Seema Bag - Academia.edu (original) (raw)
Papers by Seema Bag
Parasitology, 2013
In view of the mandate from the World Health Organization (WHO) for developing novel drug candida... more In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide-acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
Future Medicinal Chemistry, 2015
Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against... more Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. Results: The compounds were evaluated against Mtb (H 37 Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 μM and 6i minimum inhibitory concentration: 1.57 μM) along with low cytotoxicity (CC 50 : >300 μM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. Conclusion: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.
Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications VI, 2014
Photoacoustic imaging (PAI) is emerging as a key in vivo imaging technique. Endogenous contrast a... more Photoacoustic imaging (PAI) is emerging as a key in vivo imaging technique. Endogenous contrast agents alone are insufficient to obtain high contrast images necessitating a need for synthetic exogenous contrast agents. In recent years a great deal of research has been devoted to the development of nanoparticle based contrast agents with little effort on molecular systems. Here we report on the design and evaluation of BODIPY inspired molecular photoacoustic contrast agents (MPACs). Through chemical modification of the established BODIPY fluorophore, increasing its vibrational freedom and appending with non-emissive functionalities, it is demonstrated that the S0S1 absorbed excitation energy is redirected towards a nonradiative excited-state decay pathway. Optical and photoacoustic characterization of the modified BODIPY MPACs demonstrates a stronger photoacoustic signal compared to the corresponding fluorescent BODIPY probes. Downloaded From: http://spiedigitallibrary.org/ on 07/17/2014 Terms of Use: http://spiedl.org/terms Proc. of SPIE Vol. 8956 895609-2 Downloaded From: http://spiedigitallibrary.org/ on 07/17/2014 Terms of Use: http://spiedl.org/terms
Bioorganic & Medicinal Chemistry Letters, 2015
Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized ... more Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer's disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
Inorganic Chemistry, 2014
A series of ruthenium polypyridyl complexes are presented incorporating π-extended electron rich ... more A series of ruthenium polypyridyl complexes are presented incorporating π-extended electron rich derivatives of the 8-oxyquinolate (OQN) ligand. The π-donating property of the OQN ligand introduces covalent character to the Ru(dπ)-OQN(π) bonding scheme enhancing its light harvesting properties and diversifying its redox properties, relative to the classic ruthenium(II) trisbipyridyl complex [Ru(bpy)3](2+). Synthesis and characterization is presented for the complexes [Ru(bpy)2(R-OQN)](PF6), where bpy = 2,2'-bipyridine and R = 5-phenyl, 5,7-diphenyl, 2,4-diphenyl, 5,7-bis(4-methoxyphenyl), 5,7-bis(4-(diphenylamino)phenyl). A comprehensive bonding analysis is presented for the [Ru(bpy)2(OQN)](+) system illustrating the origin of its unique spectroscopic and redox properties relative to [Ru(bpy)3](2+). This model is then extended to enable a consistent interpretation of spectra and redox properties for the π-extended [Ru(bpy)2(R-OQN)](PF6) series. Electronic structures have been probed experimentally by a combination of electrochemical and spectroscopic techniques (UV-vis-NIR absorption, emission, EPR spectroscopy) where (metal-ligand)-to-ligand (MLLCT) charge-transfer properties are described by time dependent-density functional theory (TD-DFT) analysis, at the B3LYP/6-31g(d,p) level of approximation. Substantial mixing, due to bonding and antibonding combinations of Ru(dπ) and OQN(π) orbitals, is observed at the HOMO and HOMO-3 levels for the ruthenium-oxyanion bond in [Ru(bpy)2(OQN)](+), which is responsible for the low-energy MLLCT based electronic transition and destabilization of the HOMO level viz. cyclic voltammetry. This noninnocent π-bonding phenomenon is consistent throughout the series which allows for controlled tuning of complex redox potentials while maintaining panchromatic absorption properties across the visible spectrum. Extensive charge delocalization is observed for the one-electron oxidized species using a combination of UV-vis-NIR, EPR spectroelectrochemistry, and Mulliken spin-density analysis, giving strong evidence for hole-delocalization across the delocalized Ru(dπ)-OQN(π) system, in particular for the electron rich 5,7-bis(4-methoxyphenyl) and 5,7-bis(4-(diphenylamino)phenyl) systems.
