Browsing by Author "Udayakumar, D."

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A novel and ultrasensitive high-surface porous carbon-based electrochemical biosensor for early detection of dengue virus
(Elsevier Ltd, 2024) Hegde, S.S.; Naik, S.; Badekai Ramachandra, B.R.; Mishra, P.; Udayakumar, D.; Ahmed, M.U.; Santos, G.N.
Dengue fever, a mosquito-borne viral infection, poses a significant global health threat, and early diagnosis is crucial for effective disease management. The utilization of advanced materials in the design ensures an improved surface area, facilitating a heightened interaction between the sensor and the target. In this study, the incorporation of biomass-derived high-surface porous carbon-based materials not only contributed to the sensor's sensitivity but also ensured a cost-effective and scalable manufacturing process. The electrochemical nature of the biosensor added a layer of precision to the detection process and offered a reliable, rapid method for identifying the infection of the dengue virus. The enhanced sensitivity of the biosensor allowed the detection of even trace amounts of the NS1 protein, enabling early diagnosis in the initial stages of dengue infection. The system exhibited a high sensitivity with a wide linear range between 1 pg/mL and 100 μg/mL, and the extremely low detection limit of 0.665 pg/mL ranks this as one of the most efficient biosensors for the detection of dengue virus NS1 protein. Selectivity studies, coupled with computational insights, showcased the biosensor's prowess in distinguishing NS1 protein from potential interfering substances, laying the foundation for reliable diagnostics in complex biological matrices. Real sample analysis using human serum spiked with NS1 protein offers a tantalizing glimpse into the transformative potential of biosensors in real-world scenarios. This innovative biosensor holds great promise for addressing the pressing need for early detection of dengue virus infections. © 2024 The Authors
Amelioration of opto - Electronic response of thiophene - Imidazo[2,1- b] [1,3,4]thiadiazole based organic semiconductors
(2019) Viprabha, K.; Udayakumar, D.
Two new donor-acceptor (D - A) type organic semiconductors V-1 and V-2 containing thiophene as the donor unit were designed and synthesized following Knoevenagel condensation reaction. The structures of the synthesized molecules were characterized by mass spectroscopy and 1H NMR spectroscopy. The photophysical properties were investigated by UV-vis spectroscopy and fluorescence spectroscopy. The electrochemical properties were studied by cyclic voltammetry. The density functions theory (DFT) studies were performed to examine the frontier molecular orbital energy states. Both electrochemical analysis and DFT studies revealed that the HOMO of V-2 is shifted to higher energy compared to that of V-1 due to the stronger electron donating ability of methoxy group in V-2 compared to that of methyl group in V-1. The optical and electrochemical results revealed that the synthesized organic semiconductors are suitable donor materials for bulk hetero - junction solar cells. � 2018 Author(s).
The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles
(2020) Reddyrajula, R.; Udayakumar, D.
Tuberculosis remains as a major public health risk which causes the highest mortality rate globally and an improved regimen is required to treat the drug-resistant strains. Pyrazinamide is a first-line antitubercular drug used in combination therapy with other anti-TB drugs. Herein, we describe the modification of pyrazinamide structure using bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for their in vitro inhibitory potency against mycobacterium tuberculosis H37Rv. The pyrazine-1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds, seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56 ?g/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well. Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME prediction revealed good oral bioavailability for the potent molecules. 2019 Elsevier Ltd
D-A conjugated polymers containing substituted thiophene, 1,3,4-oxadiazole and non-conjugation linkers: Synthesis and study of optical and electrochemical properties
(Springer India sanjiv.goswami@springer.co.in, 2016) Prashanth Kumar, K.R.; Udayakumar, D.; Siji Narendran, N.K.; Chandrasekharan, K.; Srivastava, R.
In this communication, we report synthesis and characterization of new D-A conjugated polymers (P1-P3) consisting of electron-donating (D) 3,4-didodecyloxythiophene, electron-accepting (A) 1,3,4-oxadiazole unit and non-conjugation linkers. The conjugated segment in P1-P3 contains only five aromatic rings resulting in short conjugation length, but has an alternate D-A arrangement which significantly enhances the intramolecular charge transfer (ICT) interaction within the segment. As a result, these polymers exhibited low optical band gap in the range 2.51–2.76 eV. Fluorescence emission studies revealed that the polymer thin films emit intense blue light with emission maxima in the wavelength rage 430–480 nm. All three polymers undergo both oxidation and reduction processes under electrochemical conditions. Further, these polymers (P1–P3) exhibit low-lying HOMO and LUMO levels as a result of D-A structure of the conjugated segment. Polymer light-emitting devices were fabricated using these polymers as emissive layer with a device configuration of ITO/MoO 3/polymer/LiF/Al. The test device based on P2 emitted blue light with a low threshold voltage of 5 V. Z-scan studies reveal that the polymers exhibit a strong optical limiting behavior. The value of the nonlinear absorption coefficient (?) of polymers is of the order 10 ?11m/W which indicates that these materials may be accomplished for fabricating optical limiters. [Figure not available: see fulltext.] © 2016, Indian Academy of Sciences.
