Faculty of Applied Sciences
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Item Synthesis, characterization and antimicrobial evaluation of piperazinyl-quinolinyl-a-aminophosphonates(2019) Rajkoomar, Nikisha; Gengan, Robert Moonsamyα-Aminophosphonates (α-APs) is an important motif among heterocycles particularly in medicinal chemistry due to their reduced levels of cytotoxicity and structural resemblance to the corresponding α-amino acids. They are useful intermediates in synthetic organic processes and present with a broad spectrum of biological activities. Hence, there is an ongoing interest in the development of improved synthetic methods for the preparation of these α-APs. The complex molecules were initially synthesized in a step-wise reaction but this method suffered several drawbacks such as long reaction times and resulted in low yields. However, since the development of multi-component reactions (MCRs), three or more substrates can undergo an efficient one-pot reaction which results in higher product yields. The first step in the synthetic aspect of this study involved the preparation of a novel palladium supported strontium titanate (Pd-SrTiO3) material. Herein, an aqueous solution of strontium (II) nitrate was mixed with citric acid followed by reflux in an ethanolic solution of titanium (IV) butoxide. Thereafter, the dried solid was mixed with palladium (II) nitrate and this solution mixture was refluxed, filtered, calcined and subsequently dried. The characterization of Pd- SrTiO3 was undertaken with FT-IR, P-XRD, SEM, BET, SEM-EDX and Raman spectroscopic techniques. The synthesis of a series of novel -αAPs in a MCR system comprising an aldehyde, diethyl phosphate and selected aniline derivatives via the Kabachnik Fields reaction approach in the presence of catalytic amounts of Pd-SrTiO3 was investigated Twenty methyl piperazinyl-quinolinyl α-aminophosphonates (MPQ-α-APs) (4a-4t) were synthesized, purified and characterized by FT-IR, 1H-NMR, 13C-NMR, 31P-NMR, 2D-NMR and high resolution mass spectroscopic techniques. Valuable features of this routine included high yields, extensive substrate range, straight forward procedures and excellent catalytic properties. The cytotoxicity of 4d, 4e, 4f, 4m, 4q, 4r and 4s was evaluated using the Brine shrimp lethality assay. These compounds showed Artemia salina death < 50 % thereby suggesting their potential for other biological evaluation. The antimicrobial evaluation was conducted using the agar disc diffusion assay. The twenty MPQ-α-APs were assessed against Bacillus cereus , Staphylococcus aureus , Klebsiella pneumonia and Micrococcus luteus ; and three yeast cultures Candida albicans, Caraipa utilis and Saccharomyces cerevisiae. Compound 4m showed slight bacterial growth inhibition for the test species Bacillus cereus and Micrococcus luteus while compound 4r was marginally inhibitory to the growth of Staphylococcus aureus. Finally, the MPQ-α-APs were screened for their antioxidant activity by the DPPH assay. Compounds 4f and 4r demonstrated significant free radical scavenging potential of 94.24 % and 67.32 %, respectively. The remaining compounds showed low antioxidant activity within the range of 21 – 42 %.Item Synthesis, characterisation and biological activity of selected pyrazoles and naphthyrides(2019) Makhanya, Talent Raymond; Gengan, Robert MoonsamyThe world continue to be threaten by various diseases from viruses, fungi and bacteria that cannot be cured. This arises due to the emergency of multidrug resistance in microorganisms hence current available drugs are becoming less potent. The solution to overcome this predicament is to further synthesize novel heterocyclic compounds which can display good therapeutic properties. Hence, this study focuses on the synthesis, characterization and biological evaluation of selected novel naphthyridinones, naphthyridines and pyrazoles. A total of 53 novel compounds were prepared by using multi-component reactions (MCRs), Povarov’s [4+2] and Povarov’s [3+2] reactions. The MCR was used for a solvent free synthesis of eight novel [1, 8] naphthyridinones from a mixture of 2-aminopicoline, various benzaldehyde derivatives and dimedone. A conventional heating protocol was used whilst the reaction was catalysed by phosphotungstic acid. The compounds were identified as 4, 8, 8-trimethyl-5- phenyl-5, 5a, 8, 9-tetrahydrobenzo[b] [1, 8] naphthyridin-6(7H)-ones with the aid of spectroscopic