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OBJECTIVES: The present study aimed to establish significant and validated quantitative structure-activity relationship (QSAR) models for neuraminidase inhibitors and correlate their physicochemical, steric, and electrostatic properties with their anti-influenza activity. MATERIALS AND METHODS: We have developed and validated 2D and 3D QSAR models by using multiple linear regression, partial least square regression, and k-nearest neighbor-molecular field analysis methods. RESULTS: 2D QSAR models had q(2): 0.950 and pred_r(2): 0.877 and 3D QSAR models had q(2): 0.899 and pred_r(2): 0.957. These results showed that the models werere predictive. CONCLUSION: Parameters such as hydrogen count and hydrophilicity were involved in 2D QSAR models. The 3D QSAR study revealed that steric and hydrophobic descriptors were negatively contributed to neuraminidase inhibitory activity. The results of this study could be used as platform for design of better anti-influenza drugs.

Aim: To predict the most potent indole based HDAC2 inhibitors from several scientific reports through the process of lead identification and SAR development. Background: The current scenario is observing Histone Deacetylase (HDAC) as an alluring molecular target for the designing and development of drugs for cancer treatment. Background: The current scenario is observing Histone Deacetylase (HDAC) as an alluring molecular target for the designing and development of drugs for cancer treatment. Objective: To identify the lead and establish structure-activity correlation among indole based hydroxamic acid to find out promising HDAC2 based anticancer agent. Methods: A dataset containing 59 molecules was analyzed using structure and ligand-based integrated approach comprising atom-based 3D-QSAR (Quantitative Structure-Activity Relationship) and pharmacophore study, e-pharmacophore mapping and molecular modeling methodologies. The finest model was prepared by amalgamating the properties of electronegativity, polarizability, Vander Waals forces and other conformational aspects. Results: The result of 3D QSAR analysis, performed for 4 PLS factor, provided the following statistical information: R2 = 0.9461, Q2 = 0.7342 and low standard of deviation SD = 0.1744 for hypothesis ADDDH.10 and R2 = 0.9444, Q2= 0.7858 and again low standard of deviation SD = 0.1795 for hypothesis DDHRR.12. The XP molecular docking showed intermolecular interactions of small molecules with amino acids such as GLY154, HIP145, PHE210, HIE183, internal H2O and Zn2+. Conclusion: The interpretation of data generated as a result of this investigation clearly hints about the better biological activity of test compounds as compared to SAHA. Hence, the outcome of these structure and ligand-based integrated studies could be employed for the design of novel arylindole derivatives as a potent HDAC inhibitor.

A significant number of the anti-inflammatory drugs currently in use are becoming obsolete. These are exceptionally hazardous for long-term use because of their possible unfavourable impacts. Subsequently, in the ebb-and-flow decade, analysts and researchers are engaged in developing new anti-inflammatory drugs, and many such agents are in the later phases of clinical trials. Molecules with heterocyclic nuclei are similar to various natural antecedents, thus acquiring immense consideration from scientific experts and researchers. The arguably most adaptable heterocyclic cores are benzimidazoles containing nitrogen in a bicyclic scaffold. Numerous benzimidazole drugs are broadly used in the treatment of numerous diseases, showing promising therapeutic potential. Benzimidazole derivatives exert anti-inflammatory effects mainly by interacting with transient receptor potential vanilloid-1, cannabinoid receptors, bradykinin receptors, specific cytokines, 5-lipoxygenase activating protein and cyclooxygenase. Literature on structure–activity relationship (SAR) and investigations of benzimidazoles highlight that the substituent’s tendency and position on the benzimidazole ring significantly contribute to the anti-inflammatory activity. Reported SAR analyses indicate that substitution at the N1, C2, C5 and C6 positions of the benzimidazole scaffold greatly influence the anti-inflammatory activity. For example, benzimidazole substituted with anacardic acid on C2 inhibits COX-2, and 5-carboxamide or sulfamoyl or sulfonyl benzimidazole antagonises the cannabinoid receptor, whereas the C2 diarylamine and C3 carboxamide substitution of the benzimidazole scaffold result in antagonism of the bradykinin receptor. In this review, we examine the insights regarding the SARs of anti-inflammatory benzimidazole compounds, which will be helpful for researchers in designing and developing potential anti-inflammatory drugs to target inflammation-promoting enzymes.

Background: The development of drug-resistant by bacteria appears rapidly and thus making the effectiveness of antibiotics severely limited. Methods: A series of thiourea derivatives was synthesized, characterized and evaluated for their in vitro antibacterial, antifungal and antiviral activities. Results: Structures of the newly synthesized compounds were confirmed by elemental and spectral analysis. The biological results showed that some of the target compounds displayed comparable antimicrobial and antiviral activities with reference drugs. Structure-activity relationship studies revealed that the ortho- chloro or fluoro substituted phenyl at Ar1 and substituted pyridinyl at Ar2 positions of the thiourea nucleus are essential for their in vitro antimicrobial and anti-HIV activity. In particular, compounds 8 and 10 showed better activity against the tested bacteria, fungi and viral strains than other synthesized PET derivatives reported in the present study. Conclusion: These results provide an encouraging lead that could be used for the development of new potent antiviral and antimicrobial agents

