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Human 5-Lipoxygenase (5-LOX) is a key enzyme targeted for asthma and inflammation. Zileuton, the only drug against 5-LOX, was withdrawn from the market due to several problems. In the present study, the performance of rationally designed conjugates of thiazole (2) and thiourea (3) scaffolds from our previously reported 2-amino-4-aryl thiazole (1) is reported. They are synthesized (total 31 derivatives), characterized, and tested against the 5-LOX enzyme in vitro and the mode of action of the most active ones are determined. Compound 2m exhibited an IC of 0.9 ± 0.1 μM acting through competitive (non-redox) mechanism, unlike Zileuton, and found to be devoid of radical scavenging properties. Computational studies are in good agreement with the experimental data supporting its mechanism of action. Another lead molecule from the thiourea series (3), 3f, exhibited an IC of 1.4 ± 0.1 μM against 5-LOX whose mode of action is redox type (non-competitive). It is promising to note that the activities displayed by both the lead inhibitors, 2m and 3f, are better than the commercial drug, Zileuton (IC = 1.5 ± 0.3 μM). These inhibitors could be further developed as drugs against inflammation.
This article was published in the following journal.
Name: European journal of medicinal chemistry
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Acridines which are substituted in any position by one or more amino groups or substituted amino groups.
An approach, process, or methodology which emphasizes credible evidence and the best available scientific knowledge, judiciously integrated to achieve the best possible outcomes in structural design. For example, the design of a new OUTPATIENT CLINIC might incorporate a review of published research on outpatient clinic design, decisions on similar past projects, along with interviews with staff and consumers.
AMINO ACIDS composed of GLYCINE substituted at the nitrogen rather than the usual carbon position, resulting in the loss of HYDROGEN BONDING donors. Polymers of these compounds are called PEPTOIDS.
BENZOIC ACID substituted with an amino group. They can either be mono-, di-, or tri- substituted. Para-aminobenzoic acid (see 4-AMINOBENZOIC ACID) is considered a member of the vitamin b complex.
Toluenes in which one hydrogen of the methyl group is substituted by an amino group. Permitted are any substituents on the benzene ring or the amino group.
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