Abstract
Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (22–40) containing either substituted phenyl or heteroaryl rings at position-6 of the pyrimidine ring and evaluated their antitubercular activity. Herein, we report the antimicrobial and antiproliferative activities of 22–40. The antiproliferative activity of the target hybrids was superior to the antimicrobial activity. However, some compounds showed greater antimicrobial activity than the standard drugs. For instance, among the nineteen derivatives, compound 31 containing a 2″,4″-dichlorophenyl ring, showed the most potent antibacterial and antifungal activities (MIC 45.37 µM), followed by compounds 25 and 30 bearing 4″-nitrophenyl and 2″,4″-difluorophenyl scaffolds with minimum inhibitory concentrations (MIC) values of 48.67 µM and 50.04 µM, respectively. Compound 35, containing a bioisosteric 2″-pyridinyl ring, showed the most potent antiproliferative activity against the prostate cancer cell line (DU-145) with an IC50 value of 5 ± 1 µg/mL. Additional testing of compounds 22–40 on human normal liver cells (LO2) indicated that the compounds were more selective to cancer cell lines over normal cells. Further, molecular docking of the most potent compound 35 against dihydrofolate reductase (DHFR) (PDB ID: 1U72) had a good binding affinity with a docking score of −6.834. The SwissADME program estimated the drug-likeness properties of compound 35. Hybrid 35 is a potential lead molecule for the development of new anticancer drugs, whereas 31 is a promising antimicrobial lead candidate.
Highlights
Medicinal chemists explore the strategy of combining the entire molecule or a part of the structure such as two or more heterocyclic rings, which can lead to the generation of new types of structures that have potential bioactivities, and this approach is called molecular hybridization (MH)
A bioisosteric 6-membered nitrogenous heterocyclic ring such as 200 -pyridinyl ring containing compound 35 has very good antiproliferative activity and binding affinity compared to compounds of chloropyrazine-tethered pyrimidine hybrids with a simple phenyl ring
A bioisosteric 6-membered nitrogenous heterocyclic ring such as 2′′-pyridinyl ring containing compound 35 has very good antiproliferative activity and binding affinity compared to compounds of chloropyrazine-tethered pyrimidine hybrids with a simple phenyl ring
Summary
The design, synthesis, and screening of different heterocyclic hybrids are interesting due to their excellent pharmacological properties and ease of preparation. Pyrazine and rings belonging to Pyrazine andpyrimidine pyrimidineare areimportant importantsix-membered six-memberednitrogenous nitrogenous rings belonging atoclass of heterocyclic compounds known as diazines that are commonly distributed in a class of heterocyclic compounds known as diazines that are commonly distributed many pharmacologically useful compounds. This ring is other hand,ispyrimidine is one of the scaffold in drug molecules This ring found in drugs found used asinchemotherapeutic agents because ofagents its ability to interfere with the is drugs used as chemotherapeutic because of its ability to central metabolic including folate and nucleic acid synthesis. Considering significant ological activities of pyrimidine derivatives, previously we synthesized and evaluated the ological activities ofof pyrimidine derivatives, previously we synthesized and evaluated the biological activities pyrimidine derivatives, previously we synthesized and evaluated antitubercular activity of chloropyrazine-tethered pyrimidine hybrids (22–40) [55].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
