Department of Chemistry
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Browsing Department of Chemistry by Author "Bvumbi, M. V."
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Item Open Access Synthesis and biological evaluation of novel potential anti-diabetic drugs(2022-11-10) Tshiluka, Ndivhuwo Raymond; Mnyakeni-Moleele, S. S.; Bvumbi, M. V.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.Item Embargo Synthesis of novel 2-thiohydantoin derivatives as potential anti-diabetic drugs(2024-09-06) Tshishonga, Unarine; Mnyakeni-Moleele, S. S.; Bvumbi, M. V.Thiohydantoin is a hydantoin with one carbonyl group replaced with a thiocarbonyl group. In this study five series (glycinates, alaninates, butanoates, vallinates and norvalinates) of thiohydantoin derivatives (21a-v) were successfully synthesized and characterized using known analytical characterization techniques. The synthesis of these compounds followed four reaction steps using conventional methods from step one with nucleophilic substitution to Knoevenagel condensation reaction as the final step. All twenty two compounds were obtained in good to excellent yields and were subjected to in vitro screening for their inhibitory activity against α-glucosidase. Among the five series of thiohydantoin derivatives, the alaninate derivative 21f exhibited the highest inhibition at both concentrations of 65 μM and 130 μM, with values of 71.13±0.61 and 64.20±0.54, respectively. The glycinate derivative 21j exhibited the highest inhibition of 60.95±1.07 at 130 μM, while butanoate derivatives showed a consistant moderate inhibition. Only compound 21z exhibited concentration-dependent trends of moderate inhibition on the norvallinates derivatives and the vallinates exhibited negligible inhibition.Item Embargo Synthesis of sulfonylthioureas containing two carbon linker as potential antidiabetic drugs(2024-09-06) Mbhokazi, Tiyisela Nyeleti; Mnyakeni-Moleele, S. S.; Bvumbi, M. V.Target compounds (18a-s) from the series (morpholine, piperidine, N-methylaniline, 2,6-dimethylaniline and diethylamine) of novel sulfonylthioureas were designed and synthesized over three reaction steps using different appropriate synthetic methods. Nucleophilic substitutions were employed in order to incorporate amines, three different carbon linkers between amines and sulfonylthioureas moiety. Furthermore, nucleophilic substitution reaction was used to incorporate appropriate substituted isothiocynates as the final main step. Compounds (18a-s) were obtained in good to excellent yields and were characterized using a combination of 1H NMR, 13C NMR, IR and HRMS analysis. Compounds (18a-s) were evaluated for their antidiabetic activity against α-glucosidase and α-amylase. The in vitro screening results showed that most compounds had little to moderate activity against α-amylase at the concentrations of 60μM, 120μM and 240μM. When compounds were tested against α-glucosidase, they showed little to moderate antidiabetic activity at the concentrations of 60μM and 120μM but exhibited significant anti-diabetic activities at 240μM. Compounds that have a phenyl group substituent (18j, 18m, 18q, 18r and 18s with inhibition 70.21±5.97, 78±3.03, 76.33±2.03, 69.55±4.11 and 84.67±3.34 respectively at 240 μM) and a methyl group substituent (18q-s) exhibited stronger inhibition activity.Item Embargo Synthesis, photoisomerization and antimalarial activities of cinnamoyl chloroquinoline hybrids(2024-09-06) Nemudzivhadi, Anza Imanuel; Bvumbi, M. V.; Mnyakeni-Moleele, S. S.The primary aim of this project was to synthesize a series of cinnamoyl chloroquinoline hybrids employing a technique of molecular hybridization. Cinnamoyl chloroquinoline hybrids are compounds with the heteroaromatic core of amino-7-chloroquinoline, linked to differently substituted cinnamic acid groups by flexible primary diamines. In this study, three series (n=2, 3 and 6) of nineteen cinnamoyl chloroquinoline hybrids 18-36 were successfully synthesized by modifying known conventional methods with yields ranging from 24-74%. The structures of synthesized compounds were characterized by a combination of 1H NMR, 13C NMR, HRMS and IR analysis. Hybrids 18-36 were found to isomerize when exposed to light to form mixture of cis and trans isomers. Through chromatographic mass spectrometry (LC-MS), these isomers were studied and LC-Q-TOF-MS/MS analyses of the photo-products revealed the emergence of cis isomer which eluted before its synthesized trans counterpart, suggesting a reduced polarity. The polarity of the compounds was significantly influenced by the nature of the substituents attached to the phenyl ring. Electron-withdrawing groups such as Cl, NO2, and F increased polarity in contrast to electron donating group OCH3 which reduced polarity. The concept of photoisomerization of cinnamoyl chloroquinoline hybridswere validated by the measurement of the transformation of trans to cis isomers using 1H NMR. Compounds 18-36 were tested against wild-type drug-sensitive strain (NF54) and multidrug-resistant isolate (K1) of the human malaria parasite Plasmodium falciparum. Compounds with longer alkyl carbon chain linkers demonstrated greater antiplasmodial activity compared to those with shorter chain linkers. The in vitro studies revealed that compound 32 showed the most potent activity (in vitro 50% inhibitory concentration, 0,012 μM for strain NF54 and 0,009 μM for strain K1 and resistance index of 0.717 as a potential antimalarial agent. Other compounds (compounds 34 and 35) also showed moderate activity against a CQ-sensitive strain (NF54) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum.