Medicinal Chemistry

Abstract Quantitative relationships between molecular structure and methionine aminopeptidase-2 inhibitory activity of a series of cytotoxic anthranilic acid sulfonamides were determined by the partial least-squares (PLS) method. Evaluation of a test set of ten compounds with the developed PLS model revealed it is reliable and has good predictive power. Because the QSAR study was performed on the basis of theoretical descriptors calculated completely from molecular structure, the proposed model could potentially provide useful information about the activity of the compounds studied. Various tests and criteria, for example leave-one-out cross validation, leave-many-out cross validation, and criteria suggested by Tropsha, were used to examine the predictive power and robustness of the model. The model could explain and predict 73 and 64% of variances in the pIC 50 data. Graphical Abstract

Quantitative relationships between molecular structure and methionine aminopeptidase-2 inhibitory activity of a series of cytotoxic anthranilic acid sulfonamide derivatives were discovered. We have demonstrated the detailed application of two efficient nonlinear methods for evaluation of quantitative structureeactivity relationships of the studied compounds. Components produced by principal component analysis as input of developed nonlinear models were used. The performance of the developed models namely PC-GRNN and PC-LS-SVM were tested by several validation methods. The resulted PC-LS-SVM model had a high statistical quality (R 2 ¼ 0:91 and R 2 CV ¼ 0:81) for predicting the cytotoxic activity of the compounds. Comparison between predictability of PC-GRNN and PC-LS-SVM indicates that later method has higher ability to predict the activity of the studied molecules.

Six Schiff base derivatives of D-mannitol, 1,6-dideoxy-1,6-bis-{[(E)-arylmethylidene]amino}-D-mannitol (6: aryl = XC 6 H 4 : X = o-, m-and p-Cl or NO 2 ), have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H 37 Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in lg/mL. All three nitro derivatives exhibit significant activities: activities of (6d: X = o-NO 2 ), (6e: X = m-NO 2 ) and (6f: X = p-NO 2 ) are 12.5, 25.0 and 25.0 lg/mL, respectively. When compared with first line drugs, such as ethambutol, they can be considered as a good starting point to develop new lead compounds for the treatment of multidrug-resistant tuberculosis. Characterization of the new compounds 6 is generally achieved spectroscopically. The structure of compound 3 has been confirmed by X-ray crystallography.

A series of Mannich bases of 2-alkyl-3-hydroxy-pyridine-4-ones, namely 2-alkyl-3-hydroxy-5-N-piperidylmethyl or N,N-dialkylaminomethyl pyridine-4-ones 9, 10 and 15-18, two derivatives of N-aryl-2methyl-3-hydroxy-pyridine-4-ones 19, 20 and two N-alkyl derivatives of maltol, 21 and 22 were prepared. They were screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue Ò assay (MABA) method. Multiple linear regressions (MLR) analysis was performed for the synthesized compounds as well as a series of pyridinone and pyranone derivatives 23-43 which have been synthesized and evaluated for antimicrobial activity by other researchers previously. Studied compounds showed a better quantitative structure-activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus in comparison with other tested microorganisms.