Synthesis, characterization and biological activity of some Dithiourea Derivatives:
- Odame, Felix, Hosten, Eric, Krause, Jason, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D, Sayed, Yasien, Frost, Carminita, Lobb, Kevin A, Tshentu, Zenixole
- Authors: Odame, Felix , Hosten, Eric , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, Carminita , Lobb, Kevin A , Tshentu, Zenixole
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163046 , vital:41007 , DOI: 10.17344/acsi.2019.5689
- Description: Novel dithiourea derivatives have been designed as HIV-1 protease inhibitors using Autodock 4.2, synthesized and characterized by spectroscopic methods and microanalysis.
- Full Text:
- Date Issued: 2020
- Authors: Odame, Felix , Hosten, Eric , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, Carminita , Lobb, Kevin A , Tshentu, Zenixole
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163046 , vital:41007 , DOI: 10.17344/acsi.2019.5689
- Description: Novel dithiourea derivatives have been designed as HIV-1 protease inhibitors using Autodock 4.2, synthesized and characterized by spectroscopic methods and microanalysis.
- Full Text:
- Date Issued: 2020
Benzoyl isothiocyanates derived ligands as potential HIV-1 protease inhibitors and their reactions with gold ions
- Authors: Odame, Felix
- Date: 2016
- Subjects: HIV (Viruses) -- Enzymes Enzyme inhibitors -- Research , Pharmaceutical chemistry Biochemistry
- Language: English
- Type: Thesis , Doctoral , DPhil
- Identifier: http://hdl.handle.net/10948/33228 , vital:32585
- Description: The synthesis and evaluation of benzoyl isothiocyanate derivatives as potential HIV-1 protease inhibitors is presented. The ligands were first designed to fit the protease active site using Autodock 4.2. The design was based on the deNOVO method of drug design in which the active site coordinates from the crystal structure of protease bound to ritonavir was used. An attempt to access the scaffolds designed initially led to the formation of 2,2,4-trimethyl 2,3-dihydro-1H-1,5-benzodiazepin-5-ium isophthalate and 2-2-(3-methylphenyl-1Hbenzimidazole which could not be converted to the desired intermediate. A further attempt led to formation of amino acid and amino acid ester derivatives of benzoyl isothiocyanates which have been fully characterized and the reasons why the desired intermediates were not readily accessible explained. Scaffolds based on the benzoyl isothiocyanate derivatives of structurally diverse diamines were then screened. Sixty compounds have been synthesized and fully characterized using elemental analysis, spectroscopy, GC-MS and twenty-six crystal structures have been discussed. The DFT transition state studies of 11-phenyl- 1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (20), N-(1Hbenzimidazol-2-yl)benzamide (21), 3-(1,3-benzothiazol-2-yl)-1-(benzoyl)thiourea (23), and N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (39), have been carried out and their detailed density functional theory reaction mechanism have be computed. The Bernly algorithm was used in the determination of saddle points (transtions states), and the intrinsic reaction coordinates leading to the determination of intermediates were traced and optimized to a global minimum or in some cases a local minimum was obtained. The cell viability tests of diamine derivatives which was done by exposing white blood cells to the compounds (inhibitors) at 37 °C and a pH of 7.4 showed that 1-(4-bromobenzoyl)-3-[2- ({[(4-bromophenyl)formamido]methanethioyl}amino)phenyl]thiourea (46), 1-(3-chloro benzoyl)-3-[2-({[(3-chlorophenyl)formamido]methanethioyl}amino)phenyl]thiourea (48), 1- (3-bromobenzoyl)-3-[2-({[(3-bromophenyl)formamido]methanethioyl}amino)phenyl] thiourea (49) and 3-benzoyl-1-(4-{[(phenylformamido)methanethioyl]amino}butyl)thiourea (54), in that group of compounds were cytotoxic with EC50 values of 17.04 ± 9.75 μM, 69.20± 38.16 μM, 35.90 ± 20.55 μM and 68.37 ± 26.45 μM, respectively. 4-Bromo-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (32), 4-methoxy-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]benzamide (33) and 3-chloro-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (37) were also cytotoxic giving EC50 values of 45.47 ± 21.92, 45.09 ±13.79 and 74.94 ± 13.17 μM, respectively. 3-(1,3-Benzothiazol-2-yl)-1-(3-bromobenzoyl)thiourea (31) and 3-(1,3-benzothiazoyl-2-yl)-1-(4-nitrobenzoyl)thiourea (30) derivatives were also found to be cytotoxic with EC50 values of 1.207 ± 0.58 and 24.08 ±13.14 nM, respectively. 11-(4-Chlorophenyl-1,8,10, 12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (12), 11-(4-methoxyphenyl)-1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,9,1-pentaene-13-thione (14), and 11-phenyl-1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (20), were found to be cytotoxic giving EC50 values of 0.152 ± 0.051, 37.96 ± 21.87 and 5.28 ± 2.95 μM, respectively. In the enzyme inhibition studies compound 49 gave a percentage inhibition of 97.03 ± 10.61% at 100 μM, but the fact that it is cytoxic might make it less useful, whilst compounds 19 and 16 had a percentage inhibition of 59.57 ± 13.59% (4-nitro derivative) and 79.97 ± 11.97% (3-nitro derivative) respectively at 100 μM of inhibitor and 20 μM of enzyme (HIV-1 protease). The results suggests that the presence of the nitro group at position 3 (16) and 4 (19) leads to an increase in activity against HIV-1 protease.