Zhang/Green Techniques for Organic Synthesis and Medicinal Chemistry, 2012
ChemInform, 2010
Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bac... more Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (K d < 10 -25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC:<10HM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.
Journal of the American Chemical Society, 2014
A first approach toward understanding the targeted design of molecular photoacoustic contrast age... more A first approach toward understanding the targeted design of molecular photoacoustic contrast agents (MPACs) is presented. Optical and photoacoustic Z-scan spectroscopy was used to identify how nonlinear (excitedstate) absorption contributes to enhancing the photoacoustic emission of the curcuminBF 2 and bis-styryl (MeOPh) 2 BODIPY dyes relative to Cy3. C ombining the advantages of both ultrasound and optical imaging, photoacoustic tomography (PAT) 1−5 and photoacoustic microscopy (PAM) 6−9 are emerging as highly promising imaging alternatives. Based upon the classical photoacoustic (PA) effect, photoacoustic imaging relies upon a materials generation of acoustic waves in response to absorption of electromagnetic radiation. 10 A major advantage of PAT and PAM over their fluorescence counterparts is that the output acoustic waves are far less susceptible to scatter than optical waves, allowing for deeper penetration, which is particularly advantageous during photoacoustic tomography (PAT) in vivo. 5 However, application of both PAT and PAM is currently limited due to a lack of available contrast agents. 11 A common assumption is that any dye with a low fluorescence quantum yield will make for a suitable PA contrast agent. In this respect, cyanine dyes have been highly studied as molecular photoacoustic contrast agents (MPACs) with metallic and polymeric nanodimensional materials also attracting much interest of late. 12,14−21 Contrary to this assumption, we aim to demonstrate how a strongly fluorescent bis-styryl (MeOPh) 2 BODIPY dye (Φ fl = 0.719; 1 τ = 5.41 ns) can display an enhanced PA signal, far exceeding that of the Cy3 (Φ fl = 0.025; 1 τ = 0.28 ns) cyanine dye. More importantly, with respect to the future design of efficient MPACs, an excited-state sequential absorption mechanism is identified as responsible for this PA enhancement, highlighting the advantage of a long-lived S 1 excited state combined with a high quantum yield to facilitate a strong PA emission.
Current Computer - Aided Drug Design, 2013
One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen th... more One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidβ (Aβ) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer&amp;amp;amp;#39;s disease.
Current Computer Aided-Drug Design, 2013
One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen th... more One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidβ (Aβ) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer&amp;amp;amp;#39;s disease.
Current Organic Synthesis, 2011
The oxidative coupling of methane was investigated over alumina supported La 2 O 3 /CeO 2 catalys... more The oxidative coupling of methane was investigated over alumina supported La 2 O 3 /CeO 2 catalysts under microwave dielectric heating conditions at different oxygen concentrations. It was observed that, at a given temperature using microwave heating, selectivities for both ethane and ethylene were notably higher when oxygen was absent than that in oxygen/methane mixtures. The differences were attributed to the localised heating of microwave radiation resulting in temperature inhomogeneity in the catalyst bed. A simplified model was used to estimate the temperature inhomogeneity; the temperature at the centre of the catalyst bed was 85°C greater than that at the periphery when the catalyst was heated by microwaves in a gas mixture with an oxygen concentration of 12.5% (v/v), and the temperature difference was estimated to be 168°C in the absence of oxygen.
Parasitology, 2013
In view of the mandate from the World Health Organization (WHO) for developing novel drug candida... more In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide-acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
QSAR & Combinatorial Science, 2007
... 5 H Ā2.0334 6 H Ā1.8751 7 H Ā1.5682 8 H Ā3.3010 9 H Ā1.1461 3-D-QSAR Analysis of 2-(Oxalylami... more ... 5 H Ā2.0334 6 H Ā1.8751 7 H Ā1.5682 8 H Ā3.3010 9 H Ā1.1461 3-D-QSAR Analysis of 2-(Oxalylamino) benzoic acid Class of Protein Tyrosine Phosphatase 1B Inhibitors Page 3. 610 2007 WILEY-VCH Verlag GmbH & Co. ... b ND: not defined. Full Papers S. Ramar et al. Page 4. ...