Background: Overexpression of Histone deacetylase 1 (HDAC1) is responsible for carcinogenesis by promoting epigenetic silence of tumour suppressor genes. Thus, HDAC1 inhibitors have emerged as the potential therapeutic leads against multiple human cancers, as they can block the activity of particular HDACs, renovate the expression of several tumour suppressor genes and bring about cell differentiation, cell cycle arrest and apoptosis. Methods: The present research work comprises atom-based 3D-QSAR, docking, molecular dynamic simulations and DFT (density functional theory) studies on a diverse series of hydroxamic acid derivatives as selective HDAC1 inhibitors. Two pharmacophoric models were generated and validated by calculating the enrichment factors with the help of the decoy set. The Four different 3D-QSAR models i.e., PLS (partial least square) model, MLR (multiple linear regression) model, Field-based model and GFA (Genetic function approximation) model were developed using ‘PHASE’ v3.4 (Schrödinger) and Discovery Studio (DS) 4.1 software and validated using different statistical parameters like internal and external validation. Results and Discussion: The results showed that the best PLS model has R2=0.991 and Q2=0.787, the best MLR model has R2= 0.993 and Q2= 0.893, the best Field-based model has R2= 0.974 and Q2= 0.782 and the best GFA model has R2= 0.868 and Q2= 0.782. Cross-validated coefficients, (rcv 2) of 0.967, 0.926, 0.966 and 0.829 was found for PLS model, MLR, Field based and GFA model, respectively, indicated the satisfactory correlativity and prediction. The docking studies were accomplished to find out the conformations of the molecules and their essential binding interactions with the target protein. The trustworthiness of the docking results was further confirmed by molecular dynamics (MD) simulations studies. Density Functional Theory (DFT) study was performed which promptly optimizes the geometry, stability and reactivity of the molecule during receptor-ligand interaction. Conclusion: Thus, the present research work provides spatial fingerprints which would be beneficial for the development of potent HDAC1 inhibitors.

Histone deacetylase inhibitors (HDACi) have been demonstrated as an emerging class of anticancer drugs involved in regulation of gene expression and chromatin remodeling thus indicating valid targets for different types of cancer therapeutics. The pan-deacetylase inhibitor panobinostat (Farydac®, LBH589) is developed by Novartis Pharmaceuticals and a newly US FDA approved drug for the multiple myeloma. It is under clinical investigation for a range of hematological and solid tumors worldwide in both oral and intravenous formulations. Panobinostat inhibits tumor cell growth by interacting with acetylation of histones and nonhistone proteins as well as various apoptotic, autophagy-mediated targets and various tumorigenesis pathways involved in the development of cancer. The current article summarizes the status of panobinostat in gastrointestinal cancers. Preclinical and clinical data suggest that panobinostat has potential inhibitory activity in hepatocellular, pancreatic, colorectal, gastric and gastrointestinal stromal tumors. Clinical evaluations of panobinostat are currently underway. Herein, we have also reviewed the rationale behind the combination therapy under the trials and possible future prospective for the treatment of GI tumors.

The inhibition of histone deacetylase (HDAC) has become a well-recognized target for cancer therapy. Until now only five HDAC inhibitors i.e., SAHA, romidepsin (FK-228), belinostat, chidamide, and panobinostat have been approved by FDA. The first four of them are being employed for the treatment of cutaneous T-cell lymphoma and last one is being used for the treatment of multiple myeloma. In the present study, structure and ligand-based computational approaches were selected to design novel histone deacetylase inhibitors. A ligand-based pharmacophore model was developed employing phase module that exhibited five similar features and the generated pharmacophore models were validated by enrichment studies using the decoy set. Atom-based 3D-QSAR model was developed and validated using internal, partial least square (PLS) and external validation methods. The best 3D-QSAR model exhibited high value of regression coefficient for training set (R2) = 0.926 and test (R2) = 0.699, cross-validated coefficient (rcv2) = 0.967 and R2 pred = 0.6578 with low root mean standard deviation (RMSE) = 0.4963. Additionally, the selected pharmacophore model (AAADR.12514) was employed as a 3D query for virtual screening against the ZINC database. The hit compounds were subsequently subjected to ligand–receptor interaction studies. Further, HDAC receptor-ligand complex were subjected to MM-GBSA and molecular dynamic simulation to evaluate the binding energy, strain energy, stability, and electrostatics of complex. Moreover, ADMET studies were also performed on resulted molecules. The outcome of these studies could be utilized for identification of novel lead for the development of HDAC inhibitors.

Background Fluoroquinolones, the synthetic antibacterial agents are being successfully utilized against bacterial infections, since the time immemorial. Despite of enormous useful features, these drugs are associated with some limitations also. Large number of efforts has been made by various scientists to improve pharmacokinetic properties of these drugs and hence, to overcome the limitations associated with them. Objectives The aim of this paper is to introduce a novel scheme for synthesis of prodrug with improved pharmacokinetic properties i.e., lipophilicity and consequently, modified bioavailability of norfloxacin. Methods Fatty acid hydrazide of selected fatty acid was synthesized followed by preparation of 5-formyl salicylamide. N-Mannich base of norfloxacin was synthesized by reacting norfloxacin with 5-formyl salicylamide. The prodrug was obtained by covalently coupling this N-Mannich base of norfloxacin with fatty acid hydrazide. The synthesized lipid based prodrug was evaluated for partition coefficient by shake flask method and screened for antimicrobial activity against selected strains. Drug content determination and in vitro dissolution studies utilizing HPLC were also carried out. Results The synthesized prodrug was found to exhibit improved partition coefficient (1.15) when compared with parent drug, norfloxacin (0.46). The results of antimicrobial evaluation indicate promising antibacterial and antifungal activity. Conclusion The synthesized prodrug proved to be a good antimicrobial substance due to improved lipophilicity and would be expected to be used as a suitable candidate for exploration of possible utilities in treatment of bacterial infections in forthcoming time.

