Synthesis and biological evaluation of novel potential anti-diabetic drugs

Abstract

Glitazones are derivatives of thiazolidine with two carbonyls at 2- and 4-positions. Replacing the thio group with amino group gives rise to hydantoins while replacing carbonyl group at positions 2 with the thio group produces rhodanines. In this study, three class: glitazones, hydantoins and rhodanines were successfully synthesized using known conventional methods and evaluated for their anti-diabetic activity. The structures of synthesized compounds 103a-o, 104a-v and 105a-j were elucidated by a combination of 1H NMR, 13C NMR, HRMS and IR spectroscopic analysis. The project began by utilizing a four-step synthesis of 5-(4-arylidine)-2,4-thiazolidinedione butanoates, valinates and norvalinates 103a-o. The initial synthetic step involved conversion of 1,3-thiazolidine-2,4-dione into its potassium salt, which was then treated with ethyl (2-chloroacetamido) butanoates, valinates and norvalinates, respectively, to obtain the penultimate products. These products were then subjected to a Knoevenagel condensation reaction with different aldehydes to obtain the desired products in low to excellent yields (6-65%). Cytotoxicity results of the synthesized esters 103a-o revealed that only compound 103d and 103h were toxic exhibiting cells lives of 1374.556±168.976 and 1782.722±157.3676 μM respectively. The results of the α-glucosidase inhibitory of the newly synthesized compounds 103a-o indicated that they had no activities at 10, 50 and 100 μM. Only the butanoate 103a (33.38±5.65%), 103d (37.69±0.39%) together with valinate 103f (32.66±4.31%), 103h (29.67±3.09%) and norvalinate 103m (31.83±2.85%) and 103o (51.49 ±5.65%) were found to be moderately active against α-glucosidase at 200 μM. The second part of this study describes the synthesis of 5-(4-benzylidine)-2,4-hydantoin esters 104a-v, which were successfully synthesized over four reaction steps using conventional methods. Their synthesis began by subjecting hydantoin to Knoevenagel condensation reaction conditions with different aldehydes to obtain penultimate products which were further reacted with ethyl or methyl ethyl 2-(2-bromoacetamido) esters in order to obtain the desired products as esters in low to moderate yields (24-63%). In vitro cytotoxicity results of the synthesized intermediates showed that compounds 110c exhibiting 464±78 μM and compound 110d with live cell of 1997±80 μM were found to be toxic. Among the newly synthesized ethyl or methyl esters 104a-v, no α-glucosidase activities was observed at 10, 50 and 100 μM. At the highest concertation of 200 μM, alaninate 104a (51.65±2.92%), valinate (45.23±3.60%) norvalinate (42±76.3.60%) butanoate 104f (52.05±2.83 %), 104g (48.47±2.33%), 104o (57.77±2.79%) and 104p (57.41±6.38%) showed moderate α-glucosidase inhibition. The last part of this study was an attempt to design and synthesize a new series of novel 5-arylidene-2,4-rhodhanine conjugates with improved anti-diabetic biological properties. To this end some fused 5-(4-benzylidine)-2,4-rhodanine esters 105a-j was prepared by known conventional methods from readily available starting materials. The synthesis began by subjecting rhodhanine in Knoevenagel condensation with various aldehydes to obtain 5-(4-arylidne)-2,4-rhodhanines as intermediates. Finally, nucleophilic substitution of 5-(4-arylidne)-2,4-rhodhanines with ethyl 2-(bromoacetamido) esters gave the desired compounds 105a-j in good to excellent yields (52-94%). In vitro cytotoxicity results showed that unsubstituted phenyl 111a, piperonyl 111e, 3-hydro-4-methoxyphenyl 111f and furanyl 111g with live cells of 2716±289, 2372±172, 2464±132 and 2868±132 μM respectively were nontoxic among the synthesized intermediates 111a-g. In vitro toxicity results of the target compounds 105a-j showed that only the para fluorophenyl alaninate 105b exhibiting live cell of 2982±112, para nitrophenyl butanoate 105f with live cell of 2551±158 and para fluoro butanoate 105g exhibiting 2551±186 μM were found to be nontoxic. An in vitro antidiabetic screening results showed that all the synthesized compounds 111a-g and 105a-j were not activity against the α-glucosidase at 10, 50 and 100 μM. Only the unsubstituted phenyl derivative 111a among the synthesized intermediate 111a-g was the most active exhibiting moderate α-glucosidase activity of 50.44±1.31% at 200 μM. With the final synthesized compound 105a-j, para nitrophenyl butanoate 105f was the most active followed by, para fluorophenyl alaninate 105b and para nitrophenyl alaninate 105c, exhibiting α-glucoside inhibition of 51.32±3.62%, 42.88±4.33% and 40.20±1.65% respectively.