QSAR & Combinatorial Science, 2009
To facilitate the discovery of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) inh... more To facilitate the discovery of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) inhibitors, various molecular modeling studies such as homology modeling, pharmacophore mapping, and 3D-QSAR studies were undertaken. To address the issue of bioactive conformer in ligand-based approaches, ensemble of conformers obtained from docking studies was used for pharmacophore mapping and for 3D-QSAR studies. The developed structure-chemical-feature-based pharmacophore model was consistent with the structure-functional requirements for the binding of the DHFR inhibitors. Using the generated homology model, interactions between the reported inhibitors were explored. The results showed that the type and spatial location of chemical features encoded in the pharmacophore and 3D-QSAR contours are in agreement with the enzyme inhibitor interaction pattern identified from molecular docking. The outcomes of the study could be used for the rational design of potent and selective MAC DHFR inhibitors.
Medicinal Chemistry Research, 2009
With the aim of developing potential antifungals, a series of chalcones incorporating sulfur eith... more With the aim of developing potential antifungals, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized and tested for their in vitro activity. Some of the compounds showed appreciable activity against a fluconazole-resistant strain, and could act as new hits for the design of better analogs.
Journal of Molecular Modeling, 2008
Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrim... more Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A fivepoint pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r 2 =0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q 2 =0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors.
Journal of Heterocyclic Chemistry, 2010
Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bac... more Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (K d < 10 -25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC:<10HM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2010
Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors... more Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, ∼233-fold improved potency over trimethoprim and ∼7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.
Journal of Chemical Research, 2006
Vitamin B1 is used as catalyst for a very fast microwave-assisted benzoin condensation reaction. ... more Vitamin B1 is used as catalyst for a very fast microwave-assisted benzoin condensation reaction. -(BAG, S.; VAZE, V. V.; DEGANI*, M. S.; J. Chem.
Parasitology, 2013
In view of the mandate from the World Health Organization (WHO) for developing novel drug candida... more In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide-acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
Future Medicinal Chemistry, 2015
Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against... more Background: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. Results: The compounds were evaluated against Mtb (H 37 Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 μM and 6i minimum inhibitory concentration: 1.57 μM) along with low cytotoxicity (CC 50 : >300 μM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. Conclusion: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.
Reporters, Markers, Dyes, Nanoparticles, and Molecular Probes for Biomedical Applications VI, 2014
Photoacoustic imaging (PAI) is emerging as a key in vivo imaging technique. Endogenous contrast a... more Photoacoustic imaging (PAI) is emerging as a key in vivo imaging technique. Endogenous contrast agents alone are insufficient to obtain high contrast images necessitating a need for synthetic exogenous contrast agents. In recent years a great deal of research has been devoted to the development of nanoparticle based contrast agents with little effort on molecular systems. Here we report on the design and evaluation of BODIPY inspired molecular photoacoustic contrast agents (MPACs). Through chemical modification of the established BODIPY fluorophore, increasing its vibrational freedom and appending with non-emissive functionalities, it is demonstrated that the S0S1 absorbed excitation energy is redirected towards a nonradiative excited-state decay pathway. Optical and photoacoustic characterization of the modified BODIPY MPACs demonstrates a stronger photoacoustic signal compared to the corresponding fluorescent BODIPY probes. Downloaded From: http://spiedigitallibrary.org/ on 07/17/2014 Terms of Use: http://spiedl.org/terms Proc. of SPIE Vol. 8956 895609-2 Downloaded From: http://spiedigitallibrary.org/ on 07/17/2014 Terms of Use: http://spiedl.org/terms
Bioorganic & Medicinal Chemistry Letters, 2015
Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized ... more Sulfonamide linker-based inhibitors with extended linear structure were designed and synthesized with the aim of producing multifunctional agents against several processes involved in the pathology of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). The potency of the compounds were assessed in the inhibition of Aβ self-assembly (fibril and oligomer formation), in modulating cholinesterase (AChE, BuChE) activity, and scavenging free radicals. Several compounds exhibited promising Aβ self-assembly and cholinesterase inhibition and in parallel, showed good free radical scavenging properties. The investigation of the scaffold described in this study resulted in the identification of three compounds (14, 19 and 26) as promising leads for the further design of multifunctional drug candidates for AD.
