Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure-Activity Relationship and Preclinical Characterization.

The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.

Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3,5-diaryl-4,5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties.

A series of novel 1-acetyl-3-(3,4-dimethoxypheny)-5-(4-(3-(arylureido/arylthioureido/arylsulfonamido) phenyl)-4,5-dihydropyrazole derivatives of biological interest have been prepared by sequential cyclization of 1-(4-nitrophenyl)-3-(3,4-dimethoxyphenyl)-pro-2-ene-1 with hydrazine hydrate, reduction followed by reaction of resulting amine with different arylisocyanates or arylisothiocyanates or arylsulfonyl chlorides. All the synthesized compounds (1-32) have been screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological evaluation study showed, the compounds 4, 5, 9, 11, 14 and 16 found to have promising anti-inflammatory activity (up to 61-85% TNF-α and 76-93% IL-6 inhibitory activity) at concentration of 10 µM with reference to standard dexamethasone (76% TNF-α and 86% IL-6 inhibitory activity at 1 µM). Compounds 24, 26, 27, 28 and 29 exhibited promising antimicrobial activity at MIC values ranging from 70 to 10 µg/mL against all the selected pathogenic bacteria and fungi.

Synthesis and biological evaluation of novel piperazine derivatives of flavone as potent anti-inflammatory and antimicrobial agent.

A series of novel 6-methoxy-2-(piperazin-1-yl)-4H-chromen-4-one and 5,7-dimethoxy-2-(piperazin-1-ylmethyl)-4H-chromen-4-one derivatives of biological interest were prepared and screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Among all the compound screened (5a-j and 10k-t), the compounds 5c, 5g, 5h, 10l, 10m, 10n and 10r found to have promising anti-inflammatory activity (up to 65-87% TNF-α and 70-93% IL-6 inhibitory activity) at concentration of 10 µM with reference to standard dexamethasone (71% TNF-a and 84% IL-6 inhibitory activities at 1 µM) while the compounds 5b, 5i, 5j, 10s and 10t found to be potent antimicrobial agent showing even 2 to 2.5-fold more potency than that of standard ciprofloxacin and miconazole at the same MIC value of 10 µg/mL.

A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: synthesis, anti-inflammatory and antimicrobial evaluation.

A series of novel 4-(3-(trifluoromethyl)phenylamino-6-(4-(3-arylureiodo/arylthioureido/arylsulfonamido)-pyrimidine derivatives of biological interest were prepared by the sequential Suzuki cross coupling, acid amination, reduction followed by reaction of resulting amine with different arylisocyantes or arylisothiocyantes or arylsulfonyl chlorides. All the synthesized compounds (1-25) were screened for their pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological data revealed that among all the compounds screened, compounds 5, 6, 11, 12, 16 and 20 were found to have moderate to potent anti-inflammatory activity (up to 48-78% TNF-α and 56-96% IL-6 inhibitory activity) with reference to standard dexamethasone at 10 µM. The compounds 10, 12, 13, 18, 20, 22, 24 and 25 found to have promising antimicrobial activity against all the selected pathogenic bacteria and fungi.

The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation.

A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by sequential Bigineli's reaction, reduction followed by reaction of resulting amines with different arylisocynates. All the synthesized (1-23) compounds were screened against the pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation study reveled that among all the compounds screened, compounds 12 and 17 found to have promising anti-inflammatory activity (68-62% TNF-α and 92-86% IL-6 inhibitory activity at 10 µM). Interestingly compounds 3, 4, 5, 6, 15, 22 and 23 revealed promising antimicrobial activity at MIC of 10-30 µg/mL against selected pathogenic bacteria and fungi.