Publications by authors named "Perumal Yogeeswari"

235 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10787-021-00821-yDOI Listing
August 2021

Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties.

Sci Rep 2020 11 26;10(1):20720. Epub 2020 Nov 26.

Chemical Engineering Institute, Ural Federal University, Yekaterinburg, Russian Federation, 620002.

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand-protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from - 8.1394 to - 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-77590-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691360PMC
November 2020

Larval zebrafish model for studying the effects of valproic acid on neurodevelopment: An approach towards modeling autism.

J Pharmacol Toxicol Methods 2019 Jan - Feb;95:56-65. Epub 2018 Nov 27.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address:

Introduction: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder of early onset, characterized by impaired sociability, cognitive function and stereotypies. The etiology of ASD involves a multidimensional link between genetic, neurobiological and environmental factors. Since existing, comprehensive animal models for ASD are time consuming and laborious, the need for simple, quick approaches to study subsets of ASD-associated characteristics has always been in demand for better understanding of disease. The aim of the present study was to develop a cost and time effective zebrafish model with quantifiable parameters to facilitate mechanistic studies as well as high-throughput screening of new molecules for autism.

Methods: Zebrafish embryos were treated with valproic acid (75 μM) beginning at 4-h post fertilization to 5-days post fertilization. A series of behavioral tests (anxiety, inattentive behavior and circling behavior) and molecular studies were performed as surrogate parameters of ASD-like characteristic on the larvae at 7-dayspost fertilization for a quick screen. The study was followed by validation of model by screening positive control and negative control drugs. The social interaction test was performed on 21-days post fertilization to confirm that the surrogate phenotypes were indicative of social deficit (a core symptom of ASD).

Results: The model showed a significant behavioral impairment (2-4fold difference) in valproic acid treated larvae compared to control larvae, which was further supported by alterations in select high-risk genes and proteins, implicated in human ASD. Reversal of behavioral impairments using standard drugs marketed for symptomatic treatment in ASD and no effect on behaviors when treated with paracetamol (negative control) signifies the role of model in preliminary drug screening.

Conclusion: The model shows robust parameters to study behavior, molecular mechanism and drug screening approach in a single frame. Thus, we postulate that our 7-day larval model could be a useful preliminary screening tool to identify novel targets as well as potential drugs for autism and also can be applied to develop a high-throughput screening approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vascn.2018.11.006DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.steroids.2018.09.006DOI Listing
November 2018

Dibenzofuran, dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamides as potent inhibitors of Mycobacterium tuberculosis.

Bioorg Med Chem Lett 2018 05 19;28(9):1610-1614. Epub 2018 Mar 19.

Department of Crop Protection Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India. Electronic address:

Herein described the design, synthesis and antitubercular evaluation of novel series of dibenzofuran, dibenzothiophene and N-methyl carbazole tethered 2-aminothiazoles and their cinnamamide analogs. One pot condensation of N-methyl carbazole, dibenzofuran and dibenzothiophene methyl ketones with thiourea in the presence of Iodine and CuO gave respective 2-aminothiazoles 4-6 in very good yields. Aminothiazoles were further coupled with substituted cinnamic acids using acid-amine coupling conditions to give desired cinnamamide analogs 8a-e, 9a-e and 10a-e. All the newly synthesized compounds were fully characterized by their NMR and mass spectral analysis. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv (Mtb) resulted 8c, 10d and 10e (MIC: 0.78 µg/mL) and 2-aminothiazoles 5 and 6 (MIC: 1.56 µg/mL) as potent compounds with lower cytotoxicity profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2018.03.048DOI Listing
May 2018

Inhibition of lipopolysaccharide (LPS)-induced neuroinflammatory response by polysaccharide fractions of Khaya grandifoliola (C.D.C.) stem bark, Cryptolepis sanguinolenta (Lindl.) Schltr and Cymbopogon citratus Stapf leaves in raw 264.7 macrophages and U87 glioblastoma cells.

BMC Complement Altern Med 2018 Mar 12;18(1):86. Epub 2018 Mar 12.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad campus, Jawahar Nagar, Hyderabad, Andhra Pradesh, -500078, India.

Background: Khaya grandifoliola (C.D.C.) stem bark, Cymbopogon citratus (Stapf) and Cryptolepis sanguinolenta (Lindl.) Schltr leaves are used in Cameroonian traditional medicine for the treatment of inflammatory diseases. Several studies have been performed on the biological activities of secondary metabolites extracted from these plants. However, to the best of our knowledge, the anti-neuro inflammatory and protective roles of the polysaccharides of these three plants have not yet been elucidated. This study aimed at investigating potential use of K. grandifoliola, C. sanguinolenta and C. citratus polysaccharides in the prevention of chronic inflammation.

Methods: Firstly, the composition of polysaccharide fractions isolated from K. grandifoliola stem bark (KGF), C. sanguinolenta (CSF) and C. citratus (CCF) leaves was assessed. Secondly, the cytotoxicity was evaluated on Raw 264.7 macrophages and U87-MG glioblastoma cell lines by the MTT assay. This was followed by the in vitro evaluation of the ability of KGF, CSF and CCF to inhibit lipopolysaccharides (LPS) induced overproduction of various pro-inflammatory mediators (NO, ROS and IL1β, TNFα, IL6, NF-kB cytokines). This was done in Raw 264.7 and U87-MG cells. Finally, the in vitro protective effect of KGF, CSF and CCF against LPS-induced toxicity in the U87-MG cells was evaluated.

Results: CCF was shown to mostly contain sugar and no polyphenol while KGP and CSP contained very few amounts of these metabolites (≤ 2%). The three polysaccharide fractions were non-toxic up to 100 μg.mL. All the polysaccharides at 10 μg/mL inhibited NO production, but only KGF and CCF at 12.5 μg/mL down-regulated LPS-induced ROS overproduction. Finally, 100 μg/mL LPS reduced 50% of U87 cell viability, and pre-treatment with the three polysaccharides significantly increased the proliferation.

Conclusion: These results suggest that the polysaccharides of K. grandifoliola, C. citratus and C. sanguinolenta could be beneficial in preventing/treating neurodegenerative diseases in which neuroinflammation is part of the pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12906-018-2156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848566PMC
March 2018

Synthesis, molecular modeling and evaluation of α-glucosidase inhibition activity of 3,4-dihydroxy piperidines.

Eur J Med Chem 2018 Apr 26;150:39-52. Epub 2018 Feb 26.

Centre for Chemical Sciences & Technology, Institute of Science and Technology, JNTUH, Kukatpally, Hyderabad 500085, Telangana State, India. Electronic address:

Biological evaluation of 3,4-dihydroxy piperidines as α-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their α-glucosidase inhibition activity. Polar groups (-OH, -NH) on phenyl ring having derivatives 5i, 5l, 7g, 7i &12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2018.02.072DOI Listing
April 2018

Correlation of pharmacokinetics and brain penetration data of adult zebrafish with higher mammals including humans.

J Pharmacol Toxicol Methods 2017 Nov - Dec;88(Pt 2):147-152. Epub 2017 Sep 30.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address:

Introduction: Adult zebrafish pharmacology is evolving rapidly for creating efficacy and safety models for drug discovery. However, there is very limited research in understanding pharmacokinetics (PK) in adult zebrafish. Methods for understanding PK will help in conducting pharmacokinetic - pharmacodynamic (PK-PD) correlations and improving the quality and applicability of data obtained using zebrafish.

Methods: We conducted adult zebrafish PK and brain penetration studies on two known compounds (irinotecan and lorcaserin) with distinct PK and brain penetration properties using validated LCMS/MS method. Irinotecan was studied at a dose of 100mg/kg i.p. and levels of the parent drug and active metabolite SN-38 were measured. Loracserin was studies at a dose of 10mg/kg by two routes i.p. and p.o.

