Synthesis and in silico insights of some tetrahydrobenzothienopyrimidine candidates as multi-target antimicrobial, antiproliferative, and antiviral agents

Abstract

A new series of fused tri- and tetra-cyclic candidates including a tetrahydrobenzo[b]thiophene core was prepared through cyclo-condensation of ethyl formamidate with hydrazine and 2-cyanoethanohydrazide, respectively. The proper locations of amino and imino groups in the first key synthon 2 allowed cyclo-condensation reactions with some carbon electrophiles. The active methylene in the second key synthon 4 condensed with 3-formylpyridine and 2-hydroxybenzaldehyde. Also, thiazolidin-4-one candidate was obtained by condensation of nitrile derivative with mercaptoacetic acid. The purity of compounds obtained was ensured with HPLC analysis. The antimicrobial screening against “two Gram positive strains: B. subtilis and S. aureus, two Gram negative strains: E. coli and P. aeruginosa and one fungal strain, C. albicans” displayed the promising activity of tetracyclic candidates bearing cyanomethyl, methyl, nitrobenzylidene, or thiazolidinone scaffolds. The cytotoxic effect of promising compounds alone or combined with NAC against liver (HepG2) cancer cell line revealed the highest activity of nitrobenzylidene derivative 8 (IC₅₀ = 6.57) followed by thiazolidinone 12 (IC₅₀ = 9.76). A strong activity was offered by compounds 4 (IC₅₀ = 13.2) and 6 (IC₅₀ = 20.34). The antiviral activity against “human adenovirus (HAdV-7) and SARS-CoV-2 (hCoV-19)” indicated the highest potency of cyanomethyl derivative 4 followed by thiazolidinone 12. To understand the possible mechanisms of antibacterial, antifungal, antitumor, and antiviral actions, molecular docking analyses of potent compounds were investigated toward six target proteins including bacterial (PDB ID: 9JNP and 5TW8), fungal (PDB ID: 4LXJ), tumor (PDB ID: 5NM5), and viral (PDB ID: 5CX6 and 3PY7) proteins compared to their co-crystallized ligands and reference drugs. Most amino acids interacting with the docked compounds were common. Some compounds exhibited the same binding interactions but with different docking scores due to the electronic effects. The highest docking scores were shown by nitrobenzylidene followed by thiazolidinone candidate toward these target proteins except PBP4, which displayed a reverse order. The modeling pharmacokinetics referred to their favorable drug-likeness properties. This work reveals the potential biological profiles of these compounds and provides valuable insights into further therapeutic development.