Background: Aroylindole derivatives, the structural analogs of Combretastatin A-4 has been found to possess potent growth inhibitory activity on several cancer cell lines due to its excellent antitumor and antivascular activities. The aim of present research work is to identify lead and establish structure activity correlation of trimethoxyaroylindole derivatives, using integrated ligand and structure based computational approaches. Materials and Methods: A correlation between structure and biological activity was established using computational approaches i.e., structure activity correlation by pharmacophore and atom based 3D QSAR, molecular docking and energetic based pharmacophore mapping studies of trimethoxyaroylindole derivatives. Results and Discussion: The 3D-QSAR on trimethoxyaroylindole derivatives generated and showed best statistical result for CPHs AAARR.182 was validated by Q2 (0.6929), R2 (0.82). The Comp. 1 of the training set was employed as template for hydrogen bond donor, hydrophobic and hydrogen bond acceptor field prediction features and visualization of the 3D-QSAR model provides details of relationship between structure and biological activity of trimethoxyaroylindole derivatives. Pharmacophore model was developed by Phase and e-pharmacophore on comp. 1, the trimethoxy group with ring A, keto group, N-H group with ring B and ring C are pharmacophoric group important for the lead generation and coincide with various chemical features that may facilitate non-covalent binding between the ligand and its target receptor. Molecular docking studies showed critical interactions between Cys241, Val318 and meta, para-methoxy group at ring A while and Thr179 and NH of indole (distance 3.5 Å). The para position of trimethoxyphenyl ring bind to SH group of CYS 241 receptor molecule via hydrogen bond. Conclusion: The lead identification and establish structure activity correlation of trimethoxyaroylindole derivatives, were performed using integrated ligand and structure based computational approaches i.e., atom based 3D QSAR and pharmacophore study, molecular docking, energetic based pharmacophore mapping studies showed promising results. The outcomes of present studies could be utilized for the design of novel aroylindole derivatives including its lead optimization as potential anticancer agent.

The structure and ligand based synergistic approach is being applied to design ligands more correctly. The present report discloses the combination of structure and ligand based tactics i.e., molecular docking, energetic based pharmacophore, pharmacophore and atom based 3D-QSAR modeling for the analysis of thiophene derivatives as anticancer agent. The main purpose of using structure and ligand based synergistic approach is to ascertain a correlation between structure and its biological activity. Thiophene derivatives have been found to possess cytotoxic activity in several cancer cell lines and its mechanism of action basically involves the binding to the colchicine site on β-tubulin. The structure based approach (molecular docking) was performed on a series of thiophene derivatives. All the structures were docked to colchicine binding site of β tubulin for examining the binding affinity of compounds for antitumor activity. The pharmacophore and atom based 3D-QSAR modeling was accomplished on a series of thiophene (32 compounds) analogues. Five-point common pharmacophore hypotheses (AAAAR.38) were selected for alignment of all compounds. The atom based 3D-QSAR models were developed by selection of 23 compounds as training set and 9 compounds as test set, demonstrated good partial least squares statistical results. The generated common pharmacophore hypothesis and 3D-QSAR models were validated further externally by measuring the activity of database compounds and assessing it with actual activity. The common pharmacophore hypothesis AAAAR.38 resulted in a 3D-QSAR model with excellent PLSs data for factor two characterized by the best predication coefficient Q2 (cross validated r2) (0.7213), regression R2 (0.8311), SD (0.3672), F (49.2), P (1.89E-08), RMSE (0.3864), Stability (0.8702), Pearson-r (0.8722). The results of these molecular modeling studies i.e., molecular docking, energetic based pharmacophore, pharmacophore and atom based 3D-QSAR modeling would be fruitful to improve the pharmacophore for design of novel combretastatin A-4 based thiophenes for anticancer activity.

Pyrrole is a biologically active scaffold, which itself possess noticeable anticancer activity against several types of cancer specially leukemia, lymphoma, and myelofibrosis. SAHA and its synthetic analogs has demonstrated potent antitumor activity against numerous human cancer lines and different classes of HDACs. The HDAC inhibitor possessing pyrrole as linker moiety has been developed for anticancer property. The objective of present studies was to incorporate pyrrole as connecting unit in hydroxamic acid based HDAC inhibitors for their anticancer evaluation and molecular docking studies. A series of novel 4-substituted methyl 6-(3-acetyl-2-methyl-1H-pyrrol-1-yl)hexanoate [3(a-z)] and 4-substituted 6-(3-acetyl-2-methyl-1H-pyrrol-1-yl)-N-hydroxyhexanamide [4(a-z)] were synthesized. These analogs were evaluated for their anticancer activity using in-vitro method against leukemia (K-562), lung (A-549), breast (MCF-7), and cervical (HeLa) human cancer cell lines using Sulforhodamine B (SRB) assay method, HDAC1 and HDAC6 inhibitory assay and binding mode analysis using molecular docking studies. The in-vitro studies of 3(a-z) indicated that substitution with electron donating groups produces active or moderately active compounds. Interestingly, p-nitro-substituted molecule produced a most active derivative in the series. The in-vitro anticancer study of 4(a-z) indicated that the unsubstituted phenyl derivative, 6-(3-acetyl-2-methyl-4-phenyl-1H-pyrrol-1-yl)-N-hydroxy-hexanamide (4a) have moderate antitumor activity against K-562 human leukemia cell line. Substitution at 4-phenyl ring with weak and moderate electron withdrawing groups, such as fluoro, chloro, and bromo potentiated the cytotoxic activity. The 4(a-z)] were docked against different HDAC proteins to determine the exact binding mode and orientation. These synthetic analogs have similar binding mode as SAHA on the active pocket. The pyrrole based novel SAHA analogs 3(a-z) and 4(a-z) displayed promising anticancer activity. These studies can be further employed for the design and development of novel SAHA analogs with promising anticancer activity.

