Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: Synthesis, biological evaluation and molecular modelling studies

Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s > 10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K-i value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XI

Design, synthesis and evaluation of N-substituted saccharin derivatives as selective inhibitors of tumor-associated carbonic anhydrase XII

A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with K(I)s ranging between 11 and 390 nM, whereas they were inactive against both CA I (K(I)s > 50 mu M) and II (K(I)s ranging between 39.1 nM and 50 mu M). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones

Design, synthesis and biological evaluation of N

A series of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for their in vitro human carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound 15 showed a modest inhibition potency against hCA I (Ki = 73.7 μM) and hCA VII (Ki = 85.8 μM). Compounds 19 and 25 exhibited hCA II inhibition with Ki values of 96.0 μM and 87.8 μM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood

Recent advances in the development of selective human MAO-B inhibitors: (Hetero)arylidene-(4-substituted-thiazol-2- yl)hydrazines

A large series of (4-substituted-thiazol-2-yl)hydrazine derivatives was synthesized in good yield and assayed for their in vitro human monoamine oxidase (hMAO) inhibitory activity and selectivity. Most of them showed inhibitory activity in the nanomolar range and hMAO-B selective inhibition higher than reference drugs, demonstrating our interest in this privileged scaffold. The structure-activity relationship of the different rings on the N1-hydrazine position indicated that a pyridine ring was preferred with the presence of electron-withdrawing substituents on the aryl group at C4 of the thiazole nucleus. The substituent on the α-carbon to the N1-hydrazine moiety (methyl or hydrogen) had a great influence on the activity and hMAO-B selectivity. Moreover, the reversibility of the enzyme inhibition for the best active compound was reported

Cyclic tertiary sulfamates: Selective inhibition of the tumor-associated carbonic anhydrases IX and XII by N- and O-substituted acesulfame derivatives

Carbonic anhydrase (hCA) IX and XII isoforms are over-expressed both in primary and in metastatic cell lines of hypoxic tumors and are innovative targets for cancer diagnosis and treatment. On the basis of the importance of the pharmacophoric sulfamate moiety (bioisostere of the sulfonamide group) present in the structure of recent human CA inhibitors, we designed N-alkylated and O-allcylated derivatives of acesulfame, a cyclic tertiary sulfamate, assessing the inhibitory activity against the ubiquitous isoforms hCA I and II and the cancer-related isoforms hCA IX and XII. All derivatives were nanomolar inhibitors, with some of them possessing an outstanding selectivity towards the tumor-associated hCA IX and/or hCA XII isoforms. (c) 2014 Elsevier Masson SAS. All rights reserved

Identification of the stereochemical requirements in the 4-aryl-2-cycloalkylidenhydrazinylthiazole scaffold for the design of selective human monoamine oxidase B inhibitors

Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted C=N bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl) thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereo-separation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies