Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis

Human dihydroorotate dehydrogenase(DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis(RA), psoriasis and multiple sclerosis(MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structureeactivity relationship(SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range.Further structure optimization revealed that an acrylamide with small hydrophobic groups(Me, Cl or Br)at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53-55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic(PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

Synthesis,Characterization and Biological Activities of Novel Acrylamide Compounds

With dimethomorph and flumorph as the leading compounds, four novel acrylamide compounds with two types of structure were designed and synthesized by means of the method of ＂me too chemistry＂. The target compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The influences of solvent and raw material on the yield were investigated and optimum processing conditions were determined. The results of preliminary biological tests show that all those compounds exhibit certain antifungal activities.

Influence of Sodium Dodecyl Sulfate on the Phase Transition of Thermoresponsive Hyperbranched Polymer in Water

The influence of sodium dodecyl sulfate（SDS） on the cloud point temperature（Tcp） of the aqueous solution of thermoresponsive hyperbranched polyethylenimine derivative HPEI-IBAm was studied systematically. When pH was below 8.5, HPEI-IBAm was positively-charged. Initially, the Tcp of HPEI-IBAm decreased significantly, followed by an obvious increase with the increase of SDS concentration. The lower the pH was, the higher the SDS concentration was required to achieve the minimum Tcp. When pH was above 8.5, HPEI-IBAm was neutral and raising the SDS concentration led to the gradual increase of Tcp. Compared to linear poly（N-isopropyl acrylamide）（PNIPAm）, the Tcp of the current hyperbranched HPEI-IBAm was more sensitive to SDS. The thermoresponsive HPEI-IBAm/SDS complex was used as host to accommodate the non-polar pyrene in water. The lowest SDS concentration for effectively enhancing the solubility of pyrene in water was around 6.4 mmol·L^-1. When HPEI-IBAm was present, the SDS concentration threshhold was decreased to about 0.31 mmol·L^-1. Fluorescence technique with pyrene as the hydrophobic probe demonstrated that the SDS concentration of 7.2 mmol·L^-1 was required to form the hydrophobic domain to accommodate pyrene guests without HPEI-IBAm, while only 0.2 mmol·L^-1 of SDS was required in the presence of HPEI-IBAm.