., Kiihne, R., Ebert, R.-U., Cronin, M.T.D., Netzeva, T.I., and Schuurmann G., Modeling discrimination between antibacterial and non-antibacterial activity based on 3D molecular descriptors, QSAR Combinatorial Sci., 22, 113-128, 2003. 

This new family of oxazolidinones was described and shown to effectively displace compounds that bind the ribosomal 50S A-site (linezolid site), including chloramphenicol and Puromycin [80]. The structures of several family members (16-20) are depicted in Scheme 3. The reader is referred to the primary citations for tables of antibacterial activity data (as is the case for all case studies). Compounds such as 17 and 19 were compounds predicted to have good oral bioavailability in the QSAR model [79]. Compounds such as 16 were predicted to have good Haemophilus influenzae activity in that QSAR activity model [79]. The computational and crystallographically inspired design of novel oxazolidinones eventually led to Rib-X Pharmaceuticals clinical candidate, Radezolid (20), currently in Phase II clinical trials [31]. 

Cherkasov, A.R. and Jankovic, B. (2004) Application of inductive QSAR descriptors for quantification of antibacterial activity of cationic polypeptides. Molecules, 9, 1034-1052. 

Further attempts to amplify the antibacterial activity were undertaken by additional structural modifications. An extensive SAR study in which 78 compounds of structure A were synthesized and evaluated by QSAR methods helped to determine what substituents would give optimum results. 

The importance of deriving a QSAR model on a well-balanced set of structures, even in the presence of a much larger number of available data for the same series, was shown in two studies regarding the antibacterial and antimycotic activity of benzofused heteroaromatic derivatives [42] as well as in the antibacterial activity of quinolones [43,44], working in the PC space of a PCA performed ad hoc on the whole set of available or candidate strictures. 

It is especially noteworthy that the octanol-water partition coefficients P(o/w) (Table XIII) do not correlate well with antibacterial activity. Yet the use of P(o/w) values and of other measures of lipophilicity is the raison d etre for so much of QSAR research in general. 

Du Toil, K., Elgorashi, E. E., Malan, S. F., Mulholland, D. A., Drewes, S. E., 8c Van Staden, J. (2007). Antibacterial activity and QSAR of homoisofla-vanones isolated from six Hyacinthaceae species. South African Journal of Botany, 73, 236. 

Bagchi, M. C., Mills, D., Basak, S. C. Quantitative structure-activity relationship (QSAR) studies of quinolone antibacterials against M. fortuitum and M. smegmatis using theoretical molecular descriptors. 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

Debnath, A.K., Hansch, C., Kim, K.H., and Martin, Y.C., Mechanistic interpretation of the genotoxicity of nitrofurans (antibacterial agents) using quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA), J. Med. Chem., 36, 1009-1116, 1993. 

The CoMFA methodology was also used to describe nonlinear lipophilicity-activity relationships, c.g. the inhibitory activities of quaternary alkylbenzyl-dimethylammonium compounds vs. Clostridium welchii (eqs. 206—208) [1025], other antibacterial and hemolytic activities [1026, 1027], and toxic activities of alkanes in mice (eqs. 209-211) [1026] the results of classical QSAR studies (eqs. 206, 207, 209, and 210) [23, 440] were compared with the corresponding CoMFA results (eqs. 208 and 211) [1025-1027] only homologous series of compounds were investigated. 

In this review we have discussed published results concerning the QSAR research on antimicrobial properties of synthetic and natural compounds. Antifungal and antimicrobial activity of some coumarin derivatives, various types of biological activities of benzamides, several studies on cinnamic acid derivatives with antibacterial and antifungal activity, reports on the biological activity of homoisoflavanones and phenolic compounds, as well as pharmaceutical applications of furan derivatives have been shown. 

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