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Experimental, Spectroscopic, and theoretical investigation on structural and anticancer activities of Schiff bases derived from isonicotinohydrazide
Abstract
Isoniazid hydrazones are promising possibilities as medicines since they have preserved efficacy and are less
toxic and resistant to resistance than parent Isoniazid (INH). Here, we have synthesized a series of Schiff bases
(INH1–9) derived from a clinically approved antitubercular drug Isoniazid (INH). These synthesized ligands have
been characterized by various spectroscopic techniques like IR, UV–vis., NMR, HRMS, etc. Moreover, single
crystal of three derivatives viz. INH4, INH8, and INH9 has been determined and they crystallize in monoclinic
crystal system. Hirshfeld surface analysis has been performed to ascertain intermolecular interactions present in
these compounds. The molecular geometry optimization and vibrational analysis of these compounds were
performed using density functional theory (DFT) studies utilizing B3LYP/6–31++G(d, p) basis set. The TD-DFT
analysis was also performed to understand electronic transitions and the nature of FMO in these compounds.
There was a good correlation found between theoretical and experimental values, thereby confirming the mo-
lecular structures of synthesized compounds. Molecular docking studies were performed to obtain more insights
on potential anticancer activities of these compounds along with standard anticancer drugs 5-fluorouracil and
Tamoxifen against MDM2 (4HG7) protein. The outcome revealed a significant binding affinity of these com-
pounds with target protein even better than 5-fluorouracil and comparable to Tamoxifen. The compounds (INH4
and INH9) having the strongest binding affinity with the target protein are further experimentally evaluated for
their in-vitro cytotoxic action on Dalton’s lymphoma cells employing MTT assay, fluorescence microscopy, and
flow cytometry. IC50 value (150 µg/ml) of this compound is equated with before-reported complexes/molecules/
extracts and found it has better or comparable cytotoxicity.
... M. Ariyaeifar et al. explored the applications of the synthesized halogenated Schiff base compounds with enantiomeric purity and it was concluded that the R-enantiomer 43 comes out to be more active against cancer cell lines as compared to S-enantiomer 44 [111]. Also it is to be noted that the DNA binding affinity of the synthesized compound varies 45 (INH1-9) by leveraging the molecular framework of the clinically approved antitubercular drug Isoniazid (INH) [112]. The antiproliferative potential of compounds INH1-9 45 was explored through both theoretical and experimental approaches. ...
Ultramodern analytical techniques must also be hyphenated with cheaper and less complex techniques such as UV-visible spectrophotometry to confirm the formation of organic synthesis products. Here, the synthesis of 4 compounds (HC4ATIOF, HFEC, HCPA4NO2, and HICNM) from a clinically approved antitubercular drug, the Isoniazid, was preliminarily verified by UV-Vis spectrophotometry. Spectra recorded in the UV-Vis region for the four possible isoniazid derivatives allowed us to confirm the synthesis of just one acylhydrazone from isoniazid, the HICNM, since the absorption bands observed in the UV-Vis spectra of the reactants and the product obtained are completely different, indicating the formation of a new substance.
Three new Schiff bases of isoniazid were synthesized using microwave-assisted synthesis and conventional condensation with aromatic aldehydes. Synthesized compounds were characterized using elemental analysis, IR, NMR, and Mass spectroscopy. Synthesized compounds were evaluated for antiproliferative activity against MCF-7 cell line. The IC50 values were from 125 to 276 µM. The compounds were also evaluated for antibacterial activity against Staphylococcus aureus and Escherichia coli. Results showed that the synthesized compounds produce significant antibacterial activity in vitro. Inhibition of compounds ranged from 13 to 18 mm.
Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic infectious diseases, tuberculosis (TB), with long-term morbidity and high mortality. The emergence of drug-resistant Mtb strains, and the co-infection with human immunodeficiency virus, challenges the current WHO-TB stewardship programs. The first- line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), have obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical trial statistics, the production of well-tolerated anti-TB drug(s) is miserably low. Alternately, semi-synthesis or structural modifications of first-line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemicals with INH in a hybrid formulation could be an ideal approach for the development of potent anti-TB drug(s). The primary objective of this review was to highlight and analyze available INH–phytochemical hybrid research works. The utilization of phytochemicals through chemical conjugation is a new trend toward the development of safer/nontoxic anti-TB drugs.
Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemics infectious disease, tuberculosis (TB), with long‐term morbidity and high mortality. The emergence of drug‐resistant Mtb strains, and the co‐infection with human immunodeficiency virus, challenges the current WHO‐TB stewardship programs. The first‐line anti‐TB drugs, isoniazid (INH) and rifampicin (RIF) have become extensively obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical‐trial statistics, the production of well‐tolerated anti‐TB drug(s) is miserably low. Alternately, semi‐synthesis or structural modifications of first‐line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemical with INH in a hybrid formulation could be an ideal approach for the development of potent anti‐TB drug(s). The primary objective of this review is to highlight and analyze available on INH‐phytochemical hybrid research works as an alternative method. The utilization of phytochemicals through chemical conjugation is a new trend towards the development of safer/ non‐toxic anti‐TB drugs. The first‐line anti‐TB drugs, isoniazid (INH), has become extensively obsolete in TB control in the face of emerged drug‐resistance mechanisms of Mtb. On the other hand, the production of well‐tolerated anti‐TB drug(s) is miserably low. Alternately, semi‐synthesis or structural modifications of first‐line INH remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemical with INH in a hybrid formulation could be an ideal approach for the development of potent & less‐toxicity anti‐TB drugs.
Hydrazide ligand, (Z)-N’-(6-oxo-1,10-phenanthrolin-5(6H)-ylidene)isonicotinohydrazide, 1 forms from a 1:1 Schiff base condensation reaction between isoniazid (INH) and 1,10-phenanthroline-5,6-dione (phendione). Ag+ and Mn2+ complexes with 1:2 metal:ligand stoichiometry are prepared:[Ag(1)2]NO3, [Ag(1)2]BF4 and [Mn(1)2](NO3)2. Polymeric {[Ag(1)(NO3)]}n has 1:1 stoichiometry and forms upon infusion of CH2Cl2 into a DMSO solution of [Ag(1)2]NO3. {[Ag(1)(NO3)]}n was structurally characterized using X-ray crystallography. Metal-free 1 and its 1:2 complexes exhibit very good, broad-spectrum antimicrobial activity and are not excessively toxic to mammalian cells (A549 lineage).
Traditional knowledge (TK) based medicines have gained worldwide attention and presently the scientific community is focussing on proper pharmacological validation and identification of lead compounds for the treatment of various diseases. The North East region of India is the home of valuable traditional herbal remedies. Garcinia morella Desr. (Guttiferae) is one such medicinal plant used by traditional healers for the treatment of inflammatory disorders. The present study was aimed to evaluate the antioxidant and anticancer activity of methanol extracts of the leaf, bark and fruit of G. morella (GM) in different in vitro and in vivo experimental conditions. The results of this study showed that GM methanol extracts possessed in vitro antioxidant and anticancer properties, where the fruit extract (GF) showed maximum activity. The anticancer activity was further confirmed by the results of in vivo administration of GF (200 mg/kg) for ten days to Dalton’s lymphoma (DLA) induced mice. GF extract significantly increased the mean survival time (MST) of the animals, decreased the tumor volume and restored the hematological and biochemical parameters. The present study for the first time reported the anticancer property of GF on DLA. Further from the experiments conducted to elucidate the mechanism of action of GF on DLA, it can be concluded that GF exerts its anticancer effect through induction of caspases and DNA fragmentation that ultimately leads to apoptosis. However, further experimentation is required to elucidate the active principle and validate these findings in various in vivo settings.
Five heteroleptic Ru(II), Rh(III) and Ir(III) complexes containing ferrocene have been explored as anticancer agents. The binding behavior of these complexes with calf thymus DNA (CT-DNA) and BSA (bovine serum albumin) has been followed by UV–vis and fluorescence spectroscopy. To gain deep insight into the binding sites molecular docking studies have been carried out with DNA and HSA. Further, in vitro anticancer activities have been accessed by MTT assay, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA ladder (fragmentation) assay against Dalton's Lymphoma (DL) cells.
Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton's lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton's lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 μ g/mL in Dalton's lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton's lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved.
Cisplatin (cDDP) is an anticancer agent that is widely used in the treatment of many solid tumors. A major obstacle to successful cDDP-based chemotherapy, however, is the intrinsic and acquired resistance of tumor cells to this drug. Greater insight into the molecular mechanisms underlying the modulation of cellular responses to cDDP will aid in the development and optimization of new therapeutic strategies. Apart from induction of DNA damage, recent data have suggested that cDDP also induces the formation of reactive oxygen species that can trigger cell death. Cell death occurs as the result of several simultaneously activated signaling pathways. The specific pathway responsible for cell death depends on the cell type and the treatment conditions. This review focuses on the relationship between glutathione and BCL-2 and their protective role in cDDP-induced reactive oxygen species formation and cDDP resistance.
In response to DNA damage, ataxia-telangiectasia mutant and ataxia-telangiectasia and Rad-3 activate p53, resulting in either
cell cycle arrest or apoptosis. We report here that DNA damage stimuli, including etoposide (ETOP), adriamycin (ADR), ionizing
irradiation (IR), and ultraviolet irradiation (UV) activate ERK1/2 (ERK) mitogen-activated protein kinase in primary (MEF
and IMR90), immortalized (NIH3T3) and transformed (MCF-7) cells. ERK activation in response to ETOP was abolished in ATM−/−
fibroblasts (GM05823) and was independent of p53. The MEK1 inhibitor PD98059 prevented ERK activation but not p53 stabilization.