Results: Zebrafish PK and brain penetration profiles for both compounds were very similar to that of higher mammals including humans. Irinotecan was metabolised to SN-38 in ratios similar to ratios seen in other species and the compound had long half life with very low brain penetration in our studies. Loracasin was highly permeable in brain as compared to the exposure in blood, with long half life and high relative bioavailability, similar to other mammalian species including humans.

Discussion: Adult zebrafish PK studies are relatively an unexplored area of zebrafish research. The zebrafish data for key parameters of irinotecan and loracserin shows a high correlation to the data from higher species, including human. This report explores and discusses the use of adult zebrafish as a predictive PK tool for higher animal studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vascn.2017.09.258DOI Listing
July 2018

MG17, A Novel Triazole Derivative Abrogated Neuroinflammation and Related Neurodegenerative Symptoms in Rodents.

Curr Mol Pharmacol 2018 ;11(2):122-132

Neuropathic Pain Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Telangana, India.

Background And Objective: The objective of present study is to explore multiple effects of the compound MG17 and relate them to achieve better therapeutic potential against neuroinflammation related disorders. We examined whether our compound is acting through regulating neuroinflammatory mediators.

Methods: We have done some preliminary behavioral studies to shortlist the derivatives using rodent models of peripheral nerve injury in our earlier publication and now we extended our screening studies to explore the test compounds efficacy on other related peripheral neurological disorders such as Streptozotocin- induced diabetic peripheral neuropathy (DPN) and methyl mercury (MeHg) induced neurodegeneration in rats. Pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were quantified with RT-qPCR studies and histopathology studies were performed taking tissue samples from MeHg induced neurodegeneration rats. The effect of MG17 was assessed on local and acute inflammation through carrageenan-induced rat paw edema model.

Results: We observed the reduction in nociceptive responses in DPN rats. Pain threshold was reduced greater than 50% in various pain assessment modules. Upregulated pro-inflammatory cytokines which are thought to have a prominent role in neuroinflammation was controlled near to normal level quantified by RT-PCR studies. However, MG17 was able to regulate IL-6 and TNF-α but not IL-1β.

Conclusion: Our results clearly suggest the beneficial potential of compound MG17 through inhibition of pro-inflammatory cytokines upregulation. MG17 could be an intriguing therapeutic approach in diabetesrelated neuro-pathophysiological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1874467210666170919160245DOI Listing
January 2019

Bis-spirochromanones as potent inhibitors of Mycobacterium tuberculosis: synthesis and biological evaluation.

Mol Divers 2017 Nov 24;21(4):999-1010. Epub 2017 Aug 24.

X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana State, 500 007, India.

On the basis of reported antimycobacterial property of chroman-4-one pharmacophore, a series of chemically modified bis-spirochromanones were synthesized starting from 2-hydroxyacetophenone and 1,4-dioxaspiro[4.5] decan-8-one using a Kabbe condensation approach. The synthesized bis-spirochromanones were established based on their spectral data and X-ray crystal structure of 6e. All synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain, finding that some products exhibited good antimycobacterial activity with minimum inhibitory concentration as low as [Formula: see text]. Docking studies were carried out to identify the binding interactions of compounds II, 6a and 6n with FtsZ. Compounds exhibiting good in vitro potency in the MTB MIC assay were further evaluated for toxicity using the HEK cell line.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11030-017-9779-yDOI Listing
November 2017

Synthesis, molecular modeling and biological evaluation of aza-flavanones as α-glucosidase inhibitors.

Medchemcomm 2017 Aug 14;8(8):1618-1630. Epub 2017 Jun 14.