techniques, viz., FT-IR, NMR, EI- MS and elemental analysis. These eight compounds were screened for their anticancer activity against A549 lung cancer cells. Cell viability assays showed these compounds have a biological effect at various concentrations. Two compounds showed that good potential as an anti-proliferative agent and exhibited a dose- dependent decline in cell viability which was seen. The Povarov’s [4+2] cycloaddition reaction was used to synthesize nine novel fused indolo [1, 8] naphthyridines. Indole was used as the dienophile whilst N-aryl aldimines were selected as the diene which were produced by reacting 2-amino-4-picoline and benzaldehyde. The reaction was catalysed by indium chloride to produce 1-methyl-6-phenyl-6,6a,7,11b-tetrahydro-5H-indolo[3,2-c][1,8]naphthyridine which was characterized by FT-IR, NMR, TOF-MS and elemental analysis. Furthermore, all synthesized compounds were screened for their antimicrobial activity. The results of the bioassay demonstrated that some fused indolo [1, 8] naphthyridines exhibited good inhibitory effect with an MIC value ranging from 0.04687 to 0.09375 µM against Bacillus cereus and Staphylococcus aureus. The toxicity of the synthesized compounds were evaluated through mutagenicity test against Salmonella typhimurium TA 98 and TA100 strains. All compounds showed no mutagenic effects against Salmonella tyhphimurium TA 98 and TA 100 strains. The Povarov’s [3+2] cycloaddition was used to synthesize twenty six novel fused indolo pyrazole in the presence of a catalytic amount of indium chloride. The compounds were identified as 3- phenyl-2, 3-dihydropyrazolo [3, 4-b] indole-1(4H)-carbothioamides with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. These compounds showed good activity against Candida albicans, Candida utilis, and Saccharomyces cerevisiae with MIC of 1.5; 1.1 and 0.375 µM respectively. In addition, all the compounds showed no mutagenic activity against Salmonella tyhphimurium TA 98 and TA100 strains. The scope of the Povarov’s [3+2] reaction was further investigated using isoniazid to synthesise ten novel nicotinyl fused indolo pyrazoles in the presence of a catalytic amount of indium chloride. These compounds were identified as (3-phenyl-2,3- dihydropyrazolo[3,4-b]indol-1(4H)-yl)(pyridin-4-yl)methanone with the aid of spectroscopic techniques such as FT-IR, NMR and TOF-MS. All compounds were screened for their antimicrobial activity against various strains of pathogenic bacteria and fungi. The synthesized compounds showed weak activity against Streptococcus faecalis, Micrococcus luteus and Bacillus coagullans with a zone inhibition diameter of 9 mm and MIC of 0.75 µM. Furthermore, all synthesized compounds were tested for their toxicity against Salmonella tyhphimurium TA 98 and TA100 strains: none showed mutagenic activity.Item Synthesis, characterization and biological activities of hererocycles : peptides, O, N, and S based small molecules(2018) Thangaraj, Muthu; Gengan, Robert MoonsamyThis study is based on the synthesis and characterization of quinoline based peptides and heterocycles containing oxygen, nitrogen and sulfur atoms by using new catalysts. In addition, the biological activities of the novel small molecules is evaluated. A total of 71 small molecules were prepared by using multi-component reactions including Ugi and Kabachnik-Fields reaction. The Ugi four-component reaction was implemented for the synthesis of medicinally important 13 new quinolinyl-lipoyl peptides (QLPs) and one quinolonyl-lipoyl peptide (QOLP) by microwave irradiation using methanol as medium. A series of 12 new quinolinyl-4H-pyrans (QPs), two quinolonyl-4H-pyrans (QOPs) and one indolyl-4H-pyran (IP) were successfully synthesized via a three-component reaction using ethanol as solvent in the presence of a new catalyst: humic acid supported 1-butyl- 3-methylimidazolium thiocyanate ionic liquid catalyst (HASIL) under microwave irradiation. By using Kabachnik-Fields reaction, a total of 14 novel α-aminobenzylthio- quinolinyl phosphonates (BTQPs) were synthesized in the presence of a catalytic amount of iron-loaded boron nitride (Fe/BN) catalyst by using water as medium. A series of 14 novel benzylthioquinolinyl-1,4-dihydropyridines (BTQ-DHPs) were synthesized with high yields in short reaction time by a four-component reaction in the presence of iodine- loaded boron nitride (I/BN) catalyst by using water as solvent. A total of 14 derivatives