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The liver function test is an imperative element in chemotherapy management due to the idiosyncratic reaction of chemotherapy drugs. This study primly aimed to replace the toxic fragments of known protein tyrosine kinases inhibitors (PTKi) to develop safe and effective chemotherapy. All the current PTKi's were docked with the tyrosine kinases and metabolic enzymes to study the affinities on the target. It resulted from most of the PTKi's found higher affinity and efficacy with metabolic enzymes lead the hepatic cells damage. To overcome this limitation of PTKi's, a bioisosteric replacement strategy was achieved and conceptual analogs were designed. Specifically, the Generated pose of the Axitinib molecule showed that axitinib fragments C = C-, -C = O and NH2 produced clashes with active site residues of tyrosine kinases protein and good affinity with metabolic enzyme primes to the liver toxicity. The above said fragments were replaced with various bioisosteric groups and efficacy was measured. The resulting molecule shows improved affinity with tyrosine kinases enzyme and less interactions with metabolic enzyme were imminent molecule for the treatment of malignant cells with outside effects.Communicated by Ramaswamy H. Sarma.

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BACKGROUND: The available treatment option for any type of cancer including CTCL is chemotherapy and radiation therapy which indiscriminately persuade on the normal cells. One way out for selective destruction of CTCL cells without damaging normal cells is the use of histone deacetylase inhibitors (HDACi). Despite promising results in the treatment of CTCL, these HDACi have shown a broadband inhibition profile, moderately selective for one HDAC class but not for a particular isotype. The prevalence of drug-induced side effects leaves open a narrow window of speculation that the decreased therapeutic efficacy and observed side effects may be most likely due to non specific HDAC isoform inhibition. The aim of this paper is to synthesis and evaluates HDAC8 isoform specific inhibitors. METHODS: Based on the preliminary report on the design and in silico studies of 52 hydroxamic acid derivatives bearing multi-substituent heteroaromatic rings with chiral amine linker, five compounds were shortlisted and synthesized by microwave assisted approach and high yielding synthetic protocol. A series of in vitro assays in addition to HDAC8 inhibitory activity was used to evaluate the synthesised compounds. RESULTS: Inhibitors 1e, 2e, 3e, 4e and 5e exerted the anti-proliferative activities against CTCL cell lines at 20- 100 µM concentrations. Both the pyrimidine- and pyridine-based probes exhibited µM inhibitory activity against HDAC8. The pyrimidine-based probe 1e displayed remarkable HDAC8 selectivity superior to that of the standard drug, SAHA with an IC50 at 0.1µM. CONCLUSION: Our study demonstrated that simple modifications at different portions of pharmacophore in the hydroxamic acid analogues are effective for improving both HDAC8 inhibitory activity and isoform selectivity. Potent and highly isoform-selective HDAC8 inhibitors were identified. These findings would be expedient for further development of HDAC8-selective inhibitors.

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BACKGROUND: The Quantitative structure activity relationship for thirty two novel substituted quinoxalines was performed for their antitubercular (Mycobacterium tuberculosis H37Rv) and antileptospiral (Leptospirainterrogans) activities. The quinoxalines were substituted with azetidinones, thiazolidinones and fluoroquinolones. Several compounds exhibited good activity against both the infections and they all possess fluoroquinolone moiety with the quinoxaline. METHODS: The models developed showed good linear relationship (r2 = 0.71-0.88), with an internal predictive ability (q2> 0.61) and good external predictive ability (pred_r2>0.71). The compounds were separated into a training set on which regression was performed and a test set on which the predictive ability of the model was tested. Other statistical parameters including Ro2, Ro'2, k, k' and Z- score were in the acceptable range. RESULTS AND CONCLUSION: The descriptors obtained explained the necessity of spatial orientation of atoms including branching and adjacency, presence of electronegative groups, balance between lipophilic elements and their binding strengths.

