Nuclear-Factor kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB exists in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of physical, chemical, and biological stimuli leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (kappaB sites in the DNA), to initiate transcription. This transcription has been known to be involved in a number of diseases including cancer, AIDS, and inflammatory disorders. The present article focuses on two important issues of current and future interest- firstly a review of the main human diseases which are initiated due to NF-kappaB mediated transcription is presented. Next, comprehensive information on the current inhibitors which are targeted to interfere with the NF-kappaB pathway is provided. This latter section presents a critical review on different types of latest inhibitors targeting the complex NF-kappaB pathway at several stages. The inhibitors developed till date and still under investigation, include mainly those which interfere with the activation of NF-kappaB. Based on the complexity of NF-kappaB activation, and the current knowledge of the structural biology of NF-kappaB-DNA binding, finally it is proposed that a better approach to inhibit NF-kappaB induced transcription exists. In this context, a perspective is presented in the end, proposing de novo design of inhibitors which directly interact with the DNA Binding region of the free NF-kappaB (p50 subunit), so as to generate more specific and selective leads of NF-kappaB-DNA binding.

Cystic fibrosis (CF), a monogenetic disease caused mostly by the F508del mutation, a deletion of phenylalanine at position 508 of the CF transmembrane conductance regulator (CFTR) protein, which causes improper localization and functioning of this chloride channel in lung, pancreas, and intestine by affecting the normal fluid homeostasis. In CF the lungs are the most affected organ due to the accumulation of thick mucus, which results into heavy bacterial load and associated chronic inflammation. Therefore, novel state-of-the-art therapies are needed to circumvent this problem. To address this, a series of compounds (thiazolidin-4-one-1,3,5triazines) was tested for the inhibition of NF-κB, and compounds SP6 and SP5 showed most significant activity (respectively with relative NF-ĸB activity: 1.82 ± 1.87 and 1.96 ± 1.56). Docking studies of the active compounds in the DNA binding surface of the N-terminal domains of NF-ĸB were also carried out to identify which structural motifs are vital for activity. These compounds were also tested for antibiofilm activity against P. aeruginosa and S. aureus where they showed MIC ranges from 7.81-125 µg mL -1 . The most active compound -SP6 was further assayed by micro-Ussing chamber experiments to determine its CFTR inhibitory properties, given its structural similarity to CFTR Inh 172. Results suggest that SP6 does not inhibit CFTR alone or in combination with Inh 172 .