Synthesis, in vitro cytotoxic, anti-Mycobacterium tuberculosis and molecular docking studies of 4-pyridylamino- and 4-(ethynylpyridine)quinazolines

Abstract

• Successful synthesis of compounds of the series 4-chloro-, 4-(pyridylamino)- and 4-(ethynylpyridine)-quinazoline. • Positive results from the Alamar Blue assay ( Mtb H37Rv strain) which revealed promising MIC 90 ranging from <0.7 to >125 µM. • Candidate compounds were inductively docked into the 3ZXR enzyme and the more prominent hydrogen bond is between Nitrogen of the pyridine ring moiety of the 5 and 6 series with an OH group of SER280. • A metal coordination between the methoxy benzene moiety of compounds in the 6 series and Mg 2+ is also observed, explaining the SAR of these compounds to MtGS enzyme. A series of 4-(pyridylamino)- and 4-(ethynylpyridine)quinazolines were successfully prepared via Sonogashira cross-coupling and dechloroamination reactions on the C(4)-Cl position of the requisite 2-(p-phenyl)-4-chloroquinazolines. The prepared compounds were characterized by means of 1 H- and 13 C-NMR, FT-IR and mass spectrometry techniques. The structure of 2-(4-chlorophenyl)-4-(2-(pyridin-4-yl) ethynyl) quinazoline from the 4-(ethynylpyridine) series was confirmed by single crystal X-ray analysis which indicates monoclinic crystal system and P21/c space group. Compounds from the 4-chloro-, 4-(pyridylamino)- and 4-(ethynylpyridine)-quinazoline series were evaluated for anti- Mycobacterium tuberculosis ( Mtb ) properties in vitro employing rifampicin as a reference drug. The results from the Alamar Blue assay ( Mtb H37Rv strain) revealed promising MIC 90 ranging from <0.7 to >125 µM. The cytotoxicity of the synthesised compounds was tested against the Raw 264.7 microphage cell line at a maximum concentration of 50 µM. The possible mode of interaction against the Mtb was theoretically explained through molecular 3ZXR protein and the more prominent hydrogen bond is observed between the nitrogen of the pyridine ring moiety of the 5 and 6 series with OH group of SER280. Also, a metal coordination between the methoxy benzene moiety of compound 6e and Mg 2+ is also observed, explaining the SAR of these compounds to MtGS.