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Fluoroquinolones (FQs) belong to the class of quinolone drugs that are used to treat Urinary tract infections (UTIs) through inhibition of E. coli DNA gyrase. Resistance to FQs poses a serious problem in the treatment against resistant strains of E. coli which are associated with Ser83 to Leu and Asp87 to Asn mutations at the quinolone resistance determining region (QRDR) of the GyrA subunit of DNA gyrase. Mutant DNA GyrA (mtDNA GyrA) is deemed to be a significant target for the development of novel FQ drugs. Due to resistance to FQ drugs, discovery or development of novel FQs is crucial to inhibit the mtDNA GyrA. Hence, the present study attempts to design and develop novel FQs that are efficient against resistant E. coli strains. A three-dimensional structure of the mtDNA GyrA protein was developed by homology modeling, following which 204 novel FQ analogs were designed using target based SAR. The designed ligands were then screened using molecular docking studies, through which the pattern of interaction between the ligands and the target protein was studied. As expected, the results of the docking study revealed that the molecules FQ-147, FQ-151 and FQ-37 formed hydrogen bonding and Van der Waals interactions with Leu83 and Asn87 (mutated residues), respectively. Further, the wild-type (WT), mtDNA GyrA and docking complex were studied by molecular dynamics (MD) simulations. Subsequently, all the screened compounds were subjected to a structure and ligand based pharmacophore study followed by ADMET and toxicity (TOPKAT) prediction. Finally, eighteen hit FQ analogs which showed good results for the following properties, viz., best binding score, estimated activity (MIC value) and calculated drug-like properties, and least toxicity, were shortlisted and identified as potential leads to treat UTI caused by FQ resistant E. coli. Apart from development of novel drug candidates for inhibition of mtDNA GyrA, the present study also contributes towards a superior comprehension of the interaction pattern of ligands in the target protein. To a more extensive degree, the present work will be useful for the rational design of novel and potent drugs for UTIs.

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BACKGROUND: Drugs that inhibit cyclooxygenase-2 (COX-2) while sparing cyclooxygenase-1 (COX-1) represent a new attractive therapeutic development and offer new perspective for further use of COX-2 inhibitors. Intention of this work is to develop safer, selective COX-2 inhibitors that do not produce harmful effects. RESULTS: A series of 55 tyrosine derivatives were designed for evaluation as selective COX-2 inhibitors and investigated by in silico for their anti-inflammatory activities using C-Docker. The results of docking study showed that 35 molecules were found to selectively inhibit the enzyme COX-2. These molecules formed stable π hydrophobic and additional van der Waals interactions in the active site side pocket of COX-2. The molecules selected from docking studies were examined through ADMET descriptors and Osiris property explorer to find its safety profile as well. The tyrosine derivatives containing toxic fragments were eliminated. CONCLUSION: The results conclude that out of 55, 19 molecules possessed best binding energy (< -3.333 kcal/mol) and these molecules had more selective and safer COX-2 inhibitor profile compared to the standard celecoxib.Graphical abstract3-D structural interactions of COX-2 inhibiting tyrosine derivatives.

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The heartwood of Cedrus deodara is traditionally used for the treatment of neurological disorders in India. In this study, the compound 3,4-bis(3,4-dimethoxyphenyl) furan-2,5-dione (BDFD) isolated from the ethanolic extract of C. deodara was evaluated for its anticonvulsant activity. The experimental studies were carried out in albino mice (18­22 g) and rats (180­220 g), employing different models of convulsions. The N-methyl-D-aspartic acid (NMDA)-induced lethality test and estimation of brain gamma-aminobutyric acid (GABA) were carried out to investigate the mechanism of action of this compound. BDFD gave dose-dependent protection against pentylenetetrazole (PTZ)-, pilocarpine- and 6-Hz-induced convulsions but it could not inhibit NMDA-induced lethality. Motor incoordination was displayed when the BDFD dose exceeded 400 mg/kg, whereas the therapeutic dose was below 100 mg/kg in the PTZ, pilocarpine and 6-Hz models (39­90 mg/kg). Furthermore, brain GABA estimation revealed that this compound increases the GABA level. BDFD dose levels up to 150 mg/kg did not prevent NMDA-induced lethality, which proves its weak influence on the excitatory neurotransmitter glutamate. The findings of the experiments on various animal models clearly demonstrated that BDFD possesses anticonvulsant activity by enhancing inhibitory GABAminergic neurotransmission.