Histone deacetylase (HDAC) is a promising target for cancer treatment. HDAC inhibitors consist of three pharmacophoric features: an aromatic cap group, zinc binding group (ZBG), and a linker chain connecting cap group to ZBG. Herein, we report on (i) substituted isatin moiety as the cap group that recognizes the surface of active enzyme pocket and (ii) thiosemicarbazide moiety incorporated as linker group responsible for connecting the cap group to ZBG (hydroxamic acid). The synthesized compounds were evaluated for their antiproliferative activity and HDAC enzyme inhibition. The binding mode analysis of proposed compounds was evaluated by docking studies. Several analogs were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells, with GI50 values in the micromolar range. One compound (Vd) was found to have greater in vitro antiproliferative activity in comparison to other compounds.

Graphical abstract, Prodrugs, the inert derivatives of existing drugs have successfully contributed to the modification of their physicochemical properties. The improved antimicrobial potential due to enhanced lipophilicity of some of the synthesized prodrugs of antibacterial agents by various schemes has already been reported. In the current study, synthesis, characterization, and biological evaluation of some more lipid based prodrugs/compounds of ciprofloxacin and norfloxacin has been carried out. The synthesized prodrugs/compounds have been screened for anthelmintic activity using Indian earthworms and cytotoxic activity against human lung cancer cell lines A-549 employing sulforhodamine B (SRB) assay method. The prodrugs FQF1, 6b, 6c, and 6k were found to possess promising anthelmintic activity due to improved partition coefficient. Growth of selected cells lines was found to decrease with increase in concentration of prodrugs as compared to parent drug. Prodrug, 6k having GI50 value 28.8, has been proved to be the most active among all the synthesized prodrugs. Results of present investigation reveal that some of the synthesized prodrugs/compounds were found to possess promising biological activity.

Anticonvulsant refers to a group of pharmaceuticals used in the treatment of epileptic seizures. The use of current antiepileptic drugs has been questioned due to the non-selectivity of the drugs and the undesirable side effects produced by them. This led to the search for antiepileptic compounds with more selectivity and lower toxicity. Semicarbazones have been developed as versatile anticonvulsant pharmacophore. It has displayed potent anticonvulsant effect in a wide variety of preclinical anticonvulsant models. Till date various semicarbazone derivatives containing 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyrimidine, benzothiazole and substituted phenyl/aryl ring have been synthesized and evaluated for anticonvulsant activity. The semicarbazone based pharmacophore model with four binding sites is essential for anticonvulsant activity. This model comprises of an aryl hydrophobic binding site, hydrogen bonding domain, an electron donor group and another hydrophobic-hydrophilic site regulating the pharmacokinetic properties of the anticonvulsant. Extensive structure-activity relationship has demonstrated that compound with OH, CH3O, NO2, Cl, F, Br substituents in the arylhydrophobic pocket, nitro, hydroxy group on distant phenyl ring and a hydrogen bonding domain possess anticonvulsant activity. In this review, advances made in the application of semicarbazones as a versatile pharmacophore model for the design of new anticonvulsant drugs are being updated and suggested for future drug design and development of novel anticonvulsants.

Two simple, accurate, novel, safe and precise methods were developed for the simultaneous estimation of poorly water-soluble drugs Metronidazole (MTR) and Furazolidone (FZ) in a tablet dosage form using 2 M sodium acetate and 8 M urea solution (50:50%V/V) as a mixed hydrotropic solution. MTR and FZ show maximum absorbances at 319 and 364 nm, respectively. Sodium acetate and urea solution did not show any absorbance above 240 nm and thus no interference in the estimation of drugs was seen. MTR and FZ follow Beer’s law in the concentration range of 10–50 μg/ml and 5–25 μg/ml ( r 2 = 0.9992 and 0.9996). Method-A employs the simultaneous equation method using 319 and 364 nm as two analytical wavelengths, method-B employs the absorption ratio method, which uses 339.2 and 364 nm as two analytical wavelengths for estimation of MTR and FZ. The mean percent label claims of tablet dosage were found to be 98.715 ± 1.012 and 98.74 ± 0.912 in method A, 98.99 ± 0.872 and 97.89 ± 0.903 in method B for MTR and FZ, respectively. The developed methods were validated according to ICH guidelines and values of accuracy, precision and other statistical analysis were found to be in good accordance with the prescribed values therefore both methods can be used for routine monitoring of MTR and FZ in industry in the assay of bulk drug and tablets.

