No abstract

No abstract

No abstract

A series of novel 8-substituted-N-(4-sulfamoylphenyl)quinoline-2-carboxamides was synthesised by the reaction of 8-hydroxy-N-(4-sulfamoylphenyl) quinoline-2-carboxamide with alkyl and benzyl halides. The compounds were assayed for carbonic anhydrase (CA) inhibitory activity against four hCA isoforms, hCA I, hCA II, hCA IV, and hCA IX. Barring hCA IX, all the isoforms were inhibited from low to high nanomolar range. hCA I was inhibited in the range of 61.9–8126 nM, with compound 5h having an inhibition constant of K I = 61.9 nM. hCA II was inhibited in the range of 33.0–8759 nM, with compound 5h having an inhibition constant of 33.0 nM and compounds 5a and 5b having inhibition constants of 88.4 and 85.7 nM, respectively. hCA IV was inhibited in the range of 657.2–6757 nM. Hence, compound 5h , possessing low nanomolar hCA I and II inhibition, can be selected as a lead for the design of novel CA I and II inhibitors.

A series of coumarin-thiourea hybrids (4 a-o) has been synthesized, and the compounds have been evaluated against the tumour associated transmembrane isoform, human (h) carbonic anhydrase (CA) hCA IX and the less-explored cytosolic isoform, hCA XIII. All compounds exhibited potent inhibition of both isoforms, with K I values of < 100 nM against hCA IX. Compound 4 b was the best inhibitor (K I = 78.5 nM). All the compounds inhibited hCA XIII in the low-nanomolar to sub-micromolar range, with compound 4 b again showing the best inhibition (K I = 76.3 nM). With compound 4 b as a lead, more-selective inhibitors of hCA IX and hCA XIII or dual hCA IX/XIII inhibitors might be developed.

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with K i s in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with K i s in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with K i s in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with K i s in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.

Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N‐terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline‐based hybrids, that is (Z)‐5‐((Z)‐benzylidine)‐2‐(quinolin‐3‐ylimino)thiazolidin‐4‐ones (QYT‐4a‐i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT‐4h) against LdMetAP1. The compound QYT‐4h showed nearly 20‐fold less potency for human MetAP1 and had drug‐like features. Time–course kinetic assays suggested QYT‐4h acting through a competitive mode by binding to the metal‐activated catalytic site. Notably, QYT‐4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT‐4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT‐4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small‐molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.

No abstract