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A simple and efficient method has been developed for the synthesis of series of N-Mannich bases of (E)-3- (phenylimino/4-chlorophenylimino)-2,3-dihydro-1-[(N-substituted piperazinyl) methyl]quinoxaline-2-(1H)-one 3a-f and 4a-f. The requisite 2a and 2b were obtained by reaction between quinoxaline-2,3-dione 1 and aniline/p-chloroaniline. These compounds underwent NMannich reaction with various substituted piperazines to yield (title compounds 3a-f and 4a-f respectively. Structures of synthesized compounds were confirmed by spectral studies (IR, 1H NMR, 13C NMR and Mass) and elemental analysis. All the synthesized compounds were screened for in vitro leptospirocidal activty against Leptospira interrogans. The potent compounds 4a, 4b and 4c which showed maximum activity during in vitro studies were subjected to in vivo studies. The inhibitory activity of enzymes carboxypeptidase and transpeptidase, in leptospirosis by the synthesized compounds were determined. 3D-QSAR studies model developed showed the need for more hydrophobic and less steric groups as substituent groups to enhance the in vitro activity.

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Histone deacetylases (HDACs) are enzymes, which catalyze the removal of acetyl moiety from acetyl-lysine within the histone proteins and promote gene repression and silencing resulting in several types of cancer. HDACs are important therapeutic targets for the treatment of cancer and related diseases. Hydroxamic acid inhibitors show promising results in clinical trials against carcinogenesis. 120 hydroxamic acid derivatives were designed as inhibitors based on hydrophobic pocket and the Zn (II) catalytic site of HDAC8 active site using Structure Based Drug Design (SBDD) approach. High Throughput Virtual screening (HTVs) was used to filter the effective inhibitors. Induced Fit Docking (IFD) studies were carried out for the screening of eight inhibitors using Glide software. Hydrogen bond, hydrophobic interactions and octahedral coordination geometry with Zn (II) were observed in the IFD complexes. Prime MM-GBSA calculation was carried out for the binding free energy, to observe the stability of docked complexes. The Lipinski's rule of five was analyzed for ADME/Tox drug likeliness using Qikprop simulation. These inhibitors have good inhibitory properties as they have favorable docking score, energy, emodel, hydrogen bond and hydrophobic interactions, binding free energy and ADME/Tox. However, one compound (Cmp22) successively satisfied all the studies among the eight compounds screened and seems to be a promising potent inhibitor against HDAC8.

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Twenty new quinoxalines bearing azetidinone and thiazolidinone groups were synthesized by cyclocondensation of Schiff bases of quinoxaline-2, 3-dione and were characterized with several analytical tools. They were tested against Mycobacterium tuberculosis H37Rv at a concentration of 10 µg/mL by Microplate Alamar Blue Assay method. Quinoxaline derivatives with 2-chloro, dimethylamino and nitro substitutions exhibited in vitro activity, comparable to that of the drug, isoniazid. Three-dimensional quantitative structure-activity relationship studies indicated that electrostatic and steric field descriptors could explain the observed activity. The developed model fits the data well and has good predictive capability (r² = 0.81, q² = 0.71, F = 27.06, r² _pred = 0.84, r²(m) = 0.84, r² BS = 0.80). Electronegative groups play an important role in the antitubercular activity.

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Mucoadhesive buccal patches of Salbutamol Sulphate were prepared using five different polymers (polyvinylpyrrolidone [PVP]), polyvinyl alcohol [PVA], water soluble chitosan [CH(WS)], acid soluble chitosan [CH(AS)], hydroxypropyl methyl cellulose [HPMC])in various proportions and combinations (CH(WS)/PVP/HPMC, CH(WS)/PVA/HPMC, CH(AS)/PVP/HPMC, and CH(AS)/PVA/HPMC). A 3(2) full factorial design was used to design the experiments. A total of 72 patches were prepared. Thickness of the patches ranged between 0.3±0.003 and 0.6±0.009 mm. Mass of the patches were in the range of 68.12±4.6 to 95.02±7.2 mg. Patches showed increased mass whenever PEG -400 was used as plasticizer. The surface pH of patches were acidic to neutral (pH 4-pH 7). Patches showed satisfactory drug loading efficiency (85%to 97%). Eight formulations(C9, C18, C27, C36, D9, D18, D27, and D36)-which showed high folding endurance- were selected for further characterization. Patches with PEG -400 showed higher swelling index when compared to PG. The residence time of the patches ranged between 115 min and 120 min. Formulation C18 showed the maximum in vitro drug release of 101.4 % over a period of 120 min. Formulations D36 and C36 were best fitted to Higuchi model. The remaining formulations were best fitted to the Korsmeyer-Peppas model. Drug permeation was fast and showed the similar profile as that of the in vitro drug release. Patches were stable, during and at the end of the accelerated stability study.