In the pasture of oncology, anticancer agents having advanced modes of action are of great interest because of increasing chronicity of resistance against anticancer drugs. Heterocyclic scaffolds like benzothiazoles are reported to display an extensive range of pharmacological activities including anticancer, anti-tubercular, antiviral, fungicidal, etc. and are indispensable tools for the researchers involved in vistas of chemistry for proposing of novel anticancer drugs. Benzothiazole scaffold is a bicyclic organic compound having benzene ring fused with heterocyclic nucleus (thiazole) containing sulphur and nitrogen atoms that possess a wide range of different pharmacological activities and are still of grand and logical concern nowadays. Interesting pharmacological activities are exhibited by benzothiazoles and they were developed as successful inhibitors of a variety of biological targets such as tubulin polymerase inhibitor, DNA topoisomerase-inhibitor, an Abl kinase inhibitor, HDAC inhibitor, Aurora-B kinase inhibitor. This review highlights the latest research on the structure-activity relationship of benzothiazole scaffold against different biological targets for their anticancer activity. This survey additionally addresses the recent patents granted and novel advancement made through the application of nanocarriers in recent decades with thorough talk of benzothiazoles as conceivable anticancer mediators which may be helpful for the emerging scientific pursuits.

Histone deacetylase inhibitors (HDACi) have been actively explored as anti-cancer agents due to their ability to prevent deacetylation of histones, resulting in uncoiling of chromatin and stimulation of a range of genes associated in the regulation of cell survival, proliferation, differentiation and apoptosis. During the past several years, many HDACi have entered pre-clinical or clinical research as anti-cancer agents with satisfying results. Out of these, more than 8 novel hydroxamic acid based HDACi i.e., belinostat, abexinostat, SB939, resminostat, givinostat, quisinostat, pentobinostat, CUDC-101 are in clinical trials and one of the drug vorinostat (SAHA) has been approved by US FDA for cutaneous T-cell lymphoma (CTCL). It is clear from the plethora of new molecules and the encouraging results from clinical trials that this class of HDAC inhibitors hold a great deal of promise for the treatment of a variety of cancers. In this review, we classified the hydroxamic acid based HDACi on the basis of their structural features into saturated, unsaturated, branched, un-branched and 5, 6-membered cyclic ring linker present between zinc binding group and connecting unit. The present article enlists reports on hydroxamic acid based HDACi designed and developed using concepts of medicinal chemistry, demonstrating that hydroxamate derivatives represent a versatile class of compounds leading to novel imaging and therapeutic agents. This article will also provide a complete insight into various structural modifications required for optimum anticancer activity.

Achyranthes aspera L. (Amaranthaceae) is used traditionally in Indian system of medicine as diuretic, astringent, purgative, anticancer, dropsy, piles, and skin eruptions. To explore anti-atherosclerotic potential of crude saponins and ethanol extract of A. aspera seeds husk on hyperlipidemic diet induced rats model was used to increase the lipid profile. After 2 weeks, all the animals showed symptoms of hyperlipidemia and were treated with 100, 200 and 400 mg/kg ethanol extract (EE) respectively, while saponins (SAPN) at a dose of 10 mg/kg by gavage for 28 days. Serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum glucose and atherogenic index (A.I.) level were estimated on 0th, 14th and 42th day by using autoanalyser. EE of husks decreases TC 40.71-46.77 %, TG 23.95-37.27 %, LDL 56.49-65.50 %, serum glucose 17.48-25.54 % and A.I. 51.27-77.05 % significantly (P

Two novel series of N4-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N1-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N4-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N1-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. The rotorod test was conducted to evaluate neurotoxicity. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The outcome of the present investigations proved that the four binding sites pharmacophore model is vital for anticonvulsant activity. The efforts were also made to establish structure–activity relationships among test compounds.

Heterocycles bearing nitrogen, sulphur and thiazole moieties constitute the core structure of a number of biologically interesting compounds. Benzothiazole, a group of xenobiotic compounds containing a benzene ring fused with a thiazole ring, are used worldwide for a variety of therapeutic applications. Benzothiazole and their heterocyclic derivatives represent an important class of compounds possessing a wide spectrum of biological activities. The myriad spectrum of medicinal properties associated with benzothiazole related drugs has encouraged the medicinal chemists to synthesize a large number of novel therapeutic agents. Several analogues containing benzothiazole ring system exhibit significant antitumour, antimicrobial, antidiabetic, anti-inflammatory, anticonvulsant, antiviral, antioxidant, antitubercular, antimalarial, antiasthmatic, anthelmintic, photosensitizing, diuretic, analgesic and other activities. This article is an attempt to present the research work reported in recent scientific literature on different pharmacological activities of benzothiazole compounds.

Histone deacetylase inhibitors have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Two novel series of N-(2-amino-phenyl)-4-{[(2/3/4-substituted-phenylcarbamoyl)-methyl]-amino}-butyramide and N-(2-amino-phenyl)-4-{[(2/3/4-substituted-phenylcarbamoyl)-methyl]-amino}benzamide were designed and synthesized as novel histone deacetylase inhibitors. The anticancer potential of the compounds were determined in-vitro using MTT assay against HCT-116 and U251 (glioma) cell lines and histone deacetylase inhibitory assay. The synthesized compounds were investigated for anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells in Swiss albino mice. The efforts were also made to ascertain structure-activity relationships among test compounds. The results of the present studying represents appraisal of γ-aminobutyric acid (GABA) and para-aminobenzoic acid (PABA) as linker moiety for development of newer benzamide based histone deacetylase inhibitor.

