Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H₄ Receptor Inverse Agonists

Abstract

Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.

Binary Quantitative Structure-Activity Relationship Analysis in Retrospective Structure-Based Virtual Screening Campaigns Targeting Estrogen Receptor Alpha

“…3 and 4) as results from binary QSAR analysis using RPART [24] were evaluated for chance correlation [32,33], crosscorrelation between descriptors [33], and over fitting [34]. Since no evidence of those parameters was found in both decision trees resulted from the binary QSAR analysis using RPART [24], SBVS_2 and SBVS_3 were statistically valid to be used further in virtual screening campaigns.…”

“…Although SBVS_3 is slightly better than SBVS_2 (Table 1), employing multiple poses in SBVS_3 increases degree of freedom and could complicate the subsequent de novo design attempts compared to SBVS_2 [36]. Nevertheless, this success story offers possibilities to employ other supervised machine learning methods in post retrospective SBVS campaigns to optimize the predictive abilities [32,37].…”

Synthesis and Antimicrobial Activity of Amino Linked Heterocycles

“…1 revealed that Gram-positive bacteria were more susceptible towards the tested compounds than Gramnegative bacteria. The bis benzothiazolyl quinazolines (8) exhibited higher activity than bis benzoxazolyl quinazolines (7) and bis benzimidazolyl quinazolines (9). It was noticed that 8c and 8f having chloro and nitro substituent on the aromatic ring displayed greater activity particularly on Staphylococcus aureus.…”

“…imidazol-2-yl) quinazoline-2,4-diamine (9) were obtained by treating 3 with 5 and 6, respectively (Chart 1). The 1 H-NMR spectra of 7a, 8a and 9a displayed a broad singlet at δ 9.32, 9.49 and at 9.12 ppm due to NH protons in addition to the signals of aromatic protons.…”

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…We also noticed that the conserved F1835.47 is positioned further inside the H4 binding site, compared to its position in the H3 binding site, making it more accessible for interactions with ligands. This observation can help the design of H4 selective antagonists, as shown previously [2,[83][84][85]. With the models of H3 and H4, SDM data and fragment hits in hand, we next turned to the docking, optimization and exploration of receptors binding sites followed by VS.…”