Molecular Docking Studies of Synthesized Pyridazinone Scaffolds as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Abstract

Pyridazinone derivatives, 6-aryl-pyridazinone (2a–f) and 2-(N-substituted)-6-aryl-pyridazinone (3a–h) derivatives were synthesized and assessed for cytotoxicity action using brine shrimp assessment method and in silico molecular studies. In silico molecular study of pyridazine derivatives used as NNRTIs and Doravirine is used as reference drug. The compounds were investigated for docking modes onto probable binding sites with HIV reverse transcriptase. The majority of these demonstrated favorable binding interactive connections with the active receptor domain. The majority of the compounds exhibited a remarkable docked binding affinity score when compared with the reference drugs. Among the synthesized pyridazine derivatives, compounds 3a and 3c–h exhibited a good docking score. For the designed compounds, in silico ADME assessment indicated the favorable physicochemical properties to be a suitable drug candidate. The synthesized compounds could serve as a novel alternative in designing safe and effective anti-HIV options with reverse transcriptase inhibitor potential. In the cytotoxicity study, all the compounds were evaluated at dose levels 10, and 20 (μg/mL), and potassium dichromate was used as a reference. Compounds 2c and 2e have shown potent lethality through LC₅₀ 2.23 and 3.20 μg respectively. Various compounds, including 2a, 2b, 2d, and 2f have demonstrated significant cytotoxicity. Their LC50 values are 7.58, 6.76, 8.91, and 4.46 μg, respectively. Additionally, compounds 3b and 3d exhibited potent lethality with LC₅₀ values of 4.023 and 4.20 μg. Other compounds, namely 3g, 3f, 3c, 3h, 3a, and 3e, displayed noteworthy cytotoxicity ability13.91, 12.58, 11.91, 11.76, 10.58, 9.76, and 7.46 μg, respectively having LC₅₀ values. This study supports the use of in silico molecular design and the brine shrimp bioassay as a suitable, reliable, and simple method for assessing the bioactivity of compounds. It provides further evidence for their use in medicine.