Two-dimensional QSAR models were produced by stepwise multiple-linear regression and 3D QSAR models were developed by k-nearest neighbor-molecular field analysis on a database consists of 18 diaryl pyrimidine analogs. The developed QSAR model was evaluated for statistical significance and predictive power. The key conclusion of this study is that the electro-topological state indices for number of carbon atom connected with one double and two single bonds, retention index (fourth order), electrostatic, hydrophobic, and steric field descriptors are significantly affect the anti-HIV activity of diaryl pyrimidine analogs. The selected descriptors serve as a first guideline for the design of novel and potent diaryl pyrimidine analogs as anti-HIV agents. In the present study, we discussed the role of retention index (fourth order), electrostatic, hydrophobic and steric field descriptors in the anti-HIV activity of diaryl pyrimidine analogues.

Background: Epilepsy is a neurological disorder, characterized by seizures accompanied by loss or disturbance of consciousness affecting various physical and mental functions. Current anticonvulsant drugs are effective in controlling seizures in about 70% of cases, but their use is often limited by side effects like ataxia, megaloblastic anemia, hepatic failure. In search for a novel anticovulsant drug with better efficacy and lower toxicity, a series of novel pyrimidine based semicarbazone were designed and evaluated for antiepileptic activity. Methods: The test compounds were designed on the basis of four site binding hypothesis proposed for anticonvulsant activity. The chemical structures of the test compounds were elucidated using spectral (IR, 1H NMR, 13C NMR and MS) and elemental analysis. The minimal motor impairment activity was determined in mice using rotorod test. The maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models were employed for anticonvulsant evaluation. Results: The results reveal that 76% of the compounds were active in the MES screening as compared to 53% of the compounds in the scPTZ test. Test compounds showed some MES selectivity displaying their effectiveness in generalized seizures of the tonic-clonic type. The molecular docking analysis of semicarbazone derivatives showed good ligand-receptor interactions with specially hydrogen bond interactions with ARG192, GLU270 and THR353 amino acid of receptor. Conclusion: The present report confirms that pharmacophore model with four binding sites is crucial for anticonvulsant activity in the semicarbazones.

Background: Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. Objective: To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. Method: The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. Results: Best 3D-QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross-validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. Conclusion: The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity.

A series of novel 2-amino-3,4,5 trimethoxyaroylindole derivatives was synthesized and evaluated against selected human cancer cell lines of breast (MCF-7) and colon (HT-29). Introduction of an amino group at the C-2 position on ring A of 3,4,5-trimethoxyaroylindole derivatives resulted in novel compounds, i.e., 2-amino-3,4,5-trimethoxyaroylindole derivatives exhibiting excellent cytotoxic activity against human cancer cell lines. Substitution with methoxy group at R(6) in 2-amino-3,4,5-trimethoxyaroylindole 5d exhibited excellent cytotoxic activity against MCF-7 (0.013 μM) and colon HT-29 (0.143 μM) indicating slightly higher potency than Combretastatin A-4. Molecular modeling studies of 2-amino-3,4,5-trimethoxyaroylindole derivatives have similar structural alignment as colchicine in protein (PDB code: 1SA0) and exhibited hydrogen bond interaction between para position of 3,4,5-trimethoxyphenyl ring with CYS 241 and N-H molecule of indole ring with Val 315 of receptor molecule.

In the present investigation, synthesis and anti-bacterial, analgesic and anthelmintic evaluation of a novel series of fluoroquinolone derivatives clubbed with benzothiazole moeity has been described. The synthesized compounds were characterised by spectral analysis (IR and (1)H NMR). Preliminary results indicated that the most of the synthesized compounds demonstrated good activities against gram negative and gram positive bacterial strains. Compounds 5a, 5b, 5f and 5k demonstrated potent anti-bacterial activities. Compound 5a exhibited most potent anti-bacterial activity with MIC values of 04, 03, 08 and 15 µg/ mL against B. subtilis, S. aureus, E. coli and P. aeruginosa. Analogs 5a, 5c, 5g and 5h showed promising anthelmintic activity against Eisemia foetida in a low concentration as compared to standard drug piperazine citrate with mean paralysis time ranging 22.60 ± 2.46 to 31.60 ± 3.07 min. All synthesized compounds depicted good in vivo analgesic activity with compound 5a exhibiting the most potent activity of 55.19% inhibition of writhing in comparison to the standard drug.

A series of 1,3-thiazolidin-4-one derivatives were prepared by the reaction of respective aromatic amine, aromatic aldehyde, and thioglycolic acid in dry benzene/toluene. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, (1) HNMR, and mass spectra. The newly synthesized final compounds were evaluated for their in vitro antibacterial, antifungal, and anti-viral activities. Preliminary results indicated that some of the compounds demonstrated antibacterial activity in the range of 7-13 μg/mL, antifungal activity in the range of 13-17 μg/mL, comparable with the standard drugs, ciprofloxacin and fluconazole. Structure-activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus had a significant impact on the in vitro antimicrobial and anti-viral activity of these classes of agents.