Centre for Chemical Sciences & Technology , Institute of Science and Technology , JNTUH, Kukatpally , Hyderabad 500085 , Telangana State , India . Email:

An efficient acid catalyzed methodology has been employed to synthesize a variety of aza-flavanones and their α-glucosidase inhibitory activity is evaluated using acarbose, miglitol and voglibose as reference standards. Molecular modeling studies were performed for all compounds to identify the important binding modes responsible for the inhibition activity of α-glucosidase which helped find key interactions between the enzyme and the active compounds. Among all the compounds , and have shown high α-glucosidase inhibition activity compared to standard reference drugs and have been identified as promising potential antidiabetic agents. This study is the first biological evaluation of aza-flavanones as α-glucosidase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c7md00162bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072087PMC
August 2017

Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines.

Bioorg Med Chem Lett 2017 06 2;27(12):2818-2823. Epub 2017 May 2.

Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd, Plot. No. 28 A, IDA, Nacharam, Hyderabad 500076, Telangana State, India.

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar -NH group, 10f/11f having polar -OH group on phenyl ring displayed 3-4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.04.078DOI Listing
June 2017

Novel Thiazolidinone-Azole Hybrids: Design, Synthesis and Antimycobacterial Activity Studies.

Iran J Pharm Res 2016 ;15(4):783-790

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

To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to condensation. To evaluate their structures H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 μM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316256PMC
January 2016

Novel Zebrafish EAE model: A quick in vivo screen for multiple sclerosis.

Mult Scler Relat Disord 2017 Jan 28;11:32-39. Epub 2016 Nov 28.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad-500078, India. Electronic address:

Introduction: Pre-clinical drug discovery for multiple sclerosis (MS) is a labor intensive activity to perform in rodent models. This is owing to the long duration of disease induction and observation of treatment effects in an experimental autoimmune encephalomyelitis (EAE) model. We propose a novel adult zebrafish based model which offers a quick and simple protocol that can used to screen candidates as a step between in vitro experiments and rodent studies. The experiments conducted for this manuscript were to standardize a suitable model of EAE in adult zebrafish and validate it using known modulators.

Methods: The EAE model was developed by disease induction with myelin oligodendrocyte glycoprotein - 35-55 (MOG) and observation of survival, clinical signs and body weight changes. We have validated this model using fingolimod. We have further performed detailed validation using dimethyl fumarate, dexamethasone and SR1001, which are known modulators of rodent EAE.

Results: The immunization dose for the disease induction was observed to be 0.6mg/ml of MOG in CFA (Complete Freund's adjuvant), injected subcutaneously (s.c.) near spinal vertebrae. In the validation study with fingolimod, we have demonstrated the modulation of disease symptoms, which were also confirmed by histopathological evaluation. Furthermore, detailed validation with three other known drugs showed that our observations concur with those reported in conventional rodent models.

Discussion: We have standardized and validated the adult zebrafish EAE model. This model can help get a quick idea of in vivo activity of drugs in a week using very low quantities of candidate compounds. Further work will be required to define this model particularly as it is found that zebrafish may not express a MOG homologue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2016.11.010DOI Listing
January 2017

Design and development of novel inhibitors for the treatment of latent tuberculosis.

Int J Mycobacteriol 2016 Dec 21;5 Suppl 1:S121-S122. Epub 2016 Oct 21.

Tuberculosis Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad, India. Electronic address:

Objective/background: "The captain of all these men of death", is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents. Lysine ε-aminotransferase (LAT) in MTB plays a pivotal role in regulating amino acid synthesis, which in turn affects mycobacterial persistence. Here, developed quinoline inhibitors that targeted LAT with an objective to eliminate dormant forms of mycobacterium.

Methods: Using e-pharmacophore approaches, quinolone (PBD: 2CJD) leads were found to inhibit lysine binding to LAT. To investigate structural activity relationships, 21 analogues were synthesized and characterized based on the identified lead molecules.

Results: Among the derivatives, N-(pyridin-2-yl methyl)-2-(4-(quinolin-4-yl) piperazin-1-yl) acetamide was identified as a potent molecule, with an IC for LAT of 1.04μM. In nutrient-starved and zebra fish models, this molecule exhibited logarithmic reductions of 2.1- and 2.2-fold, respectively, at a concentration of 10μg/mL. The compound also exhibited good activity against persistent forms of mycobacteria (biofilm model), showing logarithmic reduction of 2.8-fold. Additionally, the hit molecule showed concentration-dependent kill kinetics against dormant forms of mycobacteria, and were devoid of cytotoxicity against RAW cell lines 264.7 at concentrations of 50μM.