of 2-amino-4H-pyran-3-carbonitrile derivatives (APCs) were prepared by using calcium loaded boron nitride (Ca/BN) in ethanol as solvent. This transformation transpired via a Knoevenagel condensation, Michael addition and intra-molecular cyclization. The prepared catalysts: HASIL, Fe/BN, I/BN and Ca/BN were characterized by XRD, SEM with EDX, TEM, DSC, TGA, BET, Raman spectra and FTIR analysis. All the synthesized molecules (QLPs, QOLP, QPs, QOPs, IP, BTQPs, BTQ-DHPs and APCs) were confirmed by FTIR, 1H-NMR, 13C-NMR and elemental analysis. Moreover, 19F- NMR, 31P-NMR and TOF-MS analysis were included for some selected compounds. In every chapter, one model compound was selected and discussed with two-dimensional spectra such as HSQC, DEPT 90º, DEPT 135º (selected), COSY, NOESY and HMBC. Among the synthesized compounds, a total of 48 compounds (8 QLPs, 15 (QPs, QOPs and IP), 10 BTQPs, 10 BTQ-DHPs and 5 APCs) were subjected to antimicrobial activities with Bacillus cereus, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Candida albicans and Candida utilis and antioxidant studies were observed by the radical scavenging assay. The toxicity studies were evaluated using the brine shrimp assay and the mortality rate was noted. Among them, 4 peptides, 7 pyrans, 8 aminophosphonates, 7 dihydropyridines and 5 carbonitriles showed good antimicrobial activity whilst 3 peptides, 9 pyrans, 6 aminophosphonates and 4 dihydropyridines showed antioxidant potential. Also, 4 peptides, 5 pyrans, 8 aminophosphonates and 5 dihdyropyridines showed mortality rate less than 50 % upto 48 h. The molecular docking studies were performed by Libdock score with DNA gyrase, Mtb gyrase and Staphylococcus aureus gyrase. A docking score of 183.24 kcal/mol and 165.01 kcal/mol were recorded for 2 peptides compared to ciprofloxacin. Among quinolinyl pyrans, one QP showed higher binding affinity of 96.96 kcal/mol with Mtb DNA gyrase. One BTQP showed more potency towards Staphylococcus aureus gyrase with 149.97 kcal/mol and one BTQ-DHP showed a strong ligand-protein interaction toward Staphylococcus aureus gyrase with Libdock score of 125.27 kcal/mol. The advantages of the synthetic methodology of this project are its green approach, easy work up, mild reaction conditions, the use of an inexpensive solvent, short reaction times with higher yields and recyclability of the catalyst.Item Synthesis of nitrogen heterocycles and chalcones using multi-component reactions : a spectral and protein binding investigation(2018) Murugesan, Arul; Gengan, Robert MoonsamyChemicals were purchased from Merck, Sigma Aldrich. The reaction/purity of the product was monitored and accomplished by TLC. FT-IR spectra were recorded in the range of 4000-400 cm-1 on a JASCO FT/IR-460 spectrophotometer using KBr pellets. A Bruker D2 PHASER powder diffraction instrument; Cu Kα ray (wavelength λ = 0.154056 nm), was used to measure in a continuous step-scan mode: the minimum width of the stage 0.031°, equilibrium time of 256 seconds, the operating voltage to 30 kV with 10 mA. Scanning electron microscopy (Joel JSM 7600 F) was employed to characterize the morphology. High Resolution-Transmission Electron Spectroscopy was used. The BET gas sorption isotherms were measured 77 K for N2, H2, and 273 and 298 K for CO2 using Micromeritics Auto pore 9500 system. Before recording gas sorption measurements, the sample was initially dehydrated at 423 K for 24 h under vacuum. Raman Spectroscopy was measured using the detector CCD (Triaxle) and the laser (He-Ne laser 632.8 nm). A TOF-MS analyser for accurate mass measurement was used. The melting point (mp) was recorded on a Buchi B-545 apparatus using open capillary tubes. NMR spectra were recorded in CDCl3 / DMSO-d6 on a Bruker Advance 400 MHz and 600 MHz instrument using tetramethylsilane as internal standard. In general for all compounds CDCl3 is used as a solvent, where DMSO-d6 has been used, it is mentioned in the experimental part. The chemical shifts were expressed in ppm. The following abbreviations are used in the NMR spectral data. s - Singlet d - Doublet t - Triplet q - Quartet m - Multiplet dd - doublet of doublet brs - broad singlet J - Coupling constantItem Pharmacological screening of synthetic piperidine derivatives(2016) Naicker, Leeantha; Odhav, Bharti; Venugopala, Katharigatta NarayanaswamyPiperidine derivatives are essential heterocyclic compounds that have beneficial roles in the medical and commercial