Design of new phenothiazine-thiadiazole hybrids via molecular hybridization approach for the development of potent antitubercular agents
(2015) Ramprasad, J.; Nayak, N.; Udayakumar, D.
A new library of phenothiazine and 1,3,4-thiadiazole hybrid derivatives (5a-u) was designed based on the molecular hybridization approach and the molecules were synthesized in excellent yields using a facile single-step chloro-amine coupling reaction between 2-chloro-1-(10H-phenothiazin-10-yl)ethanones and 2-amino-5-subsituted-1,3,4-thiadiazoles. The compounds were evaluated for their in vitro inhibition activity against Mycobacterium tuberculosis H37Rv (MTB). Compounds 5g and 5n were emerged as the most active compounds of the series with MIC of 0.8 ?g/mL (?1.9 ?M). Also, compounds 5a, 5b, 5c, 5e, 5l and 5m (MIC = 1.6 ?g/mL), and compounds 5j, 5k and 5o (MIC = 3.125 ?g/mL) showed significant inhibition activity. The structure-activity relationship demonstrated that an alkyl (methyl/npropyl) or substituted (4-methyl/4-Cl/4-F) phenyl groups on the 1,3,4-thiadiazole ring enhance the inhibition activity of the compounds. The cytotoxicity study revealed that none of the active molecules are toxic to a normal Vero cell line thus proving the lack of general cellular toxicity. Further, the active molecules were subjected to molecular docking studies with target enzymes InhA and CYP121. 2015 Elsevier Masson SAS. All rights reserved.
Design, Synthesis, and Biological Evaluation of New 8-Trifluoromethylquinoline Containing Pyrazole-3-carboxamide Derivatives
(2017) Nayak, N.; Ramprasad, J.; Udayakumar, D.
The article describes the design, synthesis, and characterization of a new series of 8-trifluoromethylquinoline substituted pyrazole-3-carboxamides (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) derived from different primary and secondary amines. The intermediate and target compounds were characterized using spectroscopic methods. The structures of intermediate 7 and target molecule 9d were evidenced by the single crystal X-ray study. All the synthesized target compounds (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) and three intermediates (6, 7, 8) were screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 9k and 9t, showed significant inhibition activity with MIC of 3.13 g/mL, which is comparable with the activity of standard drug, ethambutol. The carboxamides derived from benzylamine derivatives were more active than their aniline analogs. In general, the hybrid amides with a N-methylene linkage (-CONHCH2-) exhibited enhanced antitubercular activity. In the antibacterial screening, intermediate 3-hydrazinyl-2-methyl-8-(trifluoromethyl)quinoline (6) displayed remarkable activity against the tested bacterial strains. Further, the active anti-TB derivatives were non-toxic to benign NIH 3T3 cells, which demonstrate the lack of general cellular toxicity and hence signifies their suitability for further lead development. 2015 HeteroCorporation
Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2
(2019) Manjula, R.; Gokhale, N.; Unni, S.; Deshmukh, P.; Reddyrajula, R.; Srinivas, Bharath, M.M.; Udayakumar, D.; Padmanabhan, B.
Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases. 2019 Elsevier Inc.
Effects of substituents on the enrichment of the optical limiting action of novel imidazo[2,1-: B] [1,3,4]thiadiazole fused thiophene-based small molecules
(2019) Kakekochi, V.; Udayakumar, D.; Nikhil, P.P.; Chandrasekharan, K.
