Publications by authors named "Dharmarajan Sriram"

306 Publications

Canagliflozin and Dapagliflozin Attenuate Glucolipotoxicity-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Inhibition of Sodium-Glucose Cotransporter-1.

ACS Pharmacol Transl Sci 2022 Apr 9;5(4):216-225. Epub 2022 Mar 9.

Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India.

Sodium-dependent glucose cotransporter 2 inhibitors (SGLT2) are recently approved drugs for the treatment of diabetes that regulate blood glucose levels by inhibiting reabsorption of glucose and sodium in the proximal tubules of the kidney. SGLT2 inhibitors have also shown cardiovascular (CV) benefits in diabetic patients. However, the therapeutic efficacy of SGLT2 inhibitors with respect to CV disease needs further investigation. Thus, the aim of the present study was to examine the effects of SGLT2 inhibitors, canagliflozin (CANA) and dapagliflozin (DAPA) under glucolipotoxic condition by treating cultured cardiomyocytes (H9C2) with high glucose (HG) and high lipid, palmitic acid (PA), to investigate whether inhibition of sodium glucose cotransporter could prevent any harmful effects of glucolipotoxicity in these cells. SGLT1 expression was measured by immunofluorescence staining and quantitative polymerase chain reaction. Oxidative stress and apoptosis were measured by flow cytometry. Hypertrophy was measured by hematoxylin and eosin (H&E) and crystal violet staining. A significant increase in SGLT1 expression was observed in HG- and PA-treated cardiomyocytes. Also, a significant increase in reactive oxygen species generation and apoptosis was observed in HG+PA-treated cultured cardiomyocytes. HG- and PA-treated cardiomyocytes developed significant structural alterations. All these effects of HG and PA were attenuated by CANA and DAPA. In conclusion, our study demonstrates upregulation of SGLT1 induces oxidative stress and apoptosis in cultured cardiomyocytes. Thus, inhibition of SGLT1 may be used as a possible approach for the treatment of CVD in diabetic patients.
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http://dx.doi.org/10.1021/acsptsci.1c00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9003386PMC
April 2022

First-in-class pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones against leishmaniasis and tuberculosis: Rationale, in vitro, ex vivo studies and mechanistic insights.

Arch Pharm (Weinheim) 2022 Apr 1;355(4):e2100440. Epub 2022 Feb 1.

Department of Chemistry, Pondicherry University, Kalapet, Puducherry, India.

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones were synthesized, for the first time, from indole chalcones and 6-aminouracil, and their ability to inhibit leishmaniasis and tuberculosis (Tb) infections was evaluated. The in vitro antileishmanial activity against promastigotes of Leishmania donovani revealed exceptional activities of compounds 3, 12 and 13, with IC values ranging from 10.23 ± 1.50 to 15.58 ± 1.67 µg/ml, which is better than the IC value of the standard drug pentostam of 500 μg/ml. The selectivity of the compounds towards Leishmania parasites was evaluated via ex vivo studies in Swiss albino mice. The efficiency of these compounds against Tb infection was then evaluated using the in vitro anti-Tb microplate Alamar Blue assay. Five compounds, 3, 7, 8, 9 and 12, showed MIC values against the Mycobacterium tuberculosis H Rv strain at 25 µg/ml, and compound 20 yielded an MIC value of 50 µg/ml. Molecular modelling of these compounds highlighted interactions with binding sites of dihydrofolate reductase, pteridine reductase and thymidylate kinase, thus establishing the rationale of their pharmacological activity against both pathogens, which is consistent with the in vitro results. From the above results, it is clear that compounds 3 and 12 are promising lead candidates for Leishmania and Mycobacterium infections and may be promising for coinfections.
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http://dx.doi.org/10.1002/ardp.202100440DOI Listing
April 2022

Lead derivatization of ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate and 5-bromo-2-(thiophene-2-carboxamido) benzoic acid as FabG inhibitors targeting ESKAPE pathogens.

Eur J Med Chem 2022 Jan 6;228:113976. Epub 2021 Nov 6.

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

Our previous studies on FabG have identified two compounds 5-bromo-2-(thiophene-2-carboxamido) benzoic acid (A) and ethyl 6-bromo-2-((dimethylamino)methyl)-5-hydroxy-1-phenyl-1H-indole-3-carboxylate(B) as best hits with allosteric mode of inhibition. FabG is an integral part of bacterial fatty acid biosynthetic system FAS II shown to be an essential gene in most ESKAPE Pathogens. The current work is focussed on lead expansion of these two hit molecules which ended up with forty-three analogues (twenty-nine analogues from lead compound A and fourteen compounds from lead compound B). The enzyme inhibition studies revealed that compound 15 (effective against EcFabG, AbFabG, StFabG, MtFabG1) and 19 (inhibiting EcFabG and StFabG) had potency of broad-spectrum inhibition on FabG panel.
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http://dx.doi.org/10.1016/j.ejmech.2021.113976DOI Listing
January 2022

Design and characterisation of piperazine-benzofuran integrated dinitrobenzenesulfonamide as H37Rv strain inhibitors.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1751-1759

Centre for Organic and Medicinal Chemistry, Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, India.

Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against () H37Rv. - and found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of enoyl reductase.
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http://dx.doi.org/10.1080/14756366.2021.1956914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8330757PMC
December 2021

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

Inhibition of double stranded RNA dependent protein kinase (PKR) abrogates isoproterenol induced myocardial ischemia in vitro in cultured cardiomyocytes and in vivo in wistar rats.

Eur J Pharmacol 2021 Sep 1;906:174223. Epub 2021 Jun 1.

Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana, 500078, India. Electronic address:

Protein kinase R (PKR) plays a main role in inflammation, insulin resistance, and glucose balance. It is activated by various stress signals and is key mediators of diabetes and associated complications. In the present study, we investigated the effect of PKR inhibition on myocardial dysfunction, inflammatory, cell death and interrelated signalling pathways in isoproterenol induced myocardial ischemia in vivo in wistar rats and in vitro in cultured cardiomyocytes. H9C2 rat cardiomyocytes were treated with 10 μM Isoproterenol (ISO). For in vivo studies, rats were divided into 4 groups: control, ischemic group (ISO), preventive group, curative group and each group consist of 8 rats. Myocardial Ischemia (MI) was induced with two subsequent doses of ISO (100 mg/kg, s.c.). The rats were treated with PKR inhibitor, C16 (166.5 μg/kg, i.p.) for 14 days. Heart rate, systolic, diastolic and mean arterial pressures were measured by non-invasive BP apparatus. Cardiac biomarkers were measured by commercial kits. Ischemic Zone, Morphological abnormalities and fibrosis of heart was detected by TTC, haematoxylin & eosin staining, Masson's and Sirius red staining respectively. Protein expression was done by western blotting and immune histochemistry. mRNA expression was done by RT-PCR. MI was characterized by declined myocardial performance along with elevation of cardiac biomarkers and associated with increased expression of PKR, oxidative-nitrosative stress, activated various inflammatory pathways (nuclear factor kappa light chain enhancer of activated B cells -NF-κB); Mitogen-activated protein kinases-MAPK; c-Jun N-terminal kinase-JNK), increased expression of inflammatory markers (Tumour necrosis factor alpha-TNF-α), markers of fibrosis (Alpha smooth muscle actin -α-SMA; Transforming growth factor beta-TGF-β), enhanced cell death (Ischemic zone) and increased expression of extracellular regulated-kinases (ERK-1/2) and advanced glycation end products (AGE's). Interestingly, inhibition of PKR attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrosative stress, inflammation, cell death, and inter-related signalling pathways. Our findings report that inhibition of PKR improves the ischemic mediated inflammation, apoptosis, cardiac hypertrophy and fibrosis in MI induced rats. Hence, inhibition of PKR might be one of intervention therapy for the treatment of myocardial ischemia.
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http://dx.doi.org/10.1016/j.ejphar.2021.174223DOI Listing
September 2021

Antihypernociceptive effects of Petersianthus macrocarpus stem bark on neuropathic pain induced by chronic constriction injury in rats.