Maximal ERK activation in response to DNA damage was not attenuated in MEFp53−/−. However, ERK activation contributes to either cell cycle arrest or apoptosis in response to low or high intensity DNA insults,
respectively. Inhibition of ERK activation by PD98059 or U0126 attenuated p21CIP1 induction, resulting in partial release of the G2/M cell cycle arrest induced by ETOP. Furthermore, PD98059 or U0126 also strongly attenuated apoptosis induced by high dose
ETOP, ADR, or UV. Conversely, enforced activation of ERK by overexpression of MEK-1/Q56P sensitized cells to DNA damage-induced
apoptosis. Taken together, these results indicate that DNA damage activates parallel ERK and p53 pathways in an ATM-dependent
manner. These pathways might function cooperatively in cell cycle arrest and apoptosis.
The global burden of cervical cancer is continuously increasing day by day affecting the world population. Wide arrays of agents are prevalent for the treatment of this chronic disease but the survival rates are still limited. The titled compound N-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazol-2-amine (Pypao) was prepared through the cyclization of nicotinoyl-N-phenyl hydrazine carbothioamide catalyzed by manganese (II) acetate. Uv-Vis, IR, NMR, elemental analyses, and single-crystal X-ray data were utilized for the description of the compound Pypao. The crystal structure of Pypao is stabilized via intermolecular hydrogen bonding interactions, which is further confirmed with Hirshfeld surface analysis. The DFT methods were also used to optimize the Pypao and obtained bond parameters have been found coherent with the experimental data. FMO and TD-DFT studies are also performed to gain insights into the electronic behavior of Pypao. Furthermore, the binding potential of Pypao to different oncoproteins of HPV namely E6, E6AP, and E7 have been examined through a molecular docking study. The in-vitro anticancer activity of Pypao has been investigated against SiHa cells. The anticancer potential of Pypao has been evaluated through various assays including MTT, DAPI stating, AO/PI staining, etc. Both time and dose-dependent activity of Pypao have been investigated.
A new compound 2-(4-methoxyphenyl)-5-(2-pyridyl)-1,3,4-thiadiazole (Mppth) has been synthesized and characterized with the aid of IR, NMR, and single-crystal X-ray diffraction techniques. During the reaction, the substituted thiohydrazide got cyclized into the corresponding thiadiazole (Mppth) in the presence of zinc(II) nitrate via loss of H2O. The Mppth crystallizes in an orthorhombic system with space group P 21 21 21. The solid-state structure of Mppth is stabilized via intermolecular hydrogen bonding and π-π interaction between phenyl rings. The intermolecular interactions present in the crystal structure of Mppth are also confirmed with Hirshfeld surface analysis. The geometry optimization has been performed using the DFT method and geometrical parameters thus obtained for the Mppth correlate with the single-crystal X-ray data. The FMO analysis shows a small HOMO and LUMO energy gap of 5.48 eV for Mppth suggesting its potential application as NLO material. The electronic transition from the ground state to the excited state due to a transfer of electrons from the HOMO to LUMO levels is mainly associated with the π→π* transition. Molecular docking studies are also performed against CYP-19 (PDB: 3EQM), JAK2 (PDB: 5AEP), BCL-2 (PDB: 2O2F), and caspase3 (PDB: 1RE1) receptor proteins to obtain insights on anticancer activities of Mppth. The results displayed strong interactions with the receptors with binding energies -10.27, -7.40, -6.28, and -7.27 kcal/mol, respectively. From the docking results, the key binding interactions between the ligand and active site residues of the receptor were identified, which may provide important information for further research on the compound Mppth as anticancer agent.
A new iron(III) complex has been successfully prepared by the reaction of an ONO donor Schiff base, derived by condensing isoniazid and 3-ethoxysalicylaldehyde, with Fe(acac)3. The structure of the complex was explored spectroscopically through FT-IR, UV-Vis, PXRD and by elemental composition (CHN) through combustion analysis. The structure of the complex was explored by using single crystal X-ray crystallographic studies. It was revealed from the diffraction studies that both the keto and enol tautomeric forms of the ligand are present simultaneously in the Fe(III) complex. X-ray results showed that one of the ligands, due to keto-enol tautomerization, is doubly deprotonated and coordinated to the metal center through one nitrogen and two oxygen atoms, while the other ligand behaves as a monoanionic moiety and is coordinated via phenolic oxygen, iminic nitrogen, and oxygen of the carbonyl group. Furthermore, it was also investigated by diffraction studies that the Fe(III) centre adopts a distorted octahedral geometry. HSA, QTAIM, MEP, and NCI calculations were performed to explore the presence of different kinds of non-covalent interactions. NBO analysis was also used to show the donor-acceptor interactions between the HOMO and LUMO of the molecule. Theoretical calculations performed by DFT at the B3LYP/Def2-TZVP method show that the theoretically calculated results are in close association with the experimental outcomes.
