Facile synthesis of some 5-(3-substituted-thiophene)- pyrimidine derivatives and their pharmacological and computational studies.

A series of 5-(3-substituted-thiophene)-pyrimidine derivatives (3a-d)
were synthesized via Knoevenagel condensation reaction in aqueous
ethanol using H2O2:HCl as a catalyst. Their pharmacological effects
were evaluated. Analytical and spectroscopic methods confirmed the
structures of the target molecules. The antibacterial activity studies
revealed that compounds 3b and 3d exhibited the most effective zone
of inhibition against bacterial strains E. coli and S. aureus,
respectively. The in vitro cytotoxicity was carried out by MTT assay
against MCF-7 cell line. The results showed the excellent selectivity
for all four compounds, among which the compound 3a exhibited remarkable
cytotoxicity with a minimum cell viability range of 23.68 to
44.16%. The interaction of compounds with calf thymus DNA was determined
using UV-absorption spectroscopy. The results confirmed
that all the synthesized compounds interacted strongly with CT DNA
through electrostatic or groove binding. In silico ADME-toxicology
studies indicated that all the molecules under investigation are nontoxic
with good oral bioavailability. The drug-likeness score indicated
that they are suitable as drug-leads. In silico molecular docking
the specified compound 3b bounds with GlcN-6-P and P38 MAPk with
a minimum binding energy of –7.9 and –6.4 kcal/mol, respectively.
DFT study demonstrated that the compound 3d was chemically and
biologically more reactive due to less energy gap.