The effect of ethoxyzolamide, an analogue of insect juvenile hormone, nor-adrenaline and iodine on changes in the optical path difference in the excretory cells and oesophagus during exsheathment in Haemonchus contortus

Davey K. G., Sommerville R. I. and Rogers W. P. 1982. The effect of ethoxyzolamide, an analogue of insect juvenile hormone, nor-adrenaline and iodine on changes in the optical path difference in the excretory cells and oesophagus during exsheathment in Haemonchus contortus. International Journal for Parasitology12: 509–513. Ethoxyzolamide, an inhibitor of carbonic anhydrase, markedly inhibits exsheathment of Haemonchus when the larvae are subsequently exposed to an exsheathing stimulus of CO₂ at 38.5°C. Ethoxyzolamide at 2 × 10^?5M does not prevent the increase in optical path difference in the oesophageal region which normally accompanies exsheathment, but markedly inhibits the increase in optical path difference in the excretory cells. An analogue of juvenile hormone (JHA; the methyl ester of 3,7,11 trimethyl-7,11-dichloro-2-dodecenic acid) does not affect the optical path difference in either the oesophagus or the excretory cells of ensheathed worms. When worms are artificially desheathed by exposure to NaOCl, a procedure which mimics the effect of CO₂ upon the oesophagus, but which does not affect the excretory cells, subsequent exposure to JHA at room temperature increases the optical path difference in the excretory cells. This increase is enhanced by subsequent incubation of the worms at 38.5°C at 30–60 min and further enhanced when CO₂ is present during the incubation at 38.5°C. The stimulation of the excretory cells by JHA is inhibited by ethoxyzolamide at 2 × 10^?5M. Noradrenaline at 10^?3M has no effect on ensheathed larvae, but causes an increase in optical path difference in the excretory cells of larvae desheathed with NaOCl. This increase is inhibited by ethoxyzolamide. A brief exposure to I₂ blocks the response of the excretory cells of both CO₂ and JHA, but does not significantly reduce the effect of nor-adrenaline. On the basis of these and previous results, it is proposed that both CO₂ and JHA stimulate a hypothetical CO₂ receptor which leads to the release of nor-adrenaline. The noradrenaline in turn stimulates, either directly or indirectly, the excretory cells.     

Furazan and furoxan sulfonamides are strong α-carbonic anhydrase inhibitors and potential antiglaucoma agents

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3–5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3–5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39–42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.     

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design,synthesis and biochemical characterization

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (K_i = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4′-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (K_i = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.     

Structure and biological properties of first row d-transition metal complexes with N-substituted sulfonamides

Cobalt (II), copper (II), nickel (II) and zinc (II) complexes with 2-hydroxy-1-naphthaldehyde derived N-substituted sulfonamides have been synthesized and the nature of bonding and structure of compounds have been deduced from physical, analytical and spectral (IR, ¹H NMR, ¹³C NMR, Mass and electronic) data. An octahedral geometry has been suggested for the complexes. Complexes along with the ligands were assessed for their antibacterial and antifungal activities on different species of pathogenic bacteria and fungi. The results revealed the ligands to possess moderate to significant antibacterial activity which was, in many cases, enhanced on chelation. Similar results were observed for antifungal activity. Brine shrimp bioassay was also carried out for in vitro cytotoxic properties against Artemia salina.     

Metal-based sulfonamides: Their preparation,characterization and in-vitro antibacterial,antifungal & cytotoxic properties. X-ray structure of 4-[(2-hydroxybenzylidene) amino] benzenesulfonamide

Synthesis, characterization and biological studies of Schiff base-derived sulfonamides and their Co (II), Cu (II), Ni (II) and Zn (II) complexes have been reported and screened for in-vitro antibacterial activity against six Gram-negative; E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S. typhi and S. dysenteriae and four Gram-positive; B. cereus, C. diphtheriae, S. aureus and S. pyogenes bacterial strains and for in-vitro antifungal activity against T. longifusus, C. albicans, A. flavus, M. canis, F. solani, and C. glaberata. All compounds showed moderate to significant antibacterial activity, however, the zinc (II) complexes were found to be more active. Some of the compounds also showed significant antifungal activity against various fungal strains. Only compounds (6) and (10) displayed potent cytotoxic activity with LD₅₀ = 4.644 × 10^{? 4} and 4.106 × 10^{? 4} moles/mL respectively, against Artemia salina. The X-ray structure of 4-[(2-hydroxybenzylidene)amino]benzenesulfonamide is also reported.     

Synthesis,Characterization, and Anti‐Amoebic Activity of N‐(Pyrimidin‐2‐yl)benzenesulfonamide Derivatives

A new series of N‐(pyrimidin‐2‐yl)benzenesulfonamide derivatives, 3a – 3i and 4a – 4i , was synthesized from pyrimidin‐2‐amines, 2a – 2i , with the aim to explore their effects on in vitro growth of Entamoeba histolytica. The chemical structures of the compounds were elucidated by elemental analysis, FT‐IR, ¹H‐ and ¹³C‐NMR, and ESI mass‐spectral data. In vitro anti‐amoebic activity was evaluated against HM1 : IMSS strain of Entamoeba histolytica. The IC₅₀ values were calculated by using the double dilution method. The results were compared with the IC₅₀ value of the standard drug ‘metronidazole’. The selected compounds were tested for their cytotoxic activities by cell‐viability assay using H9C2 cardiac myoblasts cell line, and the results indicated that all the compounds displayed remarkable >80% viabilities to a concentration of 100 μg/ml.     

Synthesis and evaluation of 7-chloro-4-(piperazin-1-yl)quinoline-sulfonamide as hybrid antiprotozoal agents

A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1–F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC₅₀ <5 μM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC₅₀ values of 2 μM. Compound F7, whose crystal structure was also determined, inhibited β-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski ‘rule of five’ on all the compounds (F1–F11) suggested high drug likeness of F7 and F8, similar to quinine.     

Kinetic and X-ray crystallographic investigations of substituted 2-thio-6-oxo-1,6-dihydropyrimidine–benzenesulfonamides acting as carbonic anhydrase inhibitors

Herein we report an in vitro kinetic evaluation against the most relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms (I, II, IX and XII) of a small series of lactate dehydrogenase (LDH, EC 1.1.1.27) inhibitors. All compounds contain a primary sulfonamide zinc-binding group (ZBG) substituted with the 2-thio-6-oxo-1,6-dihydropyrimidine scaffold. By means of X-ray crystallographic experiments we explored the ligand–enzyme binding modes, thus highlighting the contribution of the 2-thio-6-oxo-1,6-dihydropyrimidine moiety to the stabilization of the complex.     

Isatin analogs as novel inhibitors of Candida spp. β-carbonic anhydrase enzymes

Enzyme inhibition data of structurally novel isatin-containing sulfonamides were determined for two carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic Candida species (CaNce103 from C. albicans and CgNce103 from C. glabrata). The compounds show K_I values in the low nanomolar range for the fungal CAs, while they have significantly higher K_I values for the human CAs. Homology models were constructed for the CaNce103 and CgNce103 and subsequently the ligands were docked into these models to rationalize their enzyme inhibitory properties.