Synthesis And Activity Of Quinoxalinone-based Acid And Nitro Derivatives As Aldose Reductase Inhibitors

Diabetes mellitus (DM) is a complex metabolic disorder characterized by an elevated levelof blood glucose called hyperglycemia. The polyol pathway of glucose metabolism isactivated in the hyperglycemia, which subsequently results in the development of long-termpathogenesis of diabetic complications including retinopathy, nephropathy, neuropathy,cataract and stroke. Aldose reductase (ALR2, EC1.1.1.21) is a member of aldo-ketoreductase superfamily, that major causes the development of long-term diabeticcomplications. Several lines of evidence suggested that the primary cause of long-termdiabetic complications is due to the activation of ALR2and resulting imbalance ofNADPH/NADP+and NAD+/NADH coenzymes resulting in oxidative stress inside the cellalong with overproduction of fructose. Thus inhibition of ALR2represents the strategy andan attractive approach to prevent and delay the progression and development of diabeticcomplications. In past years, a number of structurally different aldose reductase inhibitors(ARIs) comprising two chemical classes have been developed but the clinical efficacy andpotency of these compounds still pose a challenge, and most of them have deleterious sideeffects. The first class comprises carboxylic acid ARIs such as, tolrestat, zenarestat andponalrestat, and the second involves cyclic imides like sorbinil, fidarestat, minalrestat andranirestat (AS-3201). Currently, only epalrestat, a carboxylic acid drug is available on themarket and used for the treatment of neuropathy in Japan, India and China. Indeed, whereasthe carboxylic acid ARIs shows potent in vitro activity as aldose reductase inhibitors, theireffectiveness decreases in vivo. In their turn, the cyclic imide ARIs often develops toxicity and exhibits some side effects. Therefore, development of different types of ARIs is stillneeded. A preferred approach to pursue the desired therapeutic and pharmacokineticproperties is to design and synthesize specific non-carboxylic acid and non-cyclic imideARIs. Compounds with scaffolds containing nitro substituents find a wide range ofapplications in biological and pharmaceutical areas, often are involved as prodrug and drugcandidates. The dissertation describes the design and synthesis of several quinoxalinonederivatives along with their biological evaluation as ARIs (aldose reductase inhibitors).First of all, novel quinoxalinone derivatives were synthesized and tested for their inhibitoryactivity against aldose reductase. Among them, N1-acetate derivatives showed significantactivity in a range of IC50values of0.143-7.53μM. The compound2-(2-oxo-3-phenethylquinoxalin-1(2H)-yl) acetic acid (56a) bearing a C3-phenethyl sidechain was identified as the most potent inhibitor with an IC50value of0.143μM. Thestructure-activity studies of56a and2-(3-(4-fluorostyryl)-6-nitro-2-oxoquinoxalin-1(2H)-yl)acetic acid (58) suggested that both C3-phenethyl and C6-NO2groups play an importantrole in enhancing the activity and selectivity of the quinoxalinone based inhibitors.Secondly, continue our further research, a novel and non-acid series of nitroquinoxalinonederivatives was synthesized and tested for their inhibitory activity against aldose reductaseas targeting enzyme. All active nitro-quinoxalinone derivatives displayed an8-nitro group,and showed significant activity in IC50values ranging from1.54to18.17μM. Among them6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (67e), exhibited the strongestaldose reductase activity with an IC50value of1.54μM. The organophosphorouscompounds continue to receive widespread attention due to their pharmacological and biological application and their potential to serve as suitable and novel pharmaceuticals.Thirdly, we have developed the novel derivatives of phosphonates and the2-hydroxy-3-phenyl-2H-benzo[e][1,2]oxaphosphinin-4(3H)-one2-oxide (79) showed23%inhibition at10μM against the aldose reductase.