The syntheses and screening of novel synthetic molecules have gained attention as a potential therapeutic agent in the treatment of cancer. In the present study, a new compound 5(4-hydroxyphenyl)-2-(N-phenylamino)-1,3,4-oxadiazole (Hppo) has been synthesized and its anticancer activity is investigated against Dalton's lymphoma (DL) tumor cells derived from murine T-cell lymphoma. The Hppo has been characterized through IR, NMR, and single-crystal X-ray data. The structure of Hppo is stabilized via hydrogen bonding interactions and crystallizes in an orthorhombic system with space group P b c n. The fingerprint plots associated with Hirshfeld surface analysis indicate that there are different types of weak interactions viz. C-H···N, O-H···N and C-H···O. The DFT calculations are also performed to verify physiochemical properties of Hppo and the results obtained are in good agreement with the experimental results. The HOMO and LUMO energy gap of 7.344 eV for Hppo indicates good NLO properties. The cytotoxicity activity of Hppo is tested against Dalton's lymphoma cells using MTT assay which reveals that the compound showed admirable anticancer activity (IC50= 50 µg/mL), which is better than many previously reported compounds. The mechanism of action of Hppo is investigated by performing different biological studies and the results obtained reveal that Hppo acts through down-regulating mitochondrial membrane potential and up-regulating reactive oxygen species production. Molecular docking studies are also performed to obtain more insights on biological activities of Hppo and its mode of action against CYP-19 (PDB: 3EQM), JAK2 (PDB: 5AEP), BCL-2 (PDB: 2O2F), and caspase3 (PDB: 1RE1), and result displayed favorable binding interactions with binding energy -7.43, -7.96, -6.61, and -6.88 Kcal/mol.
The electrochemical water splitting by transition metal complexes is emerging very rapidly. The nickel complexes also play a very vital role in various biological activities. Here, three new ligands {H2mbhce= N'-(4-methyl-benzoyl), H2pchce = N'-(pyridine-carbonyl) and H2hbhce = N'-(2-hydroxy-benzoyl) hydrazine carbodithioic acid ethyl ester} and their corresponding Ni(II) complexes [Ni(Hmbhce)2(py)2] (1), [Ni(pchce)(o-phen)2]∙CH3OH∙H2O (2) and [Ni(hbhce)(o-phen)2]∙1.75CHCl3∙H2O (3) have been synthesized and fully characterized by various physicochemical and X-ray crystallography techniques. The photoluminescence study and thermal degradations were also examined. The treatment of K562 cells with the increasing concentrations of the nickel salts, ligands, and complexes 1, 2, and 3 showed dose-dependent cytotoxicity. The cytotoxic activity of ligands reveals that ligand H2mbhce is more potent in inhibiting the growth of tumor cells in comparison to other ligands H2pbhce and H2hbhce. Cytotoxicity assay results indicate that all complexes have remarkable cytotoxic potential in comparison to either nickel salts or the free ligands. Among these complexes, complex 1 has significantly better anti-tumor activity as compared to complexes 2 and 3. The electrochemical study of complexes 1, 2, and 3 for water oxidation reveals that all the complexes possess admirable electrocatalytic activity towards oxygen evolution reaction (OER) and have lower overpotential (328, 338, and 370 mV respectively) than many previously reported complexes and RuO2 (390 mV). Among complexes 1, 2, and 3, complex-2 shows a better water oxidation response. Consequently, these complexes have great potential to be utilized in fuel cells. The more reliable electrochemical parameter TOF is also calculated for all three complexes.
Cancer cells have high iron demand to mediate their rapid proliferation. Aiming to obtain cytotoxic compounds with potential iron metabolism disturbance in malignant cells, [Ga(HAPIH)(APIH)](NO3)2⋅2H2O (1) and [Ga(HPAmIH)(PAmIH)](NO3)2⋅2H2O (2) were synthesized with the iron chelators 2-acetylpyridine- and 2-pyridineformamide isonicotinoyl hydrazone (HAPIH and HPAmIH, respectively) and gallium(III), an iron(III) mimetic. The hydrazones and their gallium(III) complexes were assayed for their action against HL-60 (leukemia), MCF-7 (breast cancer), HCT-116 (colorectal carcinoma) and PC3 (prostate cancer) tumor cell lines, as well as non-malignant Human Embryonic Kidney 293 (HEK-293) cells. HAPIH and its complex 1 were the most cytotoxic compounds, with HCT-116 being the most susceptible line (IC50 = 1.6 μM for HAPIH and 0.4 μM for complex 1). Moreover, the compounds proved to be at least 25-fold less toxic to HEK-293 than to the tumor cells. According to clonogenic survival assays, the relative number of colonies formed by HCT-116 cells was reduced by around 95% after pretreatment with HAPIH and 1 at their IC90 concentrations (18 μM and 4 μM, respectively). Both compounds were also able to inhibit the cell cycle and increased the subdiploid DNA content of HCT-116 after 24 h treatment, which suggests they possess a pro-apoptotic potential.
Chiral sulfoxide based smart drug modafinil were studied experimentally and theoretically. Vibrational spectra were recorded in the mid IR region and electronic spectra were recorded in UV–Visible region. The molecular geometry, vibrational spectra, magnetic spectra and electronic spectra were simulated using Density Functional Theory (DFT) employed with B3LYP/6–311++G(d,p) basis set. The molecular geometry optimization, vibrational frequencies, chemical shifts and solvent effect on electronic properties were reported. The intermolecular interactions have been studied by Hirshfeld surface analysis. There is good agreement was found between calculated and observed values, thereby to confirm the molecular structure of modafinil.