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For systemic drug delivery, the buccal region offers an attractive route of drug administration. Salbutamol sulfate is a short-acting ß2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It's oral bioavailability is ∼40% due to extensive first pass metabolism. Salbutamol sulfate patches were prepared using Eudragit L-100, HPMC, PVA and Carbopol 934 in various proportions and combinations using PEG-400/PG as plasticizers. Patches were laminated on one side with a water impermeable backing layer for unidirectional drug release. The thickness of medicated patches were ranged between 0.23 ± 0.008 and 0.59 ± 0.007 mm and mass varied between 65.23 ± 3.3 and 117.92 ± 4.2 mg. Patches showed an increase in mass and swelling index with PEG-400 when compared with PG. The surface-pH of patches ranged between 6 and 7. Formulations E7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PEG-400), E12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PEG-400), F7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PG), and F12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PG) showed high folding endurance. Residence time of the tested patches ranged between 101 and 110 min. The maximum in vitro release was found to be 99.93% over a period of 120 min for formulation F12. Data of in vitro release from patches were fitted to different kinetic models such as Higuchi and Korsmeyer-Peppas models to explain the release profile. Formulations E7 and F7 were best fitted to the non-Fickian, where as formulations E12 and F12 showed Fickian/anomalous drug release. Stability studies indicated that there was no change in the chemical and physical characteristics during the test period.

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This paper describes the pharmacological evaluation pertaining to in vivo antiepileptic and locomotor activities, and subsequent QSAR studies on 4,5-diphenyl-1H-imidazole analogues. These two activities on albino mice were determined based on electroshock method and by using actophotometer respectively. Compounds with 4-fluorophenyl, 4-dimethylaminophenyl, 4-hydroxyphenyl and 4-methoxyphenyl substitutions exhibit the highest activity. Compounds with phenyl and 2-nitrophenyl substitutions exhibit the lowest activity in both the cases. Data are divided into training and test/validation sets, the former is used for developing the QSAR and the latter is used for determining the predictive capability of the developed models. The three-parameter model for the antiepileptic activity fits the data well and has a good predictive capability (For training set: R( 2) = 0.77, R( 2)(adj) = 0.72, q( 2) = 0.64, R( 2)(mod)= 0.66, for test set: R( 2) = 0.75). Total polar and solvent-accessible surface areas of the molecule are the descriptors in the model. A three parameter model and a four-parameter model for the locomotor activity fit the data well and have good predictive capability (For training set: R( 2) = 0.8-0.89, R( 2)(adj) = 0.76-0.77, q (2) = 0.7-0.86, R( 2)(mod)= 0.64-0.85, for test set: R( 2) = 0.79-0.9). Molecule shape, solvent-accessible surface area, LUMO and polar surface area are the significant descriptors. The first principal component is reverse similar51% and 50% correlated to locomotor and antiepileptic activities respectively.

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Twenty eight analogues of benzimidazoles had been synthesized and tested for their antimicrobial activity against four bacteria (Staphylococcus auerus, Escherichia coli, Bacillus pumilus and Proteus vulgaris) and two fungi (Aspergillus flavus and Aspergilus niger). Compounds with R as C6H4NO2 and R' as SO2C6H4-CH3(p), with R as C6H4OCH3 and R' as SO2C6H4-CH3(p), and with R as CH2C6H5 and R' as CH2(CH2)9Cl exhibited comparable or higher antibacterial activity than Ciprofloxacin against S. auerus and E. coli and, higher activity than Nystatin against A. flavus. Several other compounds showed better activity than the standard antibiotic for E. coli. Compounds with R as CCl3 and R' as SO2C6H4-CH3(p) or COC6H5 exhibited the lowest activity against all the organisms. Addition of methylene groups in the R' position increased activity. Many of the compounds showed better activity than Ciprofloxacin for one or more organisms. Compound with R as CH2OC6H5 and R' as CH2(CH2)9Cl exhibited higher activity against both the fungi than the control Nystatin. Quantitative structure activity relationships (QSARs) developed were good for all the organisms (R2=0.65 to 0.88; Radj2 = 0.63 to 0.86) and the predictive capability of the developed models was also reasonable (q2=0.52 to 0.83). The models had two to three independent variables. The data for the models which had three independent variables were divided into training and test/validation sets. The former set was used to develop the QSAR and these developed models were used to predict the activity of the test set data. In all the three cases the predictive capability of the models was good. The molecular descriptors identified were predominantly log P, electronic parameters, molecular size, shape and area. A positive correlation existed between the antibacterial activity and the first principal component.

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