Publications by authors named "Siva Krishna Vagolu"

11 Publications

  • Page 1 of 1

3-Aryl-substituted imidazo[1,2-a]pyridines as antituberculosis agents.

Arch Pharm (Weinheim) 2021 Oct 29;354(10):e2000419. Epub 2021 Jun 29.

Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.

Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 μg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.
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http://dx.doi.org/10.1002/ardp.202000419DOI Listing
October 2021

Stereoselective synthesis and discovery of novel spirooxindolopyrrolidine engrafted indandione heterocyclic hybrids as antimycobacterial agents.

Bioorg Chem 2021 05 5;110:104798. Epub 2021 Mar 5.

Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, Samsun 55139, Turkey.

Novel spirooxindolopyrrolidine embedded indandione heterocyclic hybrids were obtained in excellent yields via a regio- and stereoselective one-pot three component reaction between Baylis-Hillman adduct and non-stabilized azomethine ylides. The structure of newly synthesized compounds was elucidated through 1D and 2D spectroscopic data and the stereochemistry was determined by single crystal X-ray diffraction analysis. In vitro tubercular activity against Mycobacterium tuberculosis H37Rv using MABA assay reveals that the compound bearing chlorine substituted on the oxindole ring displayed the most potent activity with MIC 0.78 μg/mL and is two-fold active than the standard drug, ethambutol (MIC 1.56 μg/mL).
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http://dx.doi.org/10.1016/j.bioorg.2021.104798DOI Listing
May 2021

Design, synthesis, and biological evaluation of benzo[d]imidazole-2-carboxamides as new anti-TB agents.

Bioorg Chem 2021 02 10;107:104538. Epub 2020 Dec 10.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India; Department of Chemistry, Indian Institute of Technology - Ropar, Rupnagar, Punjab 140 001, India. Electronic address:

Tuberculosis is the leading cause of death globally among infectious diseases. Due to the development of resistance of Mycobacterium tuberculosis to currently used anti-TB medicines and the TB-HIV synergism the urgent need to develop novel anti-mycobacterial agents has been realized. The drug-to-target path has been the successful strategy for new anti-TB drug development. All the six drug candidates that have shown promise during the clinical trials and some of these being approved for treatment against MDR TB are the results of phenotype screening of small molecule compound libraries. In search of compounds belonging to novel pharmacophoric class that could be subjected to whole cell assay to generate new anti-TB leads the benzo[d]imidazole-2-carboxamide moiety has been designed as a novel anti-TB scaffold. The design was based on the identification of the benzimidazole ring as a prominent substructure of the FDA approved drugs, the structural analysis of reported anti-TB benzimidazoles, and the presence of the C-2 carboxamido functionality in novel bioisoteric anti-TB benzothiazoles. Twenty seven final compounds have been prepared via NHCl-catalyzed amidation of ethyl benzo[d]imidazole-2-carboxylates, as the required intermediates, obtained through a green "all water" one-pot synthetic route following a tandem N-arylation-reduction-cyclocondensation procedure. All of the synthesised target compounds were assessed for anti-TB potential using HRv ATCC27294 strain. Thirteen compounds were found with better MIC (0.78-6.25 µg/mL) than the standard drugs and being non-cytotoxic nature (<50% inhibition against RAW 264.7 cell lines at 50 µg/mL). The compound 8e exhibited best anti-TB activity (MIC: 2.15 µM and selectivity index: > 60) and a few others e.g., 8a, 8f, 8k and 8o are the next best anti-TB hits (MIC: 1.56 µg/mL). The determination and analysis of various physiochemical parameters revealed favorable druglike properties of the active compounds. The compounds 8a-l and 8o, with MIC values of ≤ 6.25 μg/mL, have high LipE values (10.66-11.77) that are higher than that of the suggested value of > 6 derived from empirical evidence for quality drug candidates and highlight their therapeutic potential. The highest LipE value of 11.77 of the best active compound 8e with the MIC of 0.78 μg/mL indicates its better absorption and clearance as a probable clinical candidate for anti-TB drug discovery. These findings highlight the discovery of benzimidazole-2-carboxamides for further development as new anti-TB agents.
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http://dx.doi.org/10.1016/j.bioorg.2020.104538DOI Listing
February 2021

Pyrazole-coumarin and pyrazole-quinoline chalcones as potential antitubercular agents.

Arch Pharm (Weinheim) 2020 Aug 2;353(8):e2000077. Epub 2020 Jun 2.

Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India.

Pyrazole, coumarin, and quinoline are medicinally important moieties. In this study, two series of novel pyrazole-coumarin chalcones and pyrazole-quinoline chalcones were synthesized using multiple-step reactions. All the synthesized compounds were well characterized using different spectroscopic techniques including H and C nuclear magnetic resonance, high-resolution mass spectroscopy, and electrospray ionization-mass spectrometry. The compounds were evaluated for their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain using the microplate Alamar Blue assay, and the minimal inhibitory concentrations (MIC) of the compounds were determined. Among the 32 tested compounds, compounds 3e, 3u, and 7h showed an MIC value of 3.125 µg/ml, and they were found to be nontoxic. Molecular docking studies of the compounds with the enzyme DprE1 revealed the probable mechanism of action. The chalcone derivatives exhibited binding affinity values between -7.047 and -9.353 kcal/mol. ADME parameters were predicted using the QikProp module of the Schrödinger software, and these compounds exhibited good pharmacological and oral absorption properties.
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http://dx.doi.org/10.1002/ardp.202000077DOI Listing
August 2020

Indole-fused spirochromenes as potential anti-tubercular agents: design, synthesis and in vitro evaluation.

Mol Divers 2021 Nov 30;25(4):2137-2148. Epub 2020 May 30.

Department of Chemistry, Satavahana University, Karimnagar, Telangana State, 505001, India.

As part of an ongoing effort to develop new anti-tubercular agents, a series of novel indole-fused spirochromene hybrids (7a-l) were efficiently synthesized in excellent yields by the popular 'Fisher-Indole synthesis' approach. The structure elucidation of the target compounds was carried out by different spectral techniques including H-NMR, C-NMR, ESI Mass, and FTIR analysis. Additionally, the proposed structure of 7i was proved by single-crystal X-ray analysis. These compounds (7a-l) were screened for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. The results showed that most of the targets exhibited promising antimycobacterial activity with MICs of 1.56-6.25 μg/mL and weak cytotoxicity (19.93-32.16% at 50 μg/mL). Among them, compound 7l was found to be the most active compound (MIC of 1.56 μg/mL) with a good safety profile (32.16% at 50 μg/mL).
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http://dx.doi.org/10.1007/s11030-020-10108-zDOI Listing
November 2021

Anti-tubercular activity of novel class of spiropyrrolidine tethered indenoquinoxaline heterocyclic hybrids.

Bioorg Chem 2020 06 26;99:103799. Epub 2020 Mar 26.

Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, Telangana, India.

A series of structurally intriguing novel class of spiropyrrolidine tethered quinoxaline heterocyclic hybrids has been achieved in excellent yields employing ionic liquid accelerated multicomponent 1,3-dipolar cycloaddition reaction strategy. β-Nitrostyrenes were used as dipolarophiles, while the 1,3-dipole component was the azomemthine ylide, generated in situ from indenoquinoxaline and l-phenylalanine. The reaction provided three new bonds and four contiguous stereocenter with full distereomeric control. In vitro activity of these spiroheterocyclic hybrids against Mycobacterium tuberculosis H37Rv using MABA assay revealed that the compound with nitro group on the phenyl ring is the most active candidate (1.56 µg/mL) among the other analogues of the series and has an activity similar to that of the standard drug, Ethambutol.
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http://dx.doi.org/10.1016/j.bioorg.2020.103799DOI Listing
June 2020

Imidazo[2,1-]thiazole-Coupled Natural Noscapine Derivatives as Anticancer Agents.

ACS Omega 2019 Nov 5;4(21):19382-19398. Epub 2019 Nov 5.

Fluoro and Agrochemicals Division and Applied Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, Telangana, India.

Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy is traditionally being used as an anticough drug. With a safe in vitro toxicological profile, noscapine and its analogues have been explored to show microtubule-regulating properties and anticancer activity against various mammalian cancer cell lines. Since then, our group and other research groups worldwide are working on developing new noscapinoids to tap its potential as the leading drug molecule. With our continuing efforts, we herein present synthesis and anticancer evaluation of a series of imidazothiazole-coupled noscapinoids and . Natural α-noscapine was -demethylated to nornoscapine and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant noscapinoid was coupled with various bromomethyl ketones to give -imidazothiazolyl noscapinoids in very good yields. Similarly, natural α-noscapine was -demethylated using sodium azide/sodium iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled with bromomethyl ketones to result in -imidazothiazolyl noscapinoids . All the new analogues and were fully characterized by their NMR and mass spectral analysis. In vitro cytotoxicity assay was performed for compounds , , and against four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these conjugates, , , , , , , and showed potent cytotoxicity with low IC values. Further, flow cytometry analysis revealed that MIA PaCa-2 cells treated with these compounds induced . In addition, Western blot analysis revealed that the cells treated with these conjugates accumulate tubulin in the soluble fraction and also elevate cyclin-B1 protein expression levels. Moreover, the conjugates also increased the expression of caspase-3 and PARP levels which is indicative of apoptotic cell death. In silico molecular docking studies showed several noncovalent interactions like van der Waals and hydrogen-bonding with tubulin protein and with good binding energy. The results indicated that these noscapine analogues may serve as novel compounds that can possibly inhibit tubulin protein and can be considered for further optimization as a clinical candidate for treating pancreatic cancer.
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http://dx.doi.org/10.1021/acsomega.9b02789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868913PMC
November 2019

Synthesis of Disulfide-Bridged N-Phenyl-N'-(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities.

Chem Biodivers 2019 Dec 11;16(12):e1900461. Epub 2019 Nov 11.

Department of Pharmacy, Birla Institute of Technology and Science-Pilani, 500078, Hyderabad, India.

The discovery of new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a-10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1'-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis β-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds.
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http://dx.doi.org/10.1002/cbdv.201900461DOI Listing
December 2019

Synthesis and biological evaluation of 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives as novel anti-tubercular agents.

Bioorg Med Chem Lett 2019 01 17;29(2):284-290. Epub 2018 Nov 17.

Department of Genetics and Biotechnology, Osmania University, Telangana, India.

A series of novel 1H-pyrrolo[2,3-d]pyrimidine-1,2,3-triazole derivatives have been synthesized in good to excellent yields. Through the copper-catalyzed azide-alkyne cycloaddition via reaction of 7-(prop-2-ynyl)-7H-pyrrolo[2,3-d]pyrimidine and aryl, heteroaryl and alkyl azides in the presence of CuSO·5HO and sodium ascorbate. These compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain. Most of these pyrrolopyrimidine-triazole hybrids exhibited good anti tubercular activity. The antimycobacterial assay results showed that the minimum inhibitory concentration of compounds 4q and 4r were 0.78 µg/mL. The molecular docking results also had shown highest Moldock score for same compounds. These novel compounds exhibited good inhibition activities and further structure-activity studies of the derivatives had shown promising features to use in antitubercular therapy.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.036DOI Listing
January 2019

Clickable conjugates of bile acids and nucleosides: Synthesis, characterization, in vitro anticancer and antituberculosis studies.

Steroids 2018 11 17;139:35-44. Epub 2018 Sep 17.

Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India. Electronic address:

A series of clickable bile acid-nucleosides conjugates linked directly or via amino acid linker were synthesized, and characterized by spectroscopic techniques such as H NMR, C NMR, FT-IR, HRMS and HPLC. The synthesized compounds 6a-p were screened for their in vitro anticancer property against a panel of three cancer cell lines (PC-3, MCF-7, IMR-32). In addition, the synthesized derivatives were also tested for their antimycobacterial activity against Mycobacterium tuberculosis HRv (ATCC 27294 strain). Among the screened compounds, cholic acid-uridine clicked conjugate (6c), and cholic acid-uridine clicked conjugate liked via phenylalanine moiety (6m) were found to be most active against MCF-7 and IMR-32 exhibiting an IC value of 8.084 and 8.71 µM, respectively. The antimycobacterial study of the synthesized conjugates revealed all the conjugates to be active with MIC values in the range of 4.09-15.41 µM. Deoxycholic acid-adenosine clicked conjugate (6b) showed most promising antituberculosis property with MIC value of 4.09 µM. Most of the synthesized conjugates were found to be safe at 50 µM against normal human embryonic kidney (HEK 293 T) cell line.
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http://dx.doi.org/10.1016/j.steroids.2018.09.006DOI Listing
November 2018

Lead identification and optimization of bacterial glutamate racemase inhibitors.

Bioorg Med Chem 2018 01 21;26(1):177-190. Epub 2017 Nov 21.

Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500078, India. Electronic address:

Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC 19.47 ± 0.81 μM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC 1.32 ± 0.43 μM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5).
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http://dx.doi.org/10.1016/j.bmc.2017.11.031DOI Listing
January 2018
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