Inflammopharmacology 2021 Aug 3;29(4):1241-1253. Epub 2021 Jun 3.

Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus. Jawahar Nagar, Shameerpet Mandal R.R. District, Hyderabad, Telangana, 500078, India.

Petersianthus macrocarpus (Lecythidaceae) stem bark is traditionally used in West and Central Africa for the treatment of boils and pain. The present study examined the chemical composition of the aqueous and methanolic stem bark extracts of P. macrocarpus by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) . Their antinociceptive effect was evaluated using chronic constriction injury (CCI)-induced neuropathic pain in a rat model. On the ninth day post-surgery, the pain perception (allodynia and hyperalgesia) of the animals was assessed after the administration of aqueous and methanolic extracts at the doses of 100 and 200 mg/kg. In addition, the effect of the extracts was evaluated on nitric oxide activity and on the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and NF-κB). The LC-ESI-MS analysis revealed the presence of ellagic acid as the major constituent in the methanol extract. Both extracts at the employed doses (100 and 200 mg/kg), significantly (p < 0.01 and p < 0.001) reduced the spontaneous pain, tactile and cold allodynia, and mechanical hyperalgesia. The methanolic extract used at the dose of 200 mg/kg significantly reduced the nitric oxide level (p < 0.001) and the gene expression levels of NF-κB (p < 0.05) and TNF-α (p < 0.01) in the brain. These data may indicate that stem bark extracts of P. macrocarpus possess a potent anti-hypernociceptive effect on CCI neuropathic pain. The inhibition of the nitric oxide pathway as well as the reduction in NF-κB and TNF-α gene expression in the brain may at least partially contribute to this effect. The results further support the use of this plant by traditional healers in pain conditions.
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http://dx.doi.org/10.1007/s10787-021-00821-yDOI Listing
August 2021

Synthesis and Biological Evaluation of Novel Benzhydrylpiperazine-Coupled Nitrobenzenesulfonamide Hybrids.

ACS Omega 2021 Apr 31;6(14):9731-9740. Epub 2021 Mar 31.

Centre for Organic and Medicinal Chemistry, Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, Tamil Nadu 632014, India.

A series of novel benzhydryl piperazine-coupled nitrobenzenesulfonamide hybrids were synthesized with good to excellent yields. They were tested for inhibition of mycobacterial activity against the H37Rv strain, cytotoxicity MTT (RAW 264.7cells) assay, nutrient starvation (H37Rv strain), and ability to block Cav3.2 T-type calcium channels. Novel hybrids did not inhibit T-type calcium channels, whereas they showed excellent antituberculosis (TB) activity and low cytotoxicity with a selectivity index of >30. A direct impact of the amino acid linker was not observed. Studied hybrids exhibited good inhibition activities, and the 2,4-dinitrobenzenesulfonamide group emerged as a promising scaffold for further drug design by hybridization approaches for anti-TB therapy.
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http://dx.doi.org/10.1021/acsomega.1c00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047747PMC
April 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 and Synthesis of "Chloropicolinate Amides and Urea Derivatives" as Novel Inhibitors for .

ACS Omega 2021 Jan 7;6(2):1657-1667. Epub 2021 Jan 7.

New Generation Materials Lab (NGML), Department of Science and Humanities, Vignan's Foundation for Science Technology and Research (VFSTR) (Deemed to be University), Vadlamudi, Guntur 522 213, Andhra Pradesh, India.

A series of 30 novel diamino phenyl chloropicolinate fettered carboxamides, urea, and thiourea derivatives were synthesized by coupling of methyl 4-amino-6-(2-aminophenyl)-3-chloropyridine-2-carboxylate with different acid chlorides, urea, and thiourea moieties, respectively. All of these compounds were characterized by H and C nuclear magnetic resonance spectroscopy, CHN analysis, and high-resolution mass spectra for confirmation of the structures. Two compounds were also characterized by single-crystal X-ray diffraction analysis to confirm the structures obtained by spectral analysis. All these 30 compounds were tested for their antimycobacterial activity using the microplate alamar blue assay method against . Five compounds have shown good minimum inhibitory concentration (MIC) values with low cytotoxicity when compared with the reference drugs. Moreover, some of the compounds have high MIC values compared with isoniazid, rifampicin, and so forth and also had shown good reign in the spread of bacteria by the nutrient starvation model. These antimycobacterial activity results have shown a good correlation with molecular docking model analysis with the inhibitors MurB by exhibiting strong interactions. Some of these compounds could be promising candidates against for future preclinical agent drug development.
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http://dx.doi.org/10.1021/acsomega.0c05690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818581PMC
January 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

Design and synthesis of new indanol-1,2,3-triazole derivatives as potent antitubercular and antimicrobial agents.

Bioorg Med Chem Lett 2020 11 25;30(22):127579. Epub 2020 Sep 25.

Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University SubCampus, Osmanabad 413 501, MS, India. Electronic address:

In a search of new antitubercular agents, herein we have reported a series of new thirty-two indanol-1,2,3-triazole derivatives. The synthesized compounds were screened for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, most of the compounds have displayed good antitubercular activity against Mycobacterium tuberculosis H37Rv. The compound 5g has been identified as potent antitubercular agent with MIC value 1.56 µM. The most active compounds of the series were further studied for their cytotoxicity against HEK 293 cells using MTT assay and found to be nontoxic. In addition, ten compounds were shown good antimicrobial activities against both antibacterial and antifungal pathogens. A molecular docking study against Mycobacterial enoyl-ACP-reductase (InhA) was performed to gain an insight into the molecular mechanism of antitubercular action. The pharmacokinetic parameters of these compounds were studied and displayed acceptable drug-likeness score.
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http://dx.doi.org/10.1016/j.bmcl.2020.127579DOI Listing
November 2020

Synthesis and antimicrobial evaluation of new nitric oxide-donating fluoroquinolone/oxime hybrids.

Arch Pharm (Weinheim) 2021 Jan 21;354(1):e2000180. Epub 2020 Sep 21.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.

A new series of nitric oxide-donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c-e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones.
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http://dx.doi.org/10.1002/ardp.202000180DOI Listing
January 2021

Design and synthesis of purine connected piperazine derivatives as novel inhibitors of Mycobacterium tuberculosis.

Bioorg Med Chem Lett 2020 11 29;30(22):127512. Epub 2020 Aug 29.

New Generation Materials Lab (NGML), Department of Science and Humanities, Vignan's Foundation for Science Technology and Research (VFSTR) (Deemed to be University), Vadlamudi-522 213, Guntur, Andhra Pradesh, India. Electronic address:

A series of novel purine linked piperazine derivatives were synthesized to identify new, potent inhibitors of Mycobacterium tuberculosis. The compounds were designed to target MurB disrupting the biosynthesis of the peptidoglycan and exert antiproliferative effects. The first series of purine-2,6-dione linked piperazine derivatives were synthesized using an advanced intermediate 1-(3,4-difluorobenzyl)-7-(but-2-ynyl)-3-methyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione hydrochloride (6) which was coupled with varied carboxylic acid chloride derivatives. Following this piperazine linked derivatives were also synthesized from 6 using diverse isocyanate partners. The anti-mycobacterial activity of the analogues was tested againstMycobacterium tuberculosis H37Rv which revealed a cluster of six analogues (11, 24,27, 32, 33 and34), possessed promising activity. In comparison, a set of these new compounds possessed greater potencies relative to current drugs used in the clinic such as Ethambutol. These results were also correlated with computational molecular docking analysis, providing models for strong interactions of the inhibitors with MurB providing a template for the future development of preclinical agents against Mycobacterium tuberculosis.
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http://dx.doi.org/10.1016/j.bmcl.2020.127512DOI Listing
November 2020

Synthesis of novel 4,5-dihydropyrrolo[1,2-a]quinoxalines, pyrrolo[1,2-a]quinoxalin]-2-ones and their antituberculosis and anticancer activity.

Arch Pharm (Weinheim) 2020 Dec 12;353(12):e2000192. Epub 2020 Aug 12.

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

A facile strategy was developed for the synthesis of biologically important 4,5-dihydropyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a]quinoxalin]-2-ones by treating 2-(1H-pyrrol-1-yl)anilines with imidazo[1,2-a]pyridine-3-carbaldehyde or isatin, using amidosulfonic acid (NH SO ) as a solid catalyst in water at room temperature. The protocol has been extended to electrophile ninhydrin. The catalyst could be recycled for six times without the loss of activity. The compounds were evaluated for their antituberculosis, antibacterial, and anticancer activities. It is worth noting that compounds 3d and 3e demonstrated a minimum inhibitory concentration value of 6.25 µM against Mycobacterium tuberculosis H37Rv, whereas compounds 3d, 3g, 5d, 5e, and 5i showed a remarkable inhibition of A549, DU145, HeLa, HepG2, MCF-7, and B16-F10 cell lines, respectively. Staphylococcus aureus was inhibited by compounds 5b, 5e, 5d, 5g, and 5l at 32 µg/ml.
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http://dx.doi.org/10.1002/ardp.202000192DOI Listing
December 2020

1,3-Disubstituted urea derivatives: Synthesis, antimicrobial activity evaluation and in silico studies.

Bioorg Chem 2020 09 17;102:104104. Epub 2020 Jul 17.

Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey. Electronic address:

The development of new antimicrobial compounds is in high demand to overcome the emerging drug resistance against infectious microbial pathogens. In the present study, we carried out the extensive antimicrobial screening of disubstituted urea derivatives. In addition to the classical synthesis of urea compounds by the reaction of amines and isocyanates, we also applied a new route including bromination, oxidation and azidination reactions, respectively, to convert 2-amino-3-methylpyridine to 1,3-disubstituted urea derivatives using various amines. The evaluation of antimicrobial activities against various bacterial strains, Candida albicans as well as Mycobacterium tuberculosis resulted in the discovery of new active molecules. Among them, two compounds, which have the lowest MIC values on Pseudomonas aeruginosa, were further evaluated for their inhibition capacities of biofilm formation. In order to evaluate their potential mechanism of biofilm inhibition, these two compounds were docked into the active site of LasR, which is the transcriptional regulator of bacterial signaling mechanism known as quorum sensing. Finally, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness properties.
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http://dx.doi.org/10.1016/j.bioorg.2020.104104DOI Listing
September 2020

Novel isoniazid embedded triazole derivatives: Synthesis, antitubercular and antimicrobial activity evaluation.

Bioorg Med Chem Lett 2020 10 24;30(19):127434. Epub 2020 Jul 24.

Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University SubCampus, Osmanabad 413501, MS, India. Electronic address:

In the present study, a series of new isoniazid embedded triazole derivatives have been synthesized. These compounds were evaluated for their in vitro antitubercular and antimicrobial activities. Among the screened compounds, six have exhibited potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC value 0.78 μg/mL, whereas, three compounds have displayed activity with MIC value ranging from 1.56 to 3.125 μg/mL. The cytotoxicity of the active compounds was studied against RAW 264.7 cell line by MTT assay and no toxicity was observed even at 25 μg/mL concentration. The five compounds have displayed good antimicrobial activities. Molecular docking have been performed against mycobacterial InhA enzyme to gain an insight into the plausible mechanism of action which could pave the way for our endeavor to identify potent antitubercular candidates. We believe that further optimization of these molecules may lead to potent antitubercular agents.
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http://dx.doi.org/10.1016/j.bmcl.2020.127434DOI Listing
October 2020

Regio- and diastereoselective synthesis of spiropyrroloquinoxaline grafted indole heterocyclic hybrids and evaluation of their anti- activity.