The imidazo[2,1-b][1,3,4]thiadiazole (ITD) ring is a fused, planar aromatic heterocyclic system consisting of four heteroatoms with a bridgehead nitrogen atom. In this study, three new donor-acceptor-donor (D-A-D)-type organic molecules (ThITD1-ThITD3) were designed and synthesized, wherein ITD was an electron acceptor unit and the thiophene/phenyl moieties were electron donor units that produced a D-A-D configuration. The thiophene-ITD core structure comprises three different groups viz., thiophene-2-acetonitrile (ThITD1), phenylacetonitrile (ThITD2) and rhodanine-3-acetic acid (ThITD3), and the effect of substituents on the optical and electrochemical properties have been discussed based on structural modifications. The third-order nonlinear optical (NLO) properties analyzed by the Z-scan technique reveal that the molecules exhibit effective two photon absorption (TPA) with ThITD3 possessing substantially higher effective TPA coefficient (?eff) than ThITD1 and ThITD2, which is comparable to the reported ?eff values. The results unravel that ITD as an acceptor with an appropriate ?-linker will be a promising candidate for application in the field of optoelectronics/photonics. Herein, the thiophene-ITD ring system was explored for NLO applications and reported for the first time. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Effects of substituents on the enrichment of the optical limiting action of novel imidazo[2,1-: B] [1,3,4]thiadiazole fused thiophene-based small molecules
(Royal Society of Chemistry, 2019) Kakekochi, V.; Udayakumar, D.; Nikhil, P.P.; Chandrasekharan, K.
The imidazo[2,1-b][1,3,4]thiadiazole (ITD) ring is a fused, planar aromatic heterocyclic system consisting of four heteroatoms with a bridgehead nitrogen atom. In this study, three new donor-acceptor-donor (D-A-D)-type organic molecules (ThITD1-ThITD3) were designed and synthesized, wherein ITD was an electron acceptor unit and the thiophene/phenyl moieties were electron donor units that produced a D-A-D configuration. The thiophene-ITD core structure comprises three different groups viz., thiophene-2-acetonitrile (ThITD1), phenylacetonitrile (ThITD2) and rhodanine-3-acetic acid (ThITD3), and the effect of substituents on the optical and electrochemical properties have been discussed based on structural modifications. The third-order nonlinear optical (NLO) properties analyzed by the Z-scan technique reveal that the molecules exhibit effective two photon absorption (TPA) with ThITD3 possessing substantially higher effective TPA coefficient (?eff) than ThITD1 and ThITD2, which is comparable to the reported ?eff values. The results unravel that ITD as an acceptor with an appropriate ?-linker will be a promising candidate for application in the field of optoelectronics/photonics. Herein, the thiophene-ITD ring system was explored for NLO applications and reported for the first time. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.
Facile synthesis of indole-pyrimidine hybrids and evaluation of their anticancer and antimicrobial activity
(2017) Gokhale, N.; Udayakumar, D.; Kumsi, M.
The paper describes the facile synthesis of new N-cyclopropyl-1-methyl-1H-indole-2-carboxamide derivatives bearing substituted 2-amino pyrimidine moiety at position-3 of the indole ring. All the intermediate and title compounds were characterized adeptly by 1H NMR, 13C NMR, ESI MS and elemental analyses. These compounds were evaluated for their in vitro anticancer activity against HeLa, HepG2 and MCF-7 cells. Three among 22 molecules, showed more than 70% growth inhibition against all three tested cancer cells. The nature of the substituent group on the pyrimidine ring (R2) affected significantly the anti-proliferative activity of the molecules. The anti-microbial evaluation of the title molecules revealed the significance of fluoro/chloro groups (R2) in enhancing their inhibition activity. Eight molecules which contain fluoro/chloro groups showed potent anti-microbial activity. In addition, the active molecules displayed negligible toxicity to benign Vero cells. 2015 King Saud University
Fatty acid, fatty alcohol and acrylate derivatives as friction depressive additives for ultra-low sulphur diesel
(Elsevier Ltd, 2023) Sruthi, H.; Udayakumar, D.; Hegde, P.; Manjunatha, M.G.
Herein we report the synthesis of some fatty acid, fatty alcohol and acrylate derivatives as friction depressive additives for ultra-low sulphur diesel (ULSD). The high frequency reciprocating rig (HFRR) was employed to measure the wear scar diameter (WSD) of the samples. The lubricating property of the newly synthesized samples [2a, (4a-c) and (5a-c)] was studied by dosing them to ULSD at 200 ppm (wt/vol) concentrations. Amongst them, ester derived from OLA/Polyol (4c) showed the best lubrication enhancing property (WSD 328 µm) at 200 ppm(wt/vol) dosage level. Interestingly, it maintains lubricity characteristics even at a lower blending concentration of 100 ppm with a WSD value (446 µm) lower than the than the accepted value (460 µm). Notably, additives containing polar functional groups and long non-polar carbon backbone exhibited significant lubricity properties with low WSD values. Moreover, it possesses long term antiwear stability when blended with the diesel fuel and do not alter or negatively influence the physical and chemical parameters of the diesel. The FESEM and EDS analysis revealed the formation of thin defensive layer of the additive between the moving metal surfaces supporting the friction reducing properties of the additives. © 2023
Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
(2013) Panathur, N.; Udayakumar, D.; Koushik, P.V.; Alvala, M.; Yogeeswari, P.; Sriram, D.; Kumar, V.
