Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines

Abstract

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.

Synthesis, Computer Aided Screening and Pharmacological Evaluation of 2/3-Substituted-6(4-Methylphenyl)-4,5-Dihydropyridazin3(2h)-Ones, and Pyridazine Substituted Triazine

“…In recent years, synthesis of novel pyridazinone derivatives and investigation of their chemical and biological behavior have gained more importance due to their biological, medicinal, and agricultural reason. This privileged structure attracts the interest of medicinal chemists as a nucleus of potential therapeutic utility and exhibits several pharmacological activities such as analgesic (Asif, et al, 2011), anti-inflammatory (Gokce, et al, 2009), antidepressant (Coelho, et al, 2003), antihypertensive (Demirayak, et al, 2004), anticonvulsant (Rubat, et al, 1990), cardiotonic (Amin, et al, 2010), diuretic (Akahane, et al, 1999), and anti-HIV (Livermone, et al, 1993) activities. Certain pyridazinone derivatives containing the 2-phenyl-indolyl moiety have also shown anti-cancer activity (Murty, et al, 2012).…”

ZrOCl2.8H2O as a green and efficient catalyst for the expeditious synthesis of substituted 3-arylpyrimido[4,5-c]pyridazines in water

“…This azine heterocycle is included in chemicals with a wide range of biological activities and can also be used to link other pharmacophoric groups. 10 Pyridazine derivatives have biological properties and features, such as anti-viral and anti-cancer, 11 anti-hypertensive, 12 anti-inflammatory, 13 anti-microbial, 14 anti-depressant, 15 anti-HIV 16 and etc. 3-Arylpyrimido [4,5-c]pyridazine-5,7(6H,8H)-diones possess monoamine oxidase (MAO) inhibitory activity and substituents on the diazine nucleus modulate the inhibitory activity.…”

Design, synthesis and antihypertensive screening of novel pyridazine substituted s-triazin-2-imine/one/thione derivatives

“…The quite noticeable efforts have been made on obtaining novel antihypertensive agents acting on different mechanisms to control blood pressure 3 . Pyridazines are important biologically active scaffolds, possessing antihypertensive 4 , cardiotonic 5 , analgesic 6 , anti-inflammatory 7 , antidepressant 8 , antibacterial 9 , anticancer 10 , nephrotopic drugs 11 , antithrombic 12 , diuretic 13 and anti-HIV 14 activities. Some pyridazine derivatives, such as bemoradan 15 , indolidan 16 , levosimendan 17 , pimobendan 18 , zardaverine 19 and imazodan 20 , have already appeared in the clinical market.…”