Inorganic Chemistry, 2014
A series of ruthenium polypyridyl complexes are presented incorporating π-extended electron rich ... more A series of ruthenium polypyridyl complexes are presented incorporating π-extended electron rich derivatives of the 8-oxyquinolate (OQN) ligand. The π-donating property of the OQN ligand introduces covalent character to the Ru(dπ)-OQN(π) bonding scheme enhancing its light harvesting properties and diversifying its redox properties, relative to the classic ruthenium(II) trisbipyridyl complex [Ru(bpy)3](2+). Synthesis and characterization is presented for the complexes [Ru(bpy)2(R-OQN)](PF6), where bpy = 2,2&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-bipyridine and R = 5-phenyl, 5,7-diphenyl, 2,4-diphenyl, 5,7-bis(4-methoxyphenyl), 5,7-bis(4-(diphenylamino)phenyl). A comprehensive bonding analysis is presented for the [Ru(bpy)2(OQN)](+) system illustrating the origin of its unique spectroscopic and redox properties relative to [Ru(bpy)3](2+). This model is then extended to enable a consistent interpretation of spectra and redox properties for the π-extended [Ru(bpy)2(R-OQN)](PF6) series. Electronic structures have been probed experimentally by a combination of electrochemical and spectroscopic techniques (UV-vis-NIR absorption, emission, EPR spectroscopy) where (metal-ligand)-to-ligand (MLLCT) charge-transfer properties are described by time dependent-density functional theory (TD-DFT) analysis, at the B3LYP/6-31g(d,p) level of approximation. Substantial mixing, due to bonding and antibonding combinations of Ru(dπ) and OQN(π) orbitals, is observed at the HOMO and HOMO-3 levels for the ruthenium-oxyanion bond in [Ru(bpy)2(OQN)](+), which is responsible for the low-energy MLLCT based electronic transition and destabilization of the HOMO level viz. cyclic voltammetry. This noninnocent π-bonding phenomenon is consistent throughout the series which allows for controlled tuning of complex redox potentials while maintaining panchromatic absorption properties across the visible spectrum. Extensive charge delocalization is observed for the one-electron oxidized species using a combination of UV-vis-NIR, EPR spectroelectrochemistry, and Mulliken spin-density analysis, giving strong evidence for hole-delocalization across the delocalized Ru(dπ)-OQN(π) system, in particular for the electron rich 5,7-bis(4-methoxyphenyl) and 5,7-bis(4-(diphenylamino)phenyl) systems.
Zhang/Green Techniques for Organic Synthesis and Medicinal Chemistry, 2012
ChemInform, 2010
Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bac... more Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (K d < 10 -25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC:<10HM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.
Journal of the American Chemical Society, 2014
A first approach toward understanding the targeted design of molecular photoacoustic contrast age... more A first approach toward understanding the targeted design of molecular photoacoustic contrast agents (MPACs) is presented. Optical and photoacoustic Z-scan spectroscopy was used to identify how nonlinear (excitedstate) absorption contributes to enhancing the photoacoustic emission of the curcuminBF 2 and bis-styryl (MeOPh) 2 BODIPY dyes relative to Cy3. C ombining the advantages of both ultrasound and optical imaging, photoacoustic tomography (PAT) 1−5 and photoacoustic microscopy (PAM) 6−9 are emerging as highly promising imaging alternatives. Based upon the classical photoacoustic (PA) effect, photoacoustic imaging relies upon a materials generation of acoustic waves in response to absorption of electromagnetic radiation. 10 A major advantage of PAT and PAM over their fluorescence counterparts is that the output acoustic waves are far less susceptible to scatter than optical waves, allowing for deeper penetration, which is particularly advantageous during photoacoustic tomography (PAT) in vivo. 5 However, application of both PAT and PAM is currently limited due to a lack of available contrast agents. 11 A common assumption is that any dye with a low fluorescence quantum yield will make for a suitable PA contrast agent. In this respect, cyanine dyes have been highly studied as molecular photoacoustic contrast agents (MPACs) with metallic and polymeric nanodimensional materials also attracting much interest of late. 12,14−21 Contrary to this assumption, we aim to demonstrate how a strongly fluorescent bis-styryl (MeOPh) 2 BODIPY dye (Φ fl = 0.719; 1 τ = 5.41 ns) can display an enhanced PA signal, far exceeding that of the Cy3 (Φ fl = 0.025; 1 τ = 0.28 ns) cyanine dye. More importantly, with respect to the future design of efficient MPACs, an excited-state sequential absorption mechanism is identified as responsible for this PA enhancement, highlighting the advantage of a long-lived S 1 excited state combined with a high quantum yield to facilitate a strong PA emission.
