Structural activity of synthesized pyrimidine-thiophene and pyrimidine-thiadiazole conjugates as anticancer agents

• Eight pyrimidine-thiophene and pyrimidine-thiadiazole conjugates 5 and 7 were synthesized. • The modelling of synthesized conjugates implied twisted structures. • The cytotoxic effectiveness of synthesized conjugates against different cancer cells was assessed. • The inhabitation effects of synthesized conjugates were evaluated. • The molecular docking study for synthesized conjugates was tested to predict the values and types of binding interactions. New pyrimidine linked thiophene conjugates 5a-d and thiadiazole conjugates 7a-d through a carboxamide bridge were synthesized and characterized by the spectral data (IR, NMR and mass). Exploration of the isolated conjugates’ characteristics using DFT methodology revealed that they had angular configurations with distinctive outline of the FMO’s belonging to the thienyl- and thiadiazolyl-pyrimidine classes. In accordance, the FMO’s energy values of these analogues disclosed reduced energy gap (ΔE H-L =3.66–3.86 eV) than the parent 4 (4.49 eV) and may be arranged as: 7c < 7d < 5c < 5d < 5a < 5b < 7b < 7a < 4 . Meanwhile, the cytotoxic effectiveness of the synthesized conjugates was assessed against different cancer cell lines using IC 50 values in comparison to 5-Fu, drug reference. The data showed that the acrylamide derivative 4 exhibited the most potent cytotoxicity against MCF-7 and PC3 (IC 50 6.11 ± 0.10 and 7.19 ± 0.04 μM, respectively). Moreover, the carbonic anhydrases inhibitory effect on hCA IX and hCA IIX have been evaluated, using acetazolamide (as standard), showing greater impact on hCA IX compared to hCA IIX . Molecular docking has been applied to investigate the nature of the binding interactions with the target amino acid residues, and it disclosed that the pyrimidine-thiophene conjugates 5d and 5c had the highest binding scores. Finally, the SwissADME pharmacokinetic properties of synthesized conjugates indicated that the acrylamide compound 4 exhibited acceptable pharmacokinetic manners, such GI absorption, solubility, no BBB permeation, and slight CYP450 inhibition, implying a promising therapeutic candidate.