N-benzyl-2-isonicotinoylhydrazine-1-carbothioamide (H3L) and its complexes with Co(II), Ni(II), Cu(II)
and Zn(II) have been synthesized. The metal complexes have been characterized by elemental and
thermal analyses, spectral studies of FT-IR, 1
H and 13C NMR, ESR, MS, and UV-Visible, conductance and
magnetic moments measurements. The free ligand exists in the keto-thione form, but it coordinates to
the metal ion in the keto-thiol form. The 1:1 coordinated species, M(II)-H3L, are formed. The optical band
gap (Eg) measurements indicated direct electronic transition and semi-conducting nature of the com�pounds. The cytotoxicity of H3L and its Zn(II) complex were tested against both HCT116 and HePG2. The
ligand showed strong cytotoxicity against the two investigated cell lines, while Zn(II) complex exhibited
moderate cytotoxic effect. The molecular docking on both colon and liver cancer proteins were studied
and the data support the experimental results.
The discovery of potent kinase inhibitors with tunable selectivity and specificity have gained significant impetus in the last decades. In accordance to this drift, herein we report the design and synthesis of a series of new heterocyclic derivatives comprising of 1,2,4 triazole nucleus, tethered to two flexible linkers on either sides, utilizing simple schiff base approach (Compound 1 – 16). The compounds were characterised by various spectroscopic techniques and its biological evaluation were conducted using kinase inhibition assay on two targets namely CLK1 and DYRK1A. Our investigation reveals that compounds 3 - 5 bearing hydroxy/methoxy substituents in the aromatic ring display excellent potency towards the receptors in the micromolar range . Indeed compound 5 bearing methoxy substitution at meta position possesses the added advantage of being highly specific towards CLK1 among the targets. To reinforce the observation we performed molecular modelling studies with the kinase inhibitors hymenialdisine (HMD) cocrystallized with CLK1 and harmine (HA) cocrystallized with DYRK1A kinase as references. We speculate that in either targets the cause of such high potency and selectivity might be attributed to the involvement of flexible linkers on either sides of the triazole core which might have compelled the ligands to enter into the active site of the receptor and maximize non-covalent interactions . Interestingly we consider the selectivity of compound 5 to be emanated from involvement of H- bond between SH of triazole and Glu 169 carbonyl in the receptor, which is absent in the other derivatives for both the targets. Thus our efforts focusses how variation/position of substituents in the inhibitors displays profound impact in potency and selectivity. Indeed this work establishes innovative design principles towards the development of theraupeutic agent for the treatment of neurodegenerative diseases like that of Alzheimers
ATP is an important transmitter that mediates various biological effects via purinergic receptors (P2-receptors) in cancer. We investigated the anti-tumor activity of ATP-decorated and doxorubicin-loaded mesoporous silica with bio-mineralization of calcium carbonate against a highly aggressive and metastatic murine lymphoma called Dalton’s lymphoma. Our results suggest that this nanocomposite has unique effects with respect to the morphology and properties of calcium carbonate on the surface of the nanoparticle. Doxorubicin in the nanoparticles was prevented from quick release via the interactions of the phosphate group present on ATP and calcium carbonate. This construct is significantly tumoricidal against parental and doxorubicin-resistant Dalton’s lymphoma cells and is thus a promising candidate for applications in drug delivery. The composite nanomaterial has excellent biocompatibility with higher uptake and acts via the participation of the purinergic receptor P2X7. The nanocomposite induces significantly higher apoptosis in tumor cells compared with doxorubicin alone. Treatment of Dalton’s lymphoma-bearing mice with the construct significantly reduces tumor burden, in addition to augmenting the lifespan of tumor-bearing mice as demonstrated by a sustained healthy life of the animals and improved histopathological parameters.
Tuberculosis (TB), which has been a scourge of humanity for thousands of years, is a worldwide pandemic disease caused mainly by Mycobacterium tuberculosis (MTB). The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug-resistant TB (TDR-TB) increase the challenges to eliminate TB worldwide. Isoniazid (INH), a critical frontline anti-TB drug, is one of the most effective drugs used to treatment of TB infection for more than 60 years. Unfortunately, bacterial strains resistant to INH are becoming common which mainly due to the long-term widely use even abuse. Therefore, there is an urgent need to develop novel anti-TB agents. Numerous efforts have been undertaken to develop new anti-TB agents, but no new drug has been introduced for more than 5 decades. It has been suggested that the incorporation of lipophilic moieties into the framework of INH can increase permeation of the drug into bacterial cells, thereby enhancing the anti-TB. Therefore, INH derivatives with greater lipophilicity are emerging as one of the most potential anti-TB agents. Indeed, the INH derivative LL-3858 is in initial stages of phase II clinical trial for the treatment of TB and may be approved to treat TB in the near future. This review aims to summarize the recent advances made towards the discovery anti-TB agents holding INH as a nucleus including INH hybrids and INH hydrazide-hydrazone derivatives.