sector. They can be isolated from plant material and can be chemically synthesised using simple cost efficient methods. Piperidines and their derivatives are clinically used to prevent postoperative vomiting, facilitate radiological evaluation, correct gastrointestinal function as well as speed up gastric emptying before anaesthesia. Piperidine derivatives also demonstrate a wide spectrum of biological activities which include; antimicrobial, anticancer, anti- TB, anti-HIV, anti-inflammatory, analgesic, anti-influenza, anti-inflammatory and antitumor activity. The properties of piperidine derivatives depend on the nature of the side chains and their orientation. Based on the promising data that demonstrated the synergistic effects of biological agents with piperidine derivatives, the aim of our research is to determine the pharmacological activities, i.e. (i) antimicrobial activity, (ii) anti-inflammatory, (iii) anti-oxidant activity, (iv) cytotoxicity, and (v) biosafety of six piperidine derivatives, PM1 to PM6. All six piperidine derivatives (PM1-PM6) screened for antimicrobial activity exhibit characteristics of varying degrees of microbial inhibition against some Gram-positive and Gram-negative bacteria (B. cereus, B. subtilis, E. coli, S. aureus, Kl. Pneumonia, M. liuteus and P. aurenginosa) with the exception of B. polymixa, S. marcescens and S. faecalis. Certain piperidine derivatives did not demonstrate high inhibition activity towards the fungal strains, with inhibition only shown against four fungal species; A. niger, A. flavus, C. albicans and S. cerevisiae. Thus it is proposed that minor changes could be made to the structure of the compounds so that they can alter the effect that the compounds have on the specific fungi strains. With regard to antioxidant activity it is noted that the concentrations of the test compounds are directly proportional to the percentage of scavenging capacity. In comparison of the piperidine derivatives (PM1-PM6) to Rutin (reference standard), it was illustrated that Rutin displayed the best antioxidant activity. All six piperidine derivatives (PM1-PM6) showed greater than 50% anti-inflammatory activity, whilst the anti-inflammatory reference standard NCGA displayed the greatest activity in comparison to the piperidine derivatives tested. The safety of the piperidine derivatives was tested by assaying cytotoxicity, against melanoma, MCF7 cancer cells and normal fibroblasts as well as Brine shrimp lethality assay. All piperidine derivatives demonstrated high cytotoxicity activity against both cancer cell lines (melanoma and MCF7) and around 50 – 52% cytotoxicity against healthy cells. Chloro substitution of the phenyl ring increases cytotoxicity of compounds (Aerluri et al., 2012). This compound can be used in the treatment of cancer cells while inhibiting 50% of normal cells. All six piperidine derivatives (PM1-PM6) were also tested for toxicity against Artemia salina in a brine shrimp lethality assay. Piperidine derivatives exhibited varying degree of toxic activity towards the shrimp, with all derivatives displaying ± 50% toxic activity at 1000 µg/mL. These results reveal a directly proportional relationship between concentration of drug and toxicity. It remains a future research objective to modify these piperidine compounds (PM1-PM6) chemically to produce more derivatives for further biological evaluation. All the studied piperidine compounds have possible leads for optimization to carry out pre-clinical trials. We can conclude that the substitution of different side chains on the piperidine nucleus results in varying degree of pharmacological activity. Also, compounds containing the substitution of a chloro group at position 4 and a fluoro group at position 2 on the phenyl ring attached to carbon 2 and 6 on the piperidine nucleus resulted in high pharmacological activity. This good pharmacological activity was also exhibited by compounds containing substitutions of a methoxy group at position 3 on the phenyl ring attached to carbon 1 and 6 on the piperidine nucleus. Compounds containing a methoxy group positioned at carbon 4 on the phenyl ring which is attached to carbon 1 and 4 on the piperidine nuleus presented low pharmacological activity. Low activity was also exhibited by compounds containing substitution of a cyano group at position 4 on the phenyl ring which is attached to carbon 2 and 6 on the piperidine ring and a methyl group at position 