- Full Text:
- Date Issued: 2016
- Authors: Odame, Felix
- Date: 2016
- Subjects: HIV (Viruses) -- Enzymes Enzyme inhibitors -- Research , Pharmaceutical chemistry Biochemistry
- Language: English
- Type: Thesis , Doctoral , DPhil
- Identifier: http://hdl.handle.net/10948/33228 , vital:32585
- Description: The synthesis and evaluation of benzoyl isothiocyanate derivatives as potential HIV-1 protease inhibitors is presented. The ligands were first designed to fit the protease active site using Autodock 4.2. The design was based on the deNOVO method of drug design in which the active site coordinates from the crystal structure of protease bound to ritonavir was used. An attempt to access the scaffolds designed initially led to the formation of 2,2,4-trimethyl 2,3-dihydro-1H-1,5-benzodiazepin-5-ium isophthalate and 2-2-(3-methylphenyl-1Hbenzimidazole which could not be converted to the desired intermediate. A further attempt led to formation of amino acid and amino acid ester derivatives of benzoyl isothiocyanates which have been fully characterized and the reasons why the desired intermediates were not readily accessible explained. Scaffolds based on the benzoyl isothiocyanate derivatives of structurally diverse diamines were then screened. Sixty compounds have been synthesized and fully characterized using elemental analysis, spectroscopy, GC-MS and twenty-six crystal structures have been discussed. The DFT transition state studies of 11-phenyl- 1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (20), N-(1Hbenzimidazol-2-yl)benzamide (21), 3-(1,3-benzothiazol-2-yl)-1-(benzoyl)thiourea (23), and N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (39), have been carried out and their detailed density functional theory reaction mechanism have be computed. The Bernly algorithm was used in the determination of saddle points (transtions states), and the intrinsic reaction coordinates leading to the determination of intermediates were traced and optimized to a global minimum or in some cases a local minimum was obtained. The cell viability tests of diamine derivatives which was done by exposing white blood cells to the compounds (inhibitors) at 37 °C and a pH of 7.4 showed that 1-(4-bromobenzoyl)-3-[2- ({[(4-bromophenyl)formamido]methanethioyl}amino)phenyl]thiourea (46), 1-(3-chloro benzoyl)-3-[2-({[(3-chlorophenyl)formamido]methanethioyl}amino)phenyl]thiourea (48), 1- (3-bromobenzoyl)-3-[2-({[(3-bromophenyl)formamido]methanethioyl}amino)phenyl] thiourea (49) and 3-benzoyl-1-(4-{[(phenylformamido)methanethioyl]amino}butyl)thiourea (54), in that group of compounds were cytotoxic with EC50 values of 17.04 ± 9.75 μM, 69.20± 38.16 μM, 35.90 ± 20.55 μM and 68.37 ± 26.45 μM, respectively. 4-Bromo-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (32), 4-methoxy-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene]benzamide (33) and 3-chloro-N-[(9E)-8,10,17-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-1(17),2,4,6,11(16),12,14-heptaen-9-ylidene] benzamide (37) were also cytotoxic giving EC50 values of 45.47 ± 21.92, 45.09 ±13.79 and 74.94 ± 13.17 μM, respectively. 3-(1,3-Benzothiazol-2-yl)-1-(3-bromobenzoyl)thiourea (31) and 3-(1,3-benzothiazoyl-2-yl)-1-(4-nitrobenzoyl)thiourea (30) derivatives were also found to be cytotoxic with EC50 values of 1.207 ± 0.58 and 24.08 ±13.14 nM, respectively. 11-(4-Chlorophenyl-1,8,10, 12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (12), 11-(4-methoxyphenyl)-1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,9,1-pentaene-13-thione (14), and 11-phenyl-1,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-2(7),3,5,9,11-pentaene-13-thione (20), were found to be cytotoxic giving EC50 values of 0.152 ± 0.051, 37.96 ± 21.87 and 5.28 ± 2.95 μM, respectively. In the enzyme inhibition studies compound 49 gave a percentage inhibition of 97.03 ± 10.61% at 100 μM, but the fact that it is cytoxic might make it less useful, whilst compounds 19 and 16 had a percentage inhibition of 59.57 ± 13.59% (4-nitro derivative) and 79.97 ± 11.97% (3-nitro derivative) respectively at 100 μM of inhibitor and 20 μM of enzyme (HIV-1 protease). The results suggests that the presence of the nitro group at position 3 (16) and 4 (19) leads to an increase in activity against HIV-1 protease.
- Full Text:
- Date Issued: 2016
A New Synthetic Method for Tetraazatricyclic Derivatives and Evaluation of Their Biological Properties
- Odame, Felix, Betz, Richard, Hosten, Eric C, Krause, Jason, Isaacs, Michelle, Hoppe, Heinrich C, Khanye, Setshaba D, Sayed, Yasien, Frost, P Carminita, Lobb, Kevin A, Tshentu, Zenixole
- Authors: Odame, Felix , Betz, Richard , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, P Carminita , Lobb, Kevin A , Tshentu, Zenixole
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123189 , vital:35413 , https://doi.org/10.1002/slct.201802930
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2018
- Authors: Odame, Felix , Betz, Richard , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, P Carminita , Lobb, Kevin A , Tshentu, Zenixole
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123189 , vital:35413 , https://doi.org/10.1002/slct.201802930
- Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
- Full Text:
- Date Issued: 2018
- «
- ‹
- 1
- ›
- »