Abstract Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may assembled multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs consistently on resistance (R) plasmids. Second, multidrug resistance may also arise by the increased expression of genes that code for multidrug efflux pumps, releasing a wide range of drugs. This research discusses design, and synthesis, of novel cyanopyridones, and fused cyanopyridones namely, pyrido[2,3-d]pyrimidines employing ring fusion and variation of substituents. One pot reaction of N-aryl-2-cyanoacetamide with malononitrile/ethyl cyanoacetate and various aldehydes via Hantzsch pyridine synthesis afforded the target compounds pyridine carbonitriles (4-9), which upon cyclo-addition with formic acid, acetic anhydride or phenyl iso/isothiocyanate afforded the corresponding pyrido[2,3-d]pyrimidines, (10-18). The synthesized compounds were docked into the active sites of DNA gyrase B and topoisomerase IV to examine their affinities. Our hits will be evaluated in vitro for their antimicrobial activity (MIC's) against Gm+ve , Gm-ve and resistant strains of microorganisms for SARs study. The promising hits will be investigated via enzyme assay compared to reference standard to explore their molecular mechanism Furthermore, determination of their cytotoxicity on normal cells will be carried.