4 on the phenyl group attached to a nitrogen at position 1 on the piperidine nucleus.Item Biological activities of synthetic coumarin derivatives(2016) Kasumbwe, Kabange; Odhav, Bharti; Venugopala, Katharigatta Narayanaswamy; Mohanlall, VireshCoumarins are naturally occurring α-benzopyrone derivatives known for their pharmacological properties such as anticoagulant, antimicrobial, anticancer, antioxidant, anti-inflammatory and antiviral properties. The pharmacological, biochemical, and curative applications of coumarins depend on the substitution around the coumarin core structure. In the present study, seven halogenated coumarins CMRN1 - CMRN7 were synthesized and evaluated for mosquito larvicidal, repellancy , and insecticidal activity against Anopheles arabiensis. Furthermore, the antimicrobial properties of compounds CMRN1 - CMRN7 were evaluated by assessing the bacterial and fungicidal activities using the disc diffusion method. The anti-inflammatory properties were evaluated using the 5-lipoxygenase kit assay. The evaluation of the safe use of the compounds was determined using the Brine shrimp lethal test. The potential carcinogenic properties of the studied compounds was done using the Salmonella mutagenicity test. The anti-cancer property of the studied compounds was evaluated against UACC62 (Melanoma), MCF-7 (Breast cancer), and PBMC (Peripheral blood mononuclear) cell lines using of MTT assay. The apoptotic potential of the synthesized coumarin was evaluated against UACC62 (Melanoma) cell by assessing their morphological changes, membrane change, mitochondria membrane potential, and caspase-3 activity using the Annexin V-PI staining, JC-1, caspase-3 enzyme kits, respectively, on flow cytometer. The results were compared to a known anti-cancer drug, doxorubicin. The results showed that compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 exerted 100% larval mortality within 24 h of exposure. All halogenated coumarins reversibly knocked down adult mosquitoes but did not kill them after 24 h of exposure. Furthermore, the adulticidal activity of the compounds was considered only mild to moderate. The antimicrobial activity of the synthetized coumarins CMRN1 - CMRN7 were assessed against E. coli, K. pneumoniae, S. marcescens, S. faecalis, B. cereus, B. coagulans, B. stearothermophilus, C. freundii, S. aureus and M. luteus bacteria and three yeast cultures, C. albicans, C. utilis, S. cerevisiae as well as two fungal species, A. flavus and A. niger. Compounds CMRN1 and CMRN2 showed bacterial growth inhibition for all the tested species except K. pneumonia and B. stearothermophilus. Compounds CMRN4 and CMRN7 showed moderate bacterial inhibition against B. cereus, M. luteus and S. aureus. The anti-inflammatory activity of the coumarins analogues showed that 1 mg/mL of the compounds CMRN1, CMRN2, CMRN4 and CMRN5 displayed moderate anti-inflammatory activity when compared to the positive control, 15-lapoxygenase. The cytotoxicity results of the studied synthetized coumarins displayed selective activity towards the cancer cell lines used in this study. Our studies showed that CMRN1, CMRN2, CMRN4, and CMRN5 had significant cytotoxity effect against UACC-62 (Melanoma) and MCF-7 ( Breast) cancer cells with an inhibitory concentration (IC50) which displayed significant cytotoxicity effect, in particular CMRN4 and CMRN5. These compounds CMRN1- CMRN7 showed no toxicity effect against PBMCs cell line. The mechanism of cell death, that is, necrosis or apoptosis induced by the coumarins was investigated against UACC-62 (Melanoma). We found that CMRN1, CMRN2, CMRN4, CMRN5 induced morphological changes, characteristic of apoptosis . Annexin V kit showed that CMRN1, CMRN2 and CMRN5 showed early apopotosis and late apoptosis was particularly higher for compound CMRN4. The disruption of the mitochondria membrane was noticed to be greater in CMRN1 and CMRN5 when compared to the positive control doxorubicin. Compound CMRN4 produced high levels of caspase-3 positive compared to the control. The coumarin compounds showed no mutagenicity and were also found to be non-toxic to brine shrimps. In conclusion, compounds CMRN1, CMRN2, CMRN4, CMRN5 and CMRN7 are potential larvicidal agents because they exhibited close to 100% activity within 24 h. Furthermore, the anti-cancer efficiency of compounds CMRN1, CMRN2, CMRN4, and CMRN5, is enough qualification for them to be optimized for increase anticancer potency.