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3- yl]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. 2013 Elsevier Masson SAS. All rights reserved.
Impact of donor acceptor alternation on optical power limiting behavior of H Shaped thiophene imidazo[2,1-b] [1,3,4]thiadiazole flanked conjugated oligomers
(2020) Kakekochi, V.; Nikhil, P, P.; Chandrasekharan, K.; Udayakumar, D.
A new series of four D A D configured conjugated oligomers with H type structure, possessing two thiophene imidazo [2,1-b][1,3,4]thiadiazole branches and thiophene (TIT), thiophene 1,3,4-oxadiazole thiophene (TITO), thiazolo [5,4-d]thiazole (TITz), phenyl thiazolo [5,4-d]thiazole phenyl (TIPTz) units as central core moieties were efficiently synthesized. These core moieties were specifically selected to increase the planarity, rigidity, stability, extend the ? conjugation and to understand the influence of central core on nonlinear absorption coefficient (?eff) and optical limiting behavior of the synthesized oligomers. The structure-property relationships of these oligomers were established by the optical absorption (UV Vis), electrochemical (CV) and theoretical (DFT) studies. The effective two photon absorption of oligomers was confirmed by single beam Z scan analysis. The exceptional increase in nonlinear response was achieved with the oligomers TITO and TIPTz with nonlinear absorption coefficient (?eff) of 1.62 and 2.71 10?10 m W?1, and limiting thresholds of 6.02 and 3.14 J cm?2, respectively, which suggest that these oligomers could be potent materials for practical applications in laser photonics. 2020 Elsevier Ltd
Indole-3-carbinol and 1,3,4-oxadiazole hybrids: Synthesis and study of anti-proliferative and anti-microbial activity
(2015) Gokhale, N.; Panathur, N.; Udayakumar, D.; Kumsi, M.
In the present study, molecular hybrids of indole-3-carbinol and 1,3,4-oxadiazole-2-thiols have been designed and synthesized. The thiol analogues consisted of diversely substituted benzyl and alkyl groups with different electronic properties. The structures of all the newly synthesized scaffolds and target compounds were ascertained using 1H NMR, 13C NMR, mass spectrometry, and elemental analyses. All the final compounds were screened in vitro for their anti-proliferative and anti-microbial activity. Three compounds showed excellent anti-proliferative activity with more than 70% cell growth inhibition against three cancer cell lines, HepG2 (human liver hepatocellular carcinoma), HeLa (human cervix carcinoma), and MCF-7 (human breast carcinoma). In the anti-microbial studies, compounds with electron-withdrawing fluoro or nitro substituent displayed appreciable activity similar to that of standard drugs. Also, the final compounds are non-toxic to non-cancerous Vero cell line. 2015 CSIRO.
An investigation on photophysical and third order nonlinear optical properties of novel thermally stable thiophene imidazo [2,1-b][1,3,4] thiadiazole based azomethines
(2019) Kakekochi, V.; Udayakumar, D.; P, N.P.; Chandrasekharan, K.
