Surya, P R (2016) Design, Synthesis, Characterization and Biological Evaluation of Novel Heterocyclic Derivatives as Anti-Tubuercular Agents. Doctoral thesis, The Tamilnadu Dr.M.G.R. Medical University, Chennai.
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Abstract
Thirty five molecules (C, F. GVA, HLA, M4F, Q, X, Y, U, NA, ATRIM, KSBA, HTPC, JA, IAF, B1B2, AFDC, PW, 2UTHIOU, 2ATHIO, 2UUREA, 2CUREA, 2CTHIOU, 2IAF UREA, RG 6, RG 7, SOS1, SOS2, NHD 1, NHD2, NHD4, INHAF and INHAP, CSP, 3rd PDT) etc. which were predicted to be effective against mycobacterium tuberculosis were selected for the synthesis through computational studies. This was achieved by the molecular docking studies against the target enzyme FabD (PDB id - 2QC3) of mycobacterium tuberculosis, insilico ADME assessment and insilico toxicity predictions. The 35 molecules which were selected for the synthesis belong to the following functional class. • “Chalcones” comprising [(furan-2-yl) moiety or (4-hydroxy phenyl) moiety], • “3, 4-dihydropyrimidine-2(1H)-thione” OR “3,4-dihydropyrimidine-2(1H)-one”, • “Thiazolo pyrimidin-3(5H)-one” OR “Oxazolo Pyrimidin-3(5H)-one”, • “2, 4, 6 triaryl-1H-imidazole”, (RG series), • “Pyridine-4-Carbohydrazide” (INH derivatives), • “Oxadiazole”(SOS derivatives), • “Pyrazolines” (TSP series), • “IsoNicotinoHydrazide” (NHD derivatives), • “Chalcones” comprising of C, F. GVA, HLA, M4F, Q, X, Y, U, NA, ATRIM, KSBA, HTPC, JA, IAF, B1B2, AFDC, PW. • 3, 4-dihydropyrimidine-2(1H)-thione” OR “3,4-dihydropyrimidine- 2(1H)-one comprising of (2A THIO, 2C THIO, 2U THIO, 2IAF UREA, 2U UREA, 2C UREA). • thiazolo pyrimidin-3(5H)-one” OR “Oxazolo Pyrimidin-3(5H)-one comprising of (3RD PRODUCT). • 2, 4, 6 triaryl-1H-imidazole”, (RG series) comprising of (RG6, RG7). • Pyridine-4-Carbohydrazide” (INH derivatives) comprising of (INHAF, INHAP). • Oxadiazole”(SOS derivatives) comprising of (SOS 1, SOS 2). • Pyrazolines” TSP series- comprising of (CSP). • IsoNicotinoHydrazide” (NHD derivatives) comprising of NHD1, NHD2, NHD4. • All the 35 molecules were synthesized. The synthesized compounds were purified and characterized. The synthesized compounds were characterized by “FT-IR, 1HNMR, 13C NMR, Mass spectra and chemical analysis”. The relative stereo chemistry of one compound was confirmed by the X-ray Crystallography. • The physical characteristics and spectral studies like “FT-IR, 1HNMR, 13C NMR, MASS spectra and elemental anayisis” confirmed the proposed structure of the synthesized compounds. • All the synthesized compounds were investigated for their in-vitro anti-tubercular potential using Microplate Alamar Blue Assay, (MABA). All the compounds showed moderate to potent in-vitro activity against MTB with MIC range 0.1-50μg/ml concentrations. Compounds HLA, M4F and ATRIM exhibited most potent in-vitro activity with MICs 0.1, 0.2, 1.6 μg/ml concentrations respectively. • In order to rationalize the correlation between the in-vitro antitubercular activity results with the docking results, a cross observational analysis was performed. The top ranked 3 compounds. • HLA, M4F and ATRIM, of in-vitro anti-tubercular activity were cross observed against docking score and selected for in-vivo study. • The compounds showing in-vitro inhibitory activity below 12.5μg/ml concentrations against Mycobacterium tuberculosis were subjected for the acute oral toxicity studies. The selected compounds codes were GVA, C, F, HLA, M4F, ATRIM, Q, U, X, Y, KSBA, PW, JA, HTPC, AFDC, RG6, SOSI, INHAF, NHD 1, NHD2, and NHD4. No signs of toxicity were noticed at the dose of 300mg/kg body weight to the group of animals were recorded. Thus the study suggests that the LD50value of the selected compounds were expected to exceed 300mg/kg b.w and was represented as class 4 (300mg/kg<LD<2000MG/KG) according to Globally Harmonized Classification System (GHS). • The three compounds (HLA, M4F and ATRIM) which exhibited effective inhibition of Mycobacterium tuberculosis in in-vitro antitubercular activity were studied for their invivo potential using Balb/c mouse model for colony forming units (CFU) and Mortality. It was found that compound ATRIM was active in-vivo anti-mycobacterial assay, when compared to the other synthesized tested compounds. It was also interesting to notice that the compound ATRIM decreased the bacterial load to 38.0±4.0 at 15 mg/kg dose, while standard drug isoniazid decreased the bacterial load to 16.7±2.5 at same 15 mg/kg dose. Thus the study concludes that, the CFU value obtained by the compound ATRIM, at the dose of 15 mg/kg was found to be significant when compared to standard drug isoniazid at same dose. CONCLUSION: In the present work, simple and efficient practical methods for the synthesis of heterocyclics, which resulted from the in-silico approach was achieved in good yield. • Chalcone derivatives of (furan-2yl)-3 derivatives, ie. Compounds HLA, M4F and ATRIM showed most potent inhibition in in-vitro anti-tubercular activity at MIC 0.1, 0.1, 0.2 and 1.6 μg/ml concentrations. • In-vivo acute toxicity studies and in-silico ADME predictions reports suggest the lead compounds HLA, M4F and ATRIM can be taken up for further studies. • It was found that lead compound ATRIM was active in in-vivo antimycobacterial assay, when compared to the other synthesized tested compounds. • The three methoxy group of ATRIM may be responsible to contribute for the better in-vivo activity results. • The compound ATRIM is having 100% Oral absorption is as compared to other synthesized compounds HLA and M4F, which may give better invivo Anti-tb activity. • ATRIM follows the rule of five with human serum albumin binding value (0.215) which is less as compared to HLA and M4F(02.34 and 0.248 respectively). • It was interesting to note that the compound ATRIM decreased the bacterial load to 38.0±4.0 at 15 mg/kg dose, while standard drug isoniazid decreased the bacterial load to 16.7±2.5 at same dose. Thus the study deserves for the conclusion that the CFU value obtained by compound ATRIM at the dose of 15mg/kg was found to be significant when compared to the standard drug isoniazid at same dose. • It was also concluded that, on increasing the dose of compound ATRIM, it may produce more or equal significant results compared to the standard drug isoniazid. • The above results findings have demonstrated that, the compound “ATRIM” with IUPAC name (2E)-1-(furan-2-yl)-3-(3, 4, 5-trimethoxyphenyl) prop-2-en-1-one is possibly a good antitb agent.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Additional Information: | 33447-1/2012 |
| Uncontrolled Keywords: | Design, Synthesis, Characterization, Biological Evaluation, Novel Heterocyclic Derivatives, Anti-Tubuercular Agents. |
| Subjects: | PHARMACY > Pharmaceutics |
| Depositing User: | Subramani R |
| Date Deposited: | 01 Jan 2019 13:21 |
| Last Modified: | 15 Oct 2022 03:46 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/10288 |
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