Conclusion: Our results indicated that the hit molecule showed activity against both active and persistent forms of infection, which is ideal for new anti-TB agents. This molecule requires further pharmacokinetic and dynamic screening for development as new drug candidate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijmyco.2016.09.006DOI Listing
December 2016

Design, synthesis, molecular-docking and antimycobacterial evaluation of some novel 1,2,3-triazolyl xanthenones.

Medchemcomm 2017 Mar 3;8(3):559-570. Epub 2017 Jan 3.

Molecular Modeling and Medicinal Chemistry Group , Department of Chemistry , Osmania University , Hyderabad , Telangana-500 007 , India.

As part of an ongoing effort to develop new antitubercular and antimicrobial agents, a series of substituted xanthenone derivatives () were synthesized. Xanthenone derivatives () were prepared a one-pot three-component thermal cyclization reaction of β-naphthol (), substituted 1-aryl-1-[1,2,3]triazole-4-carbaldehydes (), and cyclic-1,3-diones (, ) in the presence of a catalytic amount of iodine. The newly synthesized compounds were characterized by IR, NMR, mass spectral data, and elemental analysis. These compounds ( and ) were screened for antitubercular activity against the HRv (ATCC 27294) strain, for antibacterial activity against Gram-positive and Gram-negative strains, and for antifungal activity against a pathogenic strain of fungi. Among the compounds tested, most of them showed good to excellent antimicrobial and antitubercular activity. The active compounds displaying good potency in the MTB were further examined for toxicity in a HEK cell line. In addition, the structure and antitubercular activity relationship were further supported by molecular-docking studies of the active compounds against the pantothenate synthetase (PS) enzyme of .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6md00593dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072411PMC
March 2017

Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug.

Arch Pharm Res 2017 Feb 27;40(2):168-179. Epub 2016 Dec 27.

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

The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39-1.5 μg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 µg/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12272-016-0882-xDOI Listing
February 2017

Design, development of new synthetic methodology, and biological evaluation of substituted quinolines as new anti-tubercular leads.

Bioorg Med Chem Lett 2016 12 29;26(24):5960-5966. Epub 2016 Oct 29.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India. Electronic address:

Two series of quinoline-based compounds were designed, synthesised and evaluated for anti-tubercular activity against Mycobacterium tuberculosis HRv (ATCC 27294 strain). A new method for Friedländer quinoline synthesis has been developed in water under the catalytic influence of the Brønsted acid surfactant DBSA. Among the forty-two compounds tested for anti-TB activity, twenty-three compounds exhibited significant activity against the growth of M. tuberculosis (MIC 0.02-6.25μg/mL). In particular, the compounds 3b and 3c displayed excellent anti-TB activity with MIC values of 0.2 and 0.39μg/mL, respectively, and are more potent than the standard drugs E, Cfx and Z that are clinically used to treat TB. The cytotoxicity of the compounds with MIC ⩽6.25μg/mL was evaluated against Human Embryonic Kidney 293T cell lines and all of the active compounds were found to be nontoxic (<50% inhibition). The results suggest that the synthesised substituted quinolines are promising leads for development of new drug to treat TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.10.082DOI Listing
December 2016

Anti-tubercular activities of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues endowed with high activity toward non-replicative Mycobacterium tuberculosis.

Bioorg Med Chem 2016 11 9;24(21):5556-5564. Epub 2016 Sep 9.