Current Computer - Aided Drug Design, 2013
One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen th... more One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidβ (Aβ) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer&amp;amp;amp;#39;s disease.
Current Computer Aided-Drug Design, 2013
One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen th... more One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidβ (Aβ) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer&amp;amp;amp;#39;s disease.
Current Organic Synthesis, 2011
The oxidative coupling of methane was investigated over alumina supported La 2 O 3 /CeO 2 catalys... more The oxidative coupling of methane was investigated over alumina supported La 2 O 3 /CeO 2 catalysts under microwave dielectric heating conditions at different oxygen concentrations. It was observed that, at a given temperature using microwave heating, selectivities for both ethane and ethylene were notably higher when oxygen was absent than that in oxygen/methane mixtures. The differences were attributed to the localised heating of microwave radiation resulting in temperature inhomogeneity in the catalyst bed. A simplified model was used to estimate the temperature inhomogeneity; the temperature at the centre of the catalyst bed was 85°C greater than that at the periphery when the catalyst was heated by microwaves in a gas mixture with an oxygen concentration of 12.5% (v/v), and the temperature difference was estimated to be 168°C in the absence of oxygen.
Parasitology, 2013
In view of the mandate from the World Health Organization (WHO) for developing novel drug candida... more In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide-acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
QSAR & Combinatorial Science, 2007
... 5 H Ā2.0334 6 H Ā1.8751 7 H Ā1.5682 8 H Ā3.3010 9 H Ā1.1461 3-D-QSAR Analysis of 2-(Oxalylami... more ... 5 H Ā2.0334 6 H Ā1.8751 7 H Ā1.5682 8 H Ā3.3010 9 H Ā1.1461 3-D-QSAR Analysis of 2-(Oxalylamino) benzoic acid Class of Protein Tyrosine Phosphatase 1B Inhibitors Page 3. 610 2007 WILEY-VCH Verlag GmbH & Co. ... b ND: not defined. Full Papers S. Ramar et al. Page 4. ...
QSAR & Combinatorial Science, 2009
To facilitate the discovery of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) inh... more To facilitate the discovery of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) inhibitors, various molecular modeling studies such as homology modeling, pharmacophore mapping, and 3D-QSAR studies were undertaken. To address the issue of bioactive conformer in ligand-based approaches, ensemble of conformers obtained from docking studies was used for pharmacophore mapping and for 3D-QSAR studies. The developed structure-chemical-feature-based pharmacophore model was consistent with the structure-functional requirements for the binding of the DHFR inhibitors. Using the generated homology model, interactions between the reported inhibitors were explored. The results showed that the type and spatial location of chemical features encoded in the pharmacophore and 3D-QSAR contours are in agreement with the enzyme inhibitor interaction pattern identified from molecular docking. The outcomes of the study could be used for the rational design of potent and selective MAC DHFR inhibitors.
Medicinal Chemistry Research, 2009
With the aim of developing potential antifungals, a series of chalcones incorporating sulfur eith... more With the aim of developing potential antifungals, a series of chalcones incorporating sulfur either as part of a heteroaromatic ring (thiophene) or as a side chain (thiomethyl group) were synthesized and tested for their in vitro activity. Some of the compounds showed appreciable activity against a fluconazole-resistant strain, and could act as new hits for the design of better analogs.
Journal of Molecular Modeling, 2008
Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrim... more Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A fivepoint pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r 2 =0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q 2 =0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors.
Journal of Heterocyclic Chemistry, 2010
Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bac... more Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (K d < 10 -25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC:<10HM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2010
Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors... more Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, ∼233-fold improved potency over trimethoprim and ∼7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.
Journal of Chemical Research, 2006
Vitamin B1 is used as catalyst for a very fast microwave-assisted benzoin condensation reaction. ... more Vitamin B1 is used as catalyst for a very fast microwave-assisted benzoin condensation reaction. -(BAG, S.; VAZE, V. V.; DEGANI*, M. S.; J. Chem.