Discovery of novel N-phenyl 1,4-dihydropyridines with a dual mode of antimycobacterial activity.

There is an urgent need for novel drugs for the treatment of tuberculosis (TB) due to the increasing prevalence of antibiotic resistance among Mycobacterium tuberculosis (Mtb) strains against first-line and second-line therapeutics. We developed novel N-phenyl 1,4-dihydropyridines as potential antituberculotic agents. The observed activity depends on the substitution patterns of the aromatic residues. N-unsubstituted 1,4-dihydropyridines are known inhibitors of the cancer-relevant transmembrane efflux pump ABCB1. Based on the similarity of ABCB1 amino acids sequences relevant to 1,4-dihydropyridine binding and the MTb efflux pump Rv0194, we determined ABCB1-inhibitory properties of our compounds in a cell line model. We identified one compound, which substantially increased the activity of two antituberculotic drugs which are substrates of ABCB1. The data indicate that our N-phenyl 1,4-dihydropyridines represent a novel compound class which improves the efficacy of anti-TB drugs by interfering with transmembrane efflux pumps in Mtb.

Discovery of substituted 1,4-dihydroquinolines as novel promising class of P-glycoprotein inhibitors: First structure-activity relationships and bioanalytical studies.

Multidrug resistance (mdr) is the most important problem in the therapeutical treatment of cancer. One central problem in the resistance proceeding is the expression of transmembrane efflux pumps which transport drugs out of the cells. We developed novel substituted 1,4-dihydroquinolines as inhibitors of the transmembrane efflux pump P-glycoprotein. Structure-activity relationships are discussed for this first series. Promising active inhibitors have been identified and first bioanalytical studies have been carried out to address questions of cellular toxicity, P-gp substrate as well as mdr reversal properties.

Discovery of substituted 1,4-dihydroquinolines as novel class of ABCB1 modulators.

Transmembrane efflux pumps are one main cause for multidrug resistance (mdr) of cancer. One hopeful approach to combate the mdr has been the development of inhibitors of the efflux pump activity. A novel class of small-molecule inhibitors of the most important efflux pump ABCB1 (P-glycoprotein) has been discovered. Inhibitory activities are discussed in relation to substituent effects. Most active compounds have been evaluated in first bioanalytical studies to reverse the mdr of an anticancer drug. Cellular toxicity and ABCB1 substrate properties of the compounds were investigated. A cellular induction of relevant efflux pump protein expressions was not observed under inhibitor application, so that our compounds are perspective candidates for further preclinical studies.

Development of small-molecule P-gp inhibitors of the N-benzyl 1,4-dihydropyridine type: novel aspects in SAR and bioanalytical evaluation of multidrug resistance (MDR) reversal properties.

Novel series of N-benzyl 1,4-dihydropyridines have been prepared by facile syntheses. All relevant substituents of the molecular scaffold have been varied. The resulting compounds were biologically evaluated as P-glycoprotein (P-gp) inhibitors. Substitutions of the N-benzyl residue favour biological activity beside respective 3-ester functions. Most active compounds were further evaluated as multidrug resistance (MDR) modulators to restore the cytotoxic properties of varying daunorubicin applications.

Discovery of 9,10-Dihydroacridines as Novel Class of ABCB1 Inhibitors.

Nonplanar 9,10-dihydroacridines were synthesized as promising C2 symmetric molecular scaffolds as inhibitors of the transmembrane efflux pump ABCB1. Within the series structure-activity relationships are discussed revealing the importance of hydrogen bond acceptor functions. A selectivity of ABCB1 inhibition is demonstrated for selected candidates and a bioanalytical study proved nontoxicity as well as missing ABCB1 substrate properties. The results encourage to further develop the promising class of ABCB1 inhibitors.

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis.

Novel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated. Structure-activity relationships were deduced from biological results and will be used in further design of new active compounds. In particular, the acetoxymethyl substituent found at the 6-position of previously described active compounds can be replaced by an acetamidomethyl substituent without loss of potency; while the presence of an aryl ester function at the 3-position was preferred to a thioester or an amide function to induce marked biological activity. This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anti-cancer agents.