RSC Adv 2020 Jun 19;10(40):23522-23531. Epub 2020 Jun 19.

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

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel hybrid heterocycles comprising spiropyrrolidine, indenoquinoxaline and indole structural units in excellent yields, has been achieved through a one-pot multicomponent process involving 1,3-dipolar cycloaddition as a key step. The 1,3-dipolar component is the azomethine ylide generated from indenoquinoxaline and l-tryptophan and reacts with various substituted β-nitrostyrenes affording the spiroheterocyclic hybrids. The ring system thus created possesses two C-C and three C-N bonds and four adjacent stereogenic carbons, one of which is quaternary and the reaction proceeded with full diastereomeric control. All the synthesized compounds were assayed for their activity against H37Rv using MABA assay. Interestingly, the compound bearing a 2-fluoro substituent on the aryl ring displayed an equipotent activity (MIC 1.56 μg mL) to ethambutol against H37Rv.
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http://dx.doi.org/10.1039/d0ra02525aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054781PMC
June 2020

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

Some New Hydrazone Derivatives Bearing the 1,2,4-Triazole Moiety as Potential Antimycobacterial Agents.

Turk J Pharm Sci 2019 Dec 11;16(4):432-436. Epub 2019 Nov 11.

Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara, Turkey.

Objectives: The aim of this study was to synthesize, characterize, and screen some new 1-(4-((2-(4-substitutedphenyl)hydrazono)methyl)phenyl)-1H-1,2,4-triazole derivatives for their antimycobacterial activities.

Materials And Methods: The target compounds were gained by condensation of 4-(1-1,2,4-triazol-1-yl)benzaldehyde with appropriate phenylhydrazines. Their structures were elucidated by IR, H-NMR, and mass spectrometry. The antimycobacterial activities of the compounds were determined against H37Rv.

Results: The biological assay results showed that the methylsulfonyl-substituted derivative displayed the highest antimycobacterial activity in this series.

Conclusion: Although the methylsulfonyl-substituted derivative exhibited significant antimycobacterial activity, none of the synthesized compounds was as effective as isoniazid, rifampin, ethambutol, and ciprofloxacin against .
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http://dx.doi.org/10.4274/tjps.galenos.2018.43660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227891PMC
December 2019

Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.

Eur J Med Chem 2020 Aug 4;199:112402. Epub 2020 May 4.

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

Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code: 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using H NMR, C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 μg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.
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http://dx.doi.org/10.1016/j.ejmech.2020.112402DOI Listing
August 2020

Design, synthesis and biological evaluation of novel Pseudomonas aeruginosa DNA gyrase B inhibitors.

Bioorg Chem 2020 07 4;100:103905. Epub 2020 May 4.

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

In the present study, we attempted to develop a novel class of compounds active against Pseudomonas aeruginosa (Pa) by exploring the pharmaceutically well exploited enzyme targets. Since, lack of Pa gyrase B crystal structures, Thermus thermophilus gyrase B in complex with novobiocin (1KIJ) was used as template to generate model structure by performing homology modeling. Further the best model was validated and used for high-throughput virtual screening, docking and dynamics simulations using the in-house database for identification of Pa DNA gyrase B inhibitors. This study led to an identification of three lead molecules with IC values in range of 6.25-15.6 µM against Pa gyrase supercoiling assay. Lead-1 optimization and expansion resulted in 15 compounds. Among the synthesized compounds six compounds were shown good enzyme inhibition than Lead-1 (IC 6.25 µM). Compound 13 emerged as the most potential compound exhibiting inhibition of Pa gyrase supercoiling with an IC of 2.2 µM; and in-vitro Pa activity with MIC of 8 µg/mL in presence of efflux pump inhibitor; hence could be further developed as novel inhibitor for Pa gyrase B.
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http://dx.doi.org/10.1016/j.bioorg.2020.103905DOI Listing
July 2020

Upregulation of PKR pathway mediates glucolipotoxicity induced diabetic cardiomyopathy in vivo in wistar rats and in vitro in cultured cardiomyocytes.