The use of ? conjugated semiconducting materials in flexible and large area optoelectronic devices is proliferated worldwide owing to the easy structural modifications and solution processability possible, leading to the change in opto electronic properties. In this context, new class of thiophene and imidazo [2,1-b][1,3,4] thiadiazole (ITD) based conjugated azomethines (TI1 TI3) were designed and synthesized. The photophysical and electrochemical properties of the synthesized azomethines (TI1 TI3) were investigated experimentally, which were further validated with the aid of theoretical calculations. Further, the azomethines TI1 and TI2 were subjected to Z scan analysis to study the nonlinear optical (NLO) properties. The molecules exhibited effective two photon absorption (TPA) with the large nonlinear absorption coefficient (?eff) of the order of 10?10 m W?1. The planar structure of TI1 furnished a better interaction between donor and acceptor moieties and extended the ? conjugation, providing an improved ?eff (0.81 10?10 m W?1) to TI1 compared to that of TI2 (0.55 10?10 m W?1). From the results it is inferred that the molecules could be of potential materials to be used in efficient photonic devices. 2019 Elsevier Ltd
Ionic liquid-promoted one-pot synthesis of thiazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids and their antitubercular activity
(2016) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
In this paper, we report the facile and efficient one-pot three-component synthesis of 1-((6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-(4-phenylthiazol-2-yl)hydrazine derivatives (5a-w) using an ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([Bmim]Br). The compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. Compound 5s showed the highest inhibitory activity with an MIC of 6.03 ?M which is slightly lower than the MIC values of standard drugs ethambutol (15.3 ?M) and ciprofloxacin (9.4 ?M). Four other compounds of the series viz.5e, 5i, 5t and 5w also showed significant inhibitory activity with MIC values in the range of 11.7-13.9 ?M. The structure-activity relationship revealed that the trifluoromethyl substitution at position-2 and p-chlorophenyl substitution at position-6 of the imidazo[2,1-b][1,3,4]thiadiazole ring enhanced the inhibitory activity. Also, the methyl, methoxy, fluoro or nitro substituents on the thiazole ring enhanced the activity of the compounds. None of the active compounds were toxic to a normal cell line (NIH 3T3), which signifies the lack of general cellular toxicity of the molecules. In silico molecular docking studies revealed the favourable interaction of the potent compounds with the target enzymes InhA and CYP121. The Royal Society of Chemistry 2016.
Ionic liquid-promoted one-pot synthesis of thiazole-imidazo[2,1-b][1,3,4]thiadiazole hybrids and their antitubercular activity
(Royal Society of Chemistry, 2016) Ramprasad, J.; Nayak, N.; Udayakumar, D.; Yogeeswari, P.; Sriram, D.
In this paper, we report the facile and efficient one-pot three-component synthesis of 1-((6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylene)-2-(4-phenylthiazol-2-yl)hydrazine derivatives (5a-w) using an ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([Bmim]Br). The compounds were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis. Compound 5s showed the highest inhibitory activity with an MIC of 6.03 ?M which is slightly lower than the MIC values of standard drugs ethambutol (15.3 ?M) and ciprofloxacin (9.4 ?M). Four other compounds of the series viz.5e, 5i, 5t and 5w also showed significant inhibitory activity with MIC values in the range of 11.7-13.9 ?M. The structure-activity relationship revealed that the trifluoromethyl substitution at position-2 and p-chlorophenyl substitution at position-6 of the imidazo[2,1-b][1,3,4]thiadiazole ring enhanced the inhibitory activity. Also, the methyl, methoxy, fluoro or nitro substituents on the thiazole ring enhanced the activity of the compounds. None of the active compounds were toxic to a normal cell line (NIH 3T3), which signifies the lack of general cellular toxicity of the molecules. In silico molecular docking studies revealed the favourable interaction of the potent compounds with the target enzymes InhA and CYP121. © The Royal Society of Chemistry 2016.
Molecular hybridization approach for phenothiazine incorporated 1,2,3-triazole hybrids as promising antimicrobial agents: Design, synthesis, molecular docking and in silico ADME studies
(2019) Reddyrajula, R.; Udayakumar, D.; Madan, Kumar, S.
The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 ?g/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads. 2019 Elsevier Masson SAS
N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB
(Academic Press Inc., 2024) Reddyrajula, R.; Perveen, S.; Negi, A.; Etikyala, U.; Vijjulatha, V.; Sharma, R.; Udayakumar, D.
The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors. © 2024 Elsevier Inc.
New indole-isoxazolone derivatives: Synthesis, characterisation and in vitro SIRT1 inhibition studies
(2015) Panathur, N.; Gokhale, N.; Udayakumar, D.; Koushik, P.V.; Yogeeswari, P.; Sriram, D.
A new series of indole-isoxazolone hybrids bearing substituted amide, substituted [(1,2,3-triazol-4-yl)methoxy]methyl group or substituted benzylic ether at position-2 of the indole nucleus was synthesised using a facile synthetic route and the molecules were characterised using spectroscopic techniques. The molecules were screened against three human cancer cell lines to evaluate their in vitro cytotoxic property. Most of the trifluoromethyl substituted derivatives exhibited better growth inhibition activity than their methyl substituted analogues. The SIRT1 inhibition activity of two potent molecules (I17 and I18) was investigated and the SIRT1 IC50 values are 35.25 and 37.36 ?M, respectively for I17 and I18. The molecular docking studies with SIRT1 enzyme revealed favourable interactions of the molecule I17 with the amino acids constituting the receptor enzyme. 2015 Elsevier Ltd. All rights reserved.