A family of hydrazones of isoniazid and a group of hydroxybenzalaldehydes (vanillin, 5-bromovanillin, 5-chlorosalicylaldehyde and 5-bromosalicylaldehyde) were obtained and fully characterized. The results, including theoretical data, are comparatively analyzed along with the already reported hydrazone of o-vanillin. The crystal structures of three compounds were determined. The hydrazones obtained from halogenated aldehydes are isomorphic and chiral to each other. Structures are further stabilized by (pyr)NH⁺⋯Cl⁻ and OwH⋯Cl⁻ bonds. The vanillin hydrazone shows a conformer that differs from the previously reported. Neighboring molecules are linked to each other through OH⋯N(pyr) bonds, giving rise to a nearly planar polymeric structure. The conformational space was searched and geometries were optimized both in the gas phase and including solvent effects by DFT. Results are extended to describe the 5-bromovanillin hydrazone. FTIR, NMR and electronic spectra were measured and assigned with the help of computational calculations.
In present work, we have analysed the structural property of newly synthesized ligand and its coordination complex molecules with Ni²⁺, Mn²⁺ and Fe³⁺. The spectroscopic techniques UV–visible, IR, Raman and DFT methods are used. The newly synthesized ligand 1-isonicotinoyl-3-thiosemicarbazide (Hintsc) has supramolecular architecture stabilized through various intermolecular interactions viz. NH⋯O, CH⋯O, CH⋯N, NH⋯S and CH⋯S type hydrogen bonds as observed in the single crystal of the ligand. The single crystals of the complexes could not be obtained with high degree of homogeneity from the solutions therefore plausible geometry of the complexes have been proposed on the basis of Raman spectroscopy, UV–visible and DFT methods and coordination properties of Ni²⁺, Mn²⁺ and Fe³⁺ with ligand (Hintsc). The ligand Hintsc contains the thiosemicarbazide (TSC) moiety through which Ni²⁺, Mn²⁺ and Fe³⁺ metals are coordinated. Raman spectroscopy is used to investigate the binding of Ni²⁺, Mn²⁺ and Fe³⁺ with ligand (Hintsc). In Raman spectra, the disappearance of NH bending/ NH stretching and lower wavenumber region Raman spectra clearly confirms that Ni²⁺ and Mn²⁺ metals are coordinated through N3 and O sites of thiosemicarbazide (TSC) and consequently formed the chelate ring {C6N2N3MO}, where M Ni²⁺ and Mn²⁺. In Fe complex, Fe³⁺ is coordinated through N2 and S sites of TSC and formed the chelate ring {C7N3N2FeS}. The structural and molecular property of 1-isonicotinoyl-3-thiosemicarbazide (Hintsc) and its complexes with transition metals Ni²⁺, Mn²⁺, Fe³⁺ have also been studied by DFT technique. By means of UV–visible, Raman spectroscopy and DFT technique, it is found that Ni²⁺, Mn²⁺ and Fe³⁺ exhibit the octahedral coordination property with 1-isonicotinoyl-3-thiosemicarbazide (Hintsc).
In this study, a fast UHPLC-MS/MS method was developed and validated for the determination of a novel potent carvone Schiff base of isoniazid (CSB-INH) in rat plasma using carbamazepine as an internal standard (IS). After a single-step protein precipitation by acetonitrile, CSB-INH and IS were separated on an Acquity BEHTM C18 column (50 × 2.1 mm, 1.7 µm) under an isocratic mobile phase, consisting of acetonitrile: 10 mM ammonium acetate (95:5, v/v), at a flow rate of 0.3 mL/min. Quantification was performed on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring mode by using positive electrospray ionization source. The precursor to product ion transitions were set at m/z 270.08 79.93 for CSB-INH and m/z 237.00 178.97 for IS. The proposed method was validated in compliance with US Food and Drug Administration and European Medicines Agency guidelines for bioanalytical method validation. The method was found to be linear in the range of 0.35–2500 ng/mL (r2 ≥ 0.997) with a lower limit of quantification of 0.35 ng/mL. The intra- and inter-day precision values were ≤12.0% whereas accuracy values ranged from 92.3 to 108.7%. In addition, other validation results were within the acceptance criteria and the method was successfully applied in a pharmacokinetic study of CSB-INH in rats. Copyright © 2014 John Wiley & Sons, Ltd.
The title compound, C13H11N3O2, was prepared by the reaction of pyridine-4-carboxylic acid hydrazide and p-hydroxybenzaldehyde in ethanol. In the crystal structure, all non-H atoms are coplanar, with an r.m.s. deviation of 0.096 Å. N—H⋯N, O—H⋯N and O—H⋯O intermolecular hydrogen bonds stabilize the structure.