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

Thirty three derivatives of 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine analogues were synthesized by molecular modification of a reported antimycobacterial molecule (GSK163574A). Compounds were evaluated in vitro against actively replicative and nutrient starved non-replicative Mycobacterium tuberculosis (MTB), enzymatic screening and cytotoxicity against RAW 264.7 cell line. Among the compounds, 2-ethyl-N-phenethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine (5c) was found to be the most active compound against non-replicative MTB with 2.7 log reduction of bacteria at 10μg/mL and was more potent than isoniazid (1.2 log reduction) and rifampicin (2.0 log reduction) at same dose level. Compound 5c also showed activity against MTB alanine dehydrogenase enzyme with IC of 1.82±0.42μM and showed 25% cytotoxicity against RAW 264.7 cell line at 50μg/mL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2016.09.012DOI Listing
November 2016

Structural Models for the Design of PKMzeta Inhibitors with Neurobiological Indications.

Mol Inform 2015 10 14;34(10):665-78. Epub 2015 Sep 14.

Computer-Aided Drug Design Lab, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad-500078, A.P., India phone: +91-40-66303515, +91-40-66303506; fax: +91-40-66303998.

An atypical protein kinase C, PKMzeta has become an attractive target for various neurological disorders including long term potentiation, cognition, neuropathic pain and cancer. Drug discovery efforts have been hindered due to the non-availability of the protein structure and hence in the present study we attempted to build the open and closed models of the protein PKMzeta using homology modeling. The models were then used to identify PKMzeta inhibitors utilizing a high-throughput virtual screening protocol from a large commercial chemical database. Compounds were selected based on the binding interactions and Glide score. Compounds were then subjected to in vitro luminescent based kinase assay for their inhibitory activity on targeted protein. Seven compounds exhibited IC50 s less than or equal to 10 µM. Cell based assays revealed that Lead C3 and Lead C6 exhibited selectivity towards methylmercury treated neuroblastoma growth inhibition and suppressed reactive oxygen species with IC50 s of 0.89 and 0.17 µM, respectively. Furthermore, Lead C3 exhibited attenuation of proinflammatory response with least energy in dynamic simulation studies and thus emerged as a prototypical lead for further development as novel inhibitor of PKMzeta for neurological implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/minf.201500003DOI Listing
October 2015

Design and development of new class of Mycobacterium tuberculosisl-alanine dehydrogenase inhibitors.

Bioorg Med Chem 2016 09 25;24(18):4499-4508. Epub 2016 Jul 25.

Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad 500078, India. Electronic address:

Mycobacterium tuberculosisl-alanine dehydrogenase (MTB l-AlaDH) is one of the important drug targets for treating latent/persistent tuberculosis. In this study we used crystal structure of the MTB l-AlaDH bound with cofactor NAD(+) as a structural framework for virtual screening of our in-house database to identified new classes of l-AlaDH inhibitor. We identified azetidine-2,4-dicarboxamide derivative as one of the potent inhibitor with IC50 of 9.22±0.72μM. Further lead optimization by synthesis leads to compound 1-(isonicotinamido)-N(2),N(4)-bis(benzo[d]thiazol-2-yl)azetidine-2,4-dicarboxamide (18) with l-AlaDH IC50 of 3.83±0.12μM, 2.0log reduction in nutrient starved dormant MTB model and MIC of 11.81μM in actively replicative MTB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2016.07.051DOI Listing
September 2016

Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.

J Med Chem 2016 07 13;59(14):6848-59. Epub 2016 Jul 13.

Division of Molecular Structural Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet , S-171 77 Stockholm, Sweden.

Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17 312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.6b00674DOI Listing
July 2016

Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors.

Eur J Med Chem 2016 Oct 24;122:216-231. Epub 2016 Jun 24.

Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Shameerpet, R.R. District, Hyderabad, 500078, Andhra Pradesh, India. Electronic address:

A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2016.06.042DOI Listing
October 2016

Click-based synthesis and antitubercular evaluation of dibenzofuran tethered thiazolyl-1,2,3-triazolyl acetamides.

Bioorg Med Chem Lett 2016 08 2;26(15):3684-9. Epub 2016 Jun 2.

Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India. Electronic address:

A series of novel dibenzofuran tethered thiazolyl-1,2,3-triazolyl acetamides, designed by assembling antitubercular pharmacophoric fragments, dibenzofuran, 2-aminothiazole and substituted triazoles in one molecular architecture, were evaluated against Mycobacterium tuberculosis. The new analogues 6a-p accomplished in four step synthetic sequence utilizing click chemistry in the penultimate step, was fully characterized by their NMR and mass spectral data. Among the compounds 6a-p screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, three compounds 6j (MIC: 1.56μg/mL); 6a and 6p (MIC: 3.13μg/mL) was found to be most active and exhibited lower cytotoxicity. Among these three, 6j could be a candidate to consider as a drug like hit analogue for further development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.05.085DOI Listing
August 2016

Synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine-3-carboxamides.

Bioorg Med Chem Lett 2016 07 30;26(13):3135-3140. Epub 2016 Apr 30.

Organic Chemistry Division-II (CPC Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India. Electronic address:

A series of novel dibenzo[b,d]thiophene tethered imidazo[1,2-a]pyridine carboxamides 7a-s were designed and synthesized. The required building block, 2-dibenzo[b,d]thiophenyl imidazo[1,2-a]pyridine carboxylic acid (5) was synthesized from commercial dibenzo[b,d]thiophene in good yields following five-step reaction sequence. The desired carboxamides 7a-s was prepared through coupling of acid 5 with various benzyl amines. All the new analogues 7a-s was characterized by their NMR and mass spectral analysis. Among nineteen new compounds 7a-s screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, three compounds 7k (MIC: 0.78μg/mL); 7e and 7n (MIC: 1.56μg/mL) were identified as potent analogues with low cytotoxicity. The results reported here will help global efforts for identification of potential lead antimycobacterial agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.04.088DOI Listing
July 2016

Targeting multiple response regulators of Mycobacterium tuberculosis augments the host immune response to infection.

Sci Rep 2016 05 16;6:25851. Epub 2016 May 16.

Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.

The genome of M. tuberculosis (Mtb) encodes eleven paired two component systems (TCSs) consisting of a sensor kinase (SK) and a response regulator (RR). The SKs sense environmental signals triggering RR-dependent gene expression pathways that enable the bacterium to adapt in the host milieu. We demonstrate that a conserved motif present in the C-terminal domain regulates the DNA binding functions of the OmpR family of Mtb RRs. Molecular docking studies against this motif helped to identify two molecules with a thiazolidine scaffold capable of targeting multiple RRs, and modulating their regulons to attenuate bacterial replication in macrophages. The changes in the bacterial transcriptome extended to an altered immune response with increased autophagy and NO production, leading to compromised survival of Mtb in macrophages. Our findings underscore the promise of targeting multiple RRs as a novel yet unexplored approach for development of new anti-mycobacterial agents particularly against drug-resistant Mtb.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep25851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867592PMC
May 2016

Click-based synthesis and antitubercular evaluation of novel dibenzo[b,d]thiophene-1,2,3-triazoles with piperidine, piperazine, morpholine and thiomorpholine appendages.

Bioorg Med Chem Lett 2016 06 7;26(11):2649-54. Epub 2016 Apr 7.

Organic Chemistry Division-II (C P C Division), CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India; Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, Telangana, India. Electronic address:

A series of novel piperidine, piperazine, morpholine and thiomorpholine appended dibenzo[b,d]thiophene-1,2,3-triazoles were designed and synthesized utilizing azide-alkyne click chemistry in the penultimate step. The required azide building block 6a-e was synthesized from commercial dibenzo[b,d]thiophene in good yields following five step reaction sequence. All the new analogues 8a-f, 9a-f, 10a-f, 11a-f &12a-f were characterized by their NMR and mass spectral analysis. Screening all thirty new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv, resulted 8a, 8f and 11e as potent analogues with MIC 0.78μg/mL, 0.78μg/mL & 1.56μg/mL, respectively, and has shown lower cytotoxicity. Interestingly, all six piperazine appended dibenzo[b,d]thiophene-1,2,3-triazoles 11a-f exhibited Mtb inhibition activity with MIC 1.56-12.5μg/mL. To some extent, the data observed here indicated Mycobacterium tuberculosis inhibition among the appendages is in the order, piperazine>thiomorpholine>morpholine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.04.015DOI Listing
June 2016

Synthesis, biological evaluation and structure-activity relationship of 2-styrylquinazolones as anti-tubercular agents.