Biochem Pharmacol 2020 07 3;177:113948. Epub 2020 Apr 3.

Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India. Electronic address:

Aims: Protein Kinase R (PKR) plays a key role in inflammation and insulin resistance. Cytokines, high fat diet, infection and various stress signals can activate PKR. However, the functional significance of PKR in diabetic cardiomyopathy (DCM) is not explored so far. Thus the aim of the present study was to investigate the role of PKR in DCM in vivo in a rat model of DCM and underlying molecular mechanism.

Methods And Results: DCM was induced in Wistar rats by recipe of high fat diet and single injection of streptozotocin. Vital parameters were measured by non-invasive BP apparatus. Morphology, fibrosis and protein expression in heart was done by haematoxylin & eosin staining, masson's trichome/sirius red staining and western blotting respectively. For molecular mechanism studies, PKR gene silencing was done in cultured H9C2 cardiomyocytes and effect was observed in the presence of high glucose and high fat. Significant upregulation of PKR along with increase in cardiac biomarkers, decreased systolic and diastolic cardiac functions, oxidative stress, inflammatory markers, markers of fibrosis, enhanced cell death and AGEs' was observed in DCM disease model. Moreover, selective inhibition of PKR alleviated cardiac dysfunction, fibrosis, oxidative stress, inflammation and cell death. Additionally knockdown of PKR attenuated glucolipotoxicty-induced markers of inflammation, oxidative stress and apoptosis in cultured H9C2 cardiomyocytes.

Conclusion: Our present study reports for the first time that inhibition of PKR may have great therapeutic potential in the treatment of DCM by attenuating inflammation, oxidative stress, apoptosis and fibrosis.
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http://dx.doi.org/10.1016/j.bcp.2020.113948DOI Listing
July 2020

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

Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation.

Bioorg Chem 2020 06 19;99:103774. Epub 2020 Mar 19.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India. Electronic address:

In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis HRv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4-6.25 µg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (<30% inhibition at 50 µg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 µg/mL] and the compound 6d [MIC (H37Rv) of 0.78 µg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 µg/mL, respectively.
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http://dx.doi.org/10.1016/j.bioorg.2020.103774DOI Listing
June 2020

Design and development of ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues as Mycobacterium tuberculosis ketol-acid reductoisomerase inhibitors.

Eur J Med Chem 2020 May 28;193:112178. Epub 2020 Feb 28.

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

Based on our previous finding that the titled compound possesses anti-tuberculosis activity, a series of novel ((4-methoxyphenyl)carbamoyl) (5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazol-2-yl)amide analogues have been synthesized. Amongst the 22 compounds synthesized and tested, 5b, 5c and 6c showed potent inhibitory activity with K values of 2.02, 5.48 and 4.72 μM for their target, Mycobacterium tuberculosis (Mt) ketol-acid reductoisomerase (KARI). In addition, these compounds have excellent in vitro activity against Mt H37Rv with MIC values as low as 1 μM. The mode of binding for these compounds to Mt KARI was investigated through molecular docking and dynamics simulations. Furthermore, these compounds were evaluated for their activity in Mt infected macrophages, and showed inhibitory activities with up to a 1.9-fold reduction in growth (at 10 μM concentration). They also inhibited Mt growth in a nutrient starved model by up to 2.5-fold. In addition, these compounds exhibited low toxicity against HEK 293T cell lines. Thus, these compounds are promising Mt KARI inhibitors that can be further optimized into anti-tuberculosis agents.
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http://dx.doi.org/10.1016/j.ejmech.2020.112178DOI Listing
May 2020
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