Anharmonic vibrational spectroscopy calculations using MP2 and B3LYP computed potential surfaces are carried out for a series of molecules, and frequencies and intensities are compared with experiment. The vibrational self-consistent field with second order perturbation correction (VSCF-PT2) is used in computing the spectra. The test calculations have been performed for the molecules: HNO3, C2H4, C2H4O, H2SO4, CH3COOH, glycine and alanine. Both MP2 and B3LYP give results in good accord with experimental frequencies though on the whole MP2 gives slightly better agreement. A statistical analysis of deviations in frequencies from experiment is carried out which gives interesting insights. The most probable percentage deviation from experimental frequencies is about -2% (to the red of the experiment) for B3LYP and +2% (to the blue of the experiment) for MP2. There is a higher probability for relatively large percentages deviation when B3LYP is used. The calculated intensities are also found to be in good accord with experiment but the percentages deviation are much larger than for frequencies. The results show that both MP2 and B3LYP potentials, used in VSCF-PT2 calculations, account well for anharmonic effects in the spectroscopy of molecules of the types considered.
The resurgence of tuberculosis and emergence of multidrug resistant isolates has focused attention on the need for an improved understanding of molecular aspects of the disease, and for elucidation of the factors responsible for drug action and resistance. Isoniazid is the frontline drug employed in the treatment of tuberculosis. Recent research has probed the mechanism of action of isoniazid (INH), a key drug in the chemotherapy of tuberculosis and also the anti-mycobacterial potential of derivatives of isoniazid has been evaluated. We have made an attempt to compile an account of various derivatives of isoniazid reported for their diverse biological activities like anti-mycobacterial, -bacterial, -fungal and -viral activities.
A new zinc(II) complex of the mycobactericidal drug isoniazid (complex 1) was synthesized and characterized by XRD, vibrational spectroscopy (IR, Raman) and thermogravimetric analysis. The complex is constituted by two isoniazid (INH) molecules, six hydration water molecules and two perchlorate counter-ions for each metal center (C12H26N6Cl2O16Zn). Zinc(II) adopts a distorted octahedral geometry, where two INH molecules coordinate in a bidentate manner through the hydrazide group (N, O) and the other two isoniazid residues complete the coordination sphere of zinc(II) through their aromatic nitrogen atoms. This coordination pattern gives rise to a 2-D coordination polymer. Complex 1 belongs to the monoclinic system [a=8.1190(2)Å, b=17.977(4)Å, c=9.1051(2)Å and β=100.87(3)°], space group P21. A biological assay with Artemia salina was also performed. Complex 1 is almost 8.5 times more active than the free ligand. Its toxicity against A. salina correlates well with the cytotoxic activity for some human solid tumors. Therefore, antitumoral properties could be expected from complex 1.
A complete and detailed study of the hydrazone obtained from condensation of antituberculous isoniazid (hydrazide of the isonicotinic acid, INH) and o-vanillin (2-hydroxy-3-methoxybenzaldehyde, o-HVa) is performed. It includes structural and spectroscopic analyses, comparing experimental and theoretical results. The compound was obtained as a chloride of the pyridinic salt (INHOVA+Cl−) but it will be referred as INHOVA for the sake of simplicity. The conformational space was searched and optimized geometries were determined both in gas phase and including solvent effects. Vibrational (IR and Raman), electronic and NMR spectra were registered and assigned with the help of computational methods based on the Density Functional Theory. Isoniazid hydrazones are good candidates for therapeutic agents against tuberculosis with conserved efficiency and lower toxicity and resistance than parent INH.
A series of isonicotinic acid hydrazide derivatives (1-14) was synthesized and tested for their in vitro antimycobacterial activity against Mycobacterium tuberculosis and the compounds with bromo, N2-2,4-hexadienoyl, N2-lauryl and N2-octadecanoyl groups were found to be the most effective, especially isonicotinic acid-N'-octadecanoyl hydrazide (12) was more active than the standard drug isoniazid. The results of antiviral activity testing showed that none of the tested compounds were active at subtoxic concentrations. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger and the results indicated that compounds 4, 11, 12 and 14 were found to be active with Benzoic acid N'-(4-hydroxy-3,5-dimethoxy-benzylidene)-N-(pyridine-4- carbonyl)-hydrazide (14) having highest antimicrobial potential. The QSAR studies indicated the importance of topological parameters 3χ and κ1 in governing the antimicrobial activity of synthesized derivatives.
The powerful tumor suppressor p53 takes charge of a regulatory network to guard over the living cells from harmful effect of different forms of stress and eradicate the tumor cells for normal physiological condition maintenance. However the antitumor function of p53 is often attenuated or even omitted mainly due to two alternative mechanisms, direct gene alterations in p53 or negative controlled by MDM2 protein. In this article, overview on different therapeutic strategies that are exploited to restore the neoplasm therapeutic effect to p53 will be provided, including pharmacological rescue of mutant p53 and modulation of the p53-MDM2 interaction. We attempt to focus on the medicinal chemistry aspects of small molecule agents targeting the p53-MDM2 pathway and recent progress in these agents. In addition, the mechanism of action and anticancer activity of different classes of compounds targeting the p53-MDM2 pathway, as well as structure-activity relationships, are discussed.
For Abstract see ChemInform Abstract in Full Text.