A QSAR study on novel Pyrimidine derivatives as specific COX-2 inhibitory agents was performed with 69 (59 training + 10 test) compounds. Molecular modeling studies were performed using chemoffice 6.0 supplied by cambridgesoft. The sketched structures were subjected to energy minimization and the lowest energy structure was used to calculate the physiochemical properties. The regression analysis was carried out using a computer program called SYSTAT 10.2. The best models were selected from the various statistically significant equations. The study revealed that the hydrogen bond donar groups at position-4 enhances the activity, electron with-drawing groups at position-2 reduces the activity, electron donating groups at position-6 enhances the activity. The analysis resulted in QSAR equation, which suggests that, n = 59, r = 0.957, r2 = 0.915, adjusted squared multiple R = 0.901, Standard error of estimate(s) = 0.294 & validated r2(q2) = 0.642. This study can help in rational drug design and synthesis of new selective cyclooxygenase-2 inhibitor with predetermined affinity.

In search for a better anticonvulsant drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-oxadiazoles as anticonvulsant pharmacophore, a series of novel substituted semicarbazones were designed, synthesized, and evaluated for their anticonvulsant activity. The chemical structures of the synthesized molecules were confirmed by elemental and spectral (IR, (1) H NMR, (13) C NMR and MS) analysis. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure and subcutaneous pentylenetetrazole (scPTZ) models. Efforts were also made to establish structure-activity relationships among synthesized compounds. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity.

A novel series 7(a–f) 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2 phenylquinazoline-4(3H)-ones have been synthesized and screened for its anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-disubstituted-quinazolin-4(3H)-ones were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data were consistent with the structure of newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. In the prepared series, 7a was found to be active in the MES screen at 0.5 h, whereas 7f showed anticonvulsant activity at both 0.5 and 4 h.

In pursuit of more active thioureas as anti-HCV agent, QSAR studies were performed on a series of thioureas to explore the various physico-chemical parameters responsible for their activity against HCV-infected AVa 5 cell. Physico-chemical parameters were calculated using WIN CAChe 6.1. Stepwise multiple linear regression analysis was performed to derive QSAR models which were further evaluated for statistical significance and predictive power by internal and external validation. The selected best QSAR model was having correlation coefficient (R) = 0.902 and cross-validated squared correlation coefficient (Q 2) = 0.734. The developed significant QSAR model indicates that hydrophobicity, dielectric energy, valence connectivity index (order 1), and ionization potential of whole molecule play an important role in anti-HCV activity of thioureas. The hydrophobicity of thioureas was found to have parabolic relation with its anti-HCV activity. The optimum logP value for these anti-HCV compounds was found to be 4.988. In this study, the role of hydrophobicity on anti-HCV activity of thiourea derivatives is discussed. It has been found that the optimum logP value for these anti-HCV compounds was 4.988.

In pursuit for better antiepileptic drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore, a series of novel N -({5-[(6-methyl-1-benzofuran-3-yl)methyl]-1,3,4-thiadiazol-2-yl}carbamothioyl)-2/3/4-substitutedbenzamide were designed, synthesized and evaluated for their anticonvulsant activity. The findings of the present studies confirmed that the pharmacophore model with four binding sites is crucial for anticonvulsant activity. Structure–activity relationships among synthesized compounds were also established.

Selective GABA(A) receptor ligands are widely used clinically to reduce the occurrence of convulsions. Hence there is an intense interest in developing new benzimidazole derivatives demonstrating high selectivity and high affinity for GABA(A) receptors. With the purpose of designing new chemical entities with an enhanced binding affinity for GABA(A)/BZd receptor complex, we carried out a QSAR study on benzotriazine derivatives. We studied 28 potent GABA(A) receptor ligands; derivatives of benzotriazines, using a combination of various tested physicochemical, steric, electronic and thermodynamic descriptors to determine the quantitative correlation between binding affinity and structural features. The developed and validated final model showed a good correlative and predictive ability expressed by a squared correlation co-efficient (r(2)) of 0.954. The equation indicated that the binding affinity is strongly dependent upon the thermodynamic properties (CDE, DDE and PC). Correlation between these properties and anticonvulsant activity was used to synthesize compounds possessing potent anticonvulsant activity. Most of the compounds showed an ability to inhibit the maximum electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Compound 1A, i.e. 2-(4-Chloro-phenyl)-5-nitro-1H-benzimidazole exhibited maximum activity in both the convulsion models.

Objective: Histone deacetylase inhibitors (HDACi) have four essential pharmacophores as cap group, connecting unit, a linker moiety and zinc binding group for their anticancer and histone deacetylase (HDAC) inhibition activity. On the basis of this fact, the objective of this research was to evaluate the exact role of pyrazole nucleus as connecting unit and its role in the development of newer HDACi.Methods: Ligand and structure-based computer-aided drug design strategies such as pharmacophore and atom based 3D QSAR modelling, molecular docking and energetic based pharmacophore mapping have been frequently applied to design newer analogs in a precise manner. Herein, we have applied these combinatorial approaches to develop the structure-activity correlation among novel pyrazole-based derivatives.Results: the Pharmacophore-based 3D-QSAR model was developed employing Phase module and e-pharmacophore on compound 1. This 3D-QSAR model provides fruitful information regarding favourable and unfavourable substitution on pyrazole-based analogs for HDAC1 inhibition activity. Molecular docking studies indicated that all the pyrazole derivatives bind with HDAC1 proteins and showed critical hydrophobic interaction with 5ICN and 4BKX HDAC1 proteins.Conclusion: The outcome of the present research work clearly indicated that pyrazole nucleus added an essential hydrophobic feature in cap group and could be employed to design the ligand molecules more accurately.

