Synthesis of Thieno[3,2-d]pyrimidine Derivatives through Sequential SN Ar and Suzuki Reactions as Selective h-NTPDase Inhibitors.

In this study various of thieno[3,2-d]pyrimidine derivatives have been synthesized by treating different secondary amines through aromatic nucleophilic substitution reaction (SN Ar) followed by Suzuki reaction with aryl and heteroaryl boronic acids. A bis-Suzuki coupling was also performed to generate bis-aryl thienopyrimidine derivatives. The synthesized compounds were screened for the hydrolytic activity of h-NTPdase1, h-NTPdase2, h-NTPdase3, and h-NTPdase8. The compound N-benzyl-N-methyl-7-phenylthieno[3,2-d]pyrimidin-4-amine 3 j selectively inhibits the activity of h-NTPdase1 with IC50 value of 0.62±0.02 µM whereas, the compound 4 d was the most potent inhibitor of h-NTPdase2 with sub-micromolar IC50 value of 0.33±0.09 µM. Similarly, compounds 4 c and 3 b were found to be selective inhibitors for isozymes h-NTPdase3 (IC50 =0.13±0.06 µM) and h-NTPdase8 (IC50 =0.32±0.10 µM), respectively. The molecular docking study of the compounds with the highest potency and selectivity revealed the interactions with the important amino acid residues.

Influenza Treatment: Limitations of Antiviral Therapy and Advantages of Drug Combination Therapy.

Influenza infection is serious and debilitating for humans and animals. The influenza virus undergoes incessant mutation, segment recombination, and genome reassortment. As a result, new epidemics and pandemics are expected to emerge, making the elimination challenging of the disease. Antiviral therapy has been used for the treatment of influenza since the development of amantadine in the 1960s; however, its use is hampered by the emergence of novel strains and the development of drug resistance. Thus, combinational therapy with two or more antivirals or immunomodulators with different modes of action is the optimal strategy for the effective treatment of influenza infection. In this review, we describe current options for combination therapy, their performance, and constraints imposed by resistance, calling attention to the advantages of combination therapy against severe influenza infections. We also discuss the challenges of influenza therapy and the limitations of approved antiviral drugs.