Several technology-based strategies have been developed to address the significance of the two phases of drug discovery: hit identification and lead identification. Structure-based drug design (SBDD), a method that depends on possessing the knowledge of 3D structures of biological targets, is growing swiftly with the development of new technologies for searching potential ways to combat disease. The past decade has evidenced a threefold increase in the amount of software and tools in the online repositories. Herein, we review the in silico strategies and modules applied at the level of hit identification and confer the different challenges with possible solutions in enhancing the success rate of the 'hit-to-lead' phase that could eventually help the progress of SBDD in the drug discovery arena.
For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti-tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side-effects increase the demand for novel anti-tumour drugs active against untreatable tumours, with fewer side-effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti-tumour compounds of the future.
The mdm2 oncogene product, MDM2, is an ubiquitin protein ligase that inhibits the transcriptional activity of the tumor suppressor p53 and promotes its degradation. About 50% of all human cancers present mutations or deletions in the TP53 gene. In the remaining half of all human neoplasias that express the wild-type protein, aberrations of p53 regulators, such as MDM2, account for p53 inhibition. For this reason, designing small-molecule inhibitors of the p53-MDM2 protein-protein interaction is a promising strategy for the treatment of cancers retaining wild-type p53. The development of inhibitors has been challenging. Although many small-molecule MDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have demonstrated to possess acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (such as nutlins), benzodiazepines, and spiro-oxindoles. The cis-imidazolines were the first discovered potent and selective small-molecule inhibitors of the p53-MDM2 interaction and they continue to show therapeutic potential. This review will focus on recent molecular modeling approaches (molecular dynamics, pharmacophore-based, molecular docking, structure-based design) used with the aim to better understand the behavior of these proteins and to discover new small-molecule inhibitors of the p53-MDM2 protein-protein interaction for the treatment of cancer.
We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.
The effects of cisplatin (CDDP), a potent anti-cancer agent, and its various analogues were analyzed for any biochemical changes involving Ca2+ and lysosomal and membrane-associated transport enzymes in rat kidney, liver, serum, urine, tissue homogenates, and isolated mitochondria. Correlation was made with any morphological changes observed by light and electron microscopy to gain an insight into the mechanism of action of various platinum coordination complexes. CDDP in its hydrolyzed state under conditions of low chloride ion concentrations causes uncoupling of oxidative phosphorylation, calcium efflux from the mitochondria, inhibits ATP synthesis, lowers membrane-associated calcium and various membrane transport enzymes, and induces an increase in the number of lysosomes. Enzymes such as alkaline phosphatase are stripped from the brush borders of the proximal tubule cells and are discharged in the urine. However, daily IV injections of calcium (1.1 ml of 1.3% CaCl2) supplementation protect the membrane-associated enzymes from cisplatin action. Carboplatin (CBDCA), an analogue of CDDP and the least nephrotoxic of all its analogues, shows little effect on the membrane-associated transport enzymes. Therefore, cisplatin and its various analogues seem to affect the membrane transport enzymes to varying degrees with related nephrotoxicity. Calcium supplementation seems to protect these enzymes and preserve kidney function.
The three-dimensional structures of more than 4,000 macromolecules have already been solved, and the number will continue to increase steadily. Many of these macromolecules are important drug targets and it is now possible to use the knowledge of their three-dimensional structure as a good basis for drug design.
A correlation-energy formula due to Colle and Salvetti [Theor. Chim. Acta 37, 329 (1975)], in which the correlation energy density is expressed in terms of the electron density and a Laplacian of the second-order Hartree-Fock density matrix, is restated as a formula involving the density and local kinetic-energy density. On insertion of gradient expansions for the local kinetic-energy density, density-functional formulas for the correlation energy and correlation potential are then obtained. Through numerical calculations on a number of atoms, positive ions, and molecules, of both open- and closed-shell type, it is demonstrated that these formulas, like the original Colle-Salvetti formulas, give correlation energies within a few percent.
The purpose of this study was to prepare various isoniazid derivatives by introducing the isoniazid pharmacophore into several molecules and screening for antimycobacterial activity. Ortho-hydroxy acetophenone reacts with isoniazid to form acid hydrazones. The C-Mannich bases of the above acid hydrazones were prepared by reacting them with formaldehyde and various secondary amines. The synthesized compounds were screened against M. tuberculosis H(37)R(v) using the alamar blue susceptibility test. The synthesized compounds inhibit Mycobacterium tuberculosis strain H(37)R(v) with minimum inhibitory concentrations ranging from 0.56 to 4.61 microM. Compound N'-{1-[2-hydroxy-3-(piperazin-1-ylmethyl)phenyl]ethylidene}isonicotinohydrazide 8 was found to be the most active compound with an MIC of 0.56 microM, and was more potent than isoniazid (MIC of 2.04 microM). After 10 days of treatment, compound 8 decreased the bacterial load in murine lung tissue by 3.7-log10 as compared to controls, which was equipotent to isoniazid. The results demonstrate the potential and importance of developing new isoniazid derivatives against mycobacterial infections.
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