The development of isoform selective inhibitors of the carbonic anhydrase (CA; EC 4.2.1.1) enzymes represents the key approach for the successful development of druggable small molecules. Herein we report a series of new benzenesulfamide derivatives (-NH-SO2NH2) bearing the 1-benzhydrylpiperazine tail and connected by means of a β-alanyl or nipecotyl spacer. All compounds 6a–l were investigated in vitro for their ability to inhibit the physiological relevant human (h) CA isoforms such as I, II, IV and IX. Molecular modeling provided further structural support to enzyme inhibition data and structure-activity relationship. In conclusion the hCA I resulted the most inhibited isoform, whereas all the remaining ones showed different inhibition profiles.
A series of novel
benzhydryl piperazine-coupled nitrobenzenesulfonamide
hybrids were synthesized with good to excellent yields. They were
tested for
in vitro
inhibition of mycobacterial activity
against the
Mycobacterium tuberculosis
H37Rv strain,
in vitro
cytotoxicity MTT (RAW 264.7cells)
assay, nutrient starvation (H37Rv strain), and ability to block Cav3.2
T-type calcium channels. Novel hybrids did not inhibit T-type calcium
channels, whereas they showed excellent antituberculosis (TB) activity
and low cytotoxicity with a selectivity index of >30. A direct
impact
of the amino acid linker was not observed. Studied hybrids exhibited
good inhibition activities, and the 2,4-dinitrobenzenesulfonamide
group emerged as a promising scaffold for further drug design by hybridization
approaches for anti-TB therapy.
The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and β-CA classes (VchCAα, VchCAβ). The compounds were prepared by using the “tail approach”, aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure–activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAβ, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives.
Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against
Mycobacterium tuberculosis
(
Mtb
) H37Rv.
4d
–
f
and
4o
found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas
4a, 4c, 4j
displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of
Mycobacterium tuberculosis
enoyl reductase.
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