Objective: The design and development of Combretastatin A-4 analogues as anticancer agent has always attracted the attention of scientific community involved in anticancer research. The aim of the present work was to investigate the in-vivo cytotoxic activity of a novel CA-4 analogues i.e., (2-amino-3,4,5-trimethoxyphenyl)(6-methoxy-1H-indol-3-yl)methanone. Method: The in-vivo cytotoxic activity of test compound was examined using Human Tumor Xenograft model on MCF-7 cancer cell line in Balb/c mice. Result: The test compound exhibited excellent cytotoxic activity against MCF-7 (0.013 µM), and colon HT-29 (0.143 µM), slightly higher than CA-4 activity. Relative Tumor Volume (RTV) value was found to increase rapidly in control group A during the period of 1 to 18 days indicating the higher growth rates of tumor. On the other hand group B and C showed slower growth rate of tumor as a result of treatment with CA-4 and test compound, respectively . The group B treated with CA-4 (5 mg/kg) showed significant inhibition in tumor growth during day 5 to 18 with %TGI in range of 47.24%-62.31% as compared to control group. The group C treated with test compound (5mg/kg) caused significant inhibition in tumor growth during day 5 to 18 with %TGI in range of 55.66%-75.93% as compared to control group. The % survival value was found 100% indicating that CA-4 and test compound were nontoxic at the dose of 5mg/kg under experimental conditions. Conclusion: The parameters of In-vivo anticancer evaluation i.e., relative tumour volume and % tumor growth inhibition showed better anticancer potential of test compound. It was further supported by non-toxic nature of test compound as indicated by 100% survival value determined at the dose of 5 mg/kg during in-vivo studies.

The search for better anticonvulsant drug and the importance of 2,5-disubstituted 1,3,4-oxadiazoles and indole as anticonvulsant pharmacophores, prompted us to design, synthesize and evaluate a series of differently substituted 1,3,4-oxadiazoles for their potential anticonvulsant activity. The structures of the compounds were elucidated by elemental and spectral (IR, 1H NMR, 13C NMR and MS) analyses. Most of the test compounds demonstrated appreciable anticonvulsant activities in maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models.

Two novel series of oxadiazole and oxadiazoline analogs possessing an indole nucleus were synthesized for their potential anti-inflammatory activity. The structures of the compounds were elucidated by elemental and spectral (IR, (1)H-NMR, (13)C-NMR, and MS) analysis. Most of the test compounds demonstrated appreciable anti-inflammatory activities. The anti-inflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 27-66%, 14-32%, and 20-51%. protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the anti-inflammatory properties of oxadiazolines at doses of 100 mg/kg were reflected by their ability to provide 20-56%, 11-26%, and 25-47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. The ulcerogenic potential of the compounds was determined. Structure-activity relationships among synthesized compounds were also established.

There are vast numbers of pharmacologically active heterocyclic compounds in regular clinical use. The presence of heterocyclic structures in diverse types of compounds is strongly indicative of the profound effects such structure exerts on physiologic activity, and recognition of this is abundantly reflected in efforts to find useful synthetic drugs. The 1,3,4-oxadiazole nucleus has emerged as one of the potential pharmacophore responsible for diverse pharmacological properties. Medical Literature is flooded with reports of a variety of biological activities of 2,5-Disubstituted-1,3,4-oxadiazoles. The present work is an attempt to summarize and enlist the various reports published on biologically active 2,5-disubstituted-1,3,4-oxadiazoles.

A series of novel N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-(4-substituted benzaldehyde)-semicarbazone 1-12, N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl)ethanone]-semicarbazone 13-16, and N(1)-[5-(4-substituted phenyl)-1,3,4-thiadiazol-2-yl]-N(4)-[1-(4-substituted phenyl) (phenyl) methanone]-semicarbazone 17-20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, (1)H-NMR,( 13)C-NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8, 13, 15, and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among the synthesized compounds.

The search for newer non-steroidal antiinflammatory drugs (NSAIDs) and the importance of oxadiazoles as antiinflammatory agents prompted us to undertake the synthesis of some novel oxadiazole and related analogues with unreported antiinflammatory activities. The antiinflammatory potential of the compounds was investigated using the carrageenan-induced rat paw edema method and cotton pellet-induced granuloma method. Some compounds demonstrated marked antiinflammatory activities. The antiinflammatory activity of oxadiazoles at doses of 100 mg/kg was shown by their ability to provide 28-55%, 21-36%, and 27-49% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the antiinflammatory properties of oxadiazolines at doses of 100 mg/kg was reflected by their ability to provide 15-47%, 22-39%, and 23-47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. Structure-activity relationships among synthesized compounds were also studied.

One of the main aims of drug discovery process is to generate novel therapeutic agents against the vast number of potential drug targets and this demands the acceleration of the drug discovery process. It is important to look not only at the staggering cost of discovering a new drug but also at the development time. Microwave assisted organic synthesis enhances the drug discovery process by increase in synthetic yields, consistently shorter reaction time and single step synthesis of many conventional multi-step synthetic procedures. In the present article, an attempt has been made to outline the importance of microwave assisted organic synthesis in drug discovery process.

Tubulin protein is a highly imperative and feasible goal for anticancer drug discovery. Hundreds of naturally occurring, semi synthetic and synthetic antitubulin agents have been reported till now. Among these, Combretastatin A - 4 (CA - 4) is effective antimitotic agent possessing potent cytotoxicity against a panel of cancer cells, including multi-drug resistant cancer cell lines. The inadequate water solubility and inactivation of these analogs during storage