Bioorg Med Chem Lett 2016 06 7;26(11):2663-9. Epub 2016 Apr 7.

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, Punjab 160 062, India. Electronic address:

2-Styrylquinazolones are reported as a novel class of potent anti-mycobacterial agents. Forty-six target compounds have been synthesized using one pot reaction involving isatoic anhydride, amine, and triethyl orthoacetate followed by aldehyde to construct the 2-styrylquinazolone scaffold. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twenty-six compounds exhibited anti-Mtb activity in the range of 0.40-6.25μg/mL. Three compounds 8c, 8d and 8ab showed MIC of 0.78μg/mL and were found to be non-toxic (<50% inhibition at 50μg/mL) to HEK 293T cell lines with the therapeutic index >64. The most potent compound 8ar showed MIC of 0.40μg/mL with the therapeutic index >125. An early structure activity relationship for this class of compounds has been established. The computational studies indicate the possibility of these compounds binding to the penicillin binding proteins (PBPs).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.04.012DOI Listing
June 2016

Synthesis, molecular properties prediction and anticancer, antioxidant evaluation of new edaravone derivatives.

Bioorg Med Chem Lett 2016 05 9;26(10):2562-2568. Epub 2016 Mar 9.

Centre for Chemical Sciences and Technology, IST, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, Telangana State, India. Electronic address:

A series of new edaravone derivatives 3-7 have been synthesized, characterised using various spectroscopic techniques and screened for their in vitro anti-cancer, antioxidant activities. Structure of 5d was further substantiated through single crystal X-ray diffraction. Among the tested, 5l exhibited pronounced activity against PC3 cancer cells. Compounds 5i, 5l, 7c showed potent activity against A549 cancer cells. Products 5k, 6, 7c demonstrated good antioxidant activity with MIC values of 18.60, 16.27, 16.07μg/mL respectively. Further the reported analogues were also tested on normal HEK293T cells and displayed low to good safer profiles. Derivatives 5l and 7c have come out to be safer potent anticancer, antioxidant agents. Additionally, the target products were subjected to their molecular properties prediction and drug likeness by employing Molinspiration and Osiris property explorer toolkits. None of them violated Lipinski's boundaries classifying the title compounds as potential anticancer and antioxidant agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2016.03.024DOI Listing
May 2016

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole-Thiourea Scaffold as Antituberculosis Agents.

Biol Pharm Bull 2016 ;39(4):502-15

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University.

In view of the emergence and frequency of multidrug-resistant and extensively drug-resistant tuberculosis and consequences of acquired resistance to clinically used drugs, we undertook the design and synthesis of novel prototypes that possess the advantage of the two pharmacophores of thiourea and 1,3,4-thiadiazole in a single molecular backbone. Three compounds from our series were distinguished from the others by their promising activity profiles against Mycobacterium tuberculosis strain H37Rv. Compounds 11 and 19 were the most active representatives with minimum inhibitory concentration (MIC) values of 10.96 and 11.48 µM, respectively. Compound 15 was shown to inhibit M. tuberculosis strain H37Rv with an MIC value of 17.81 µM. Cytotoxicity results in the Vero cell line showed that these three derivatives had selectivity indices between 1.8 and 8.7. In order to rationalize the biological results of our compounds, molecular docking studies with the enoyl acyl carrier protein reductase (InhA) of M. tuberculosis were performed and compounds 11, 15, and 19 were found to have good docking scores in the range of -7.12 to -7.83 kcal/mol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/bpb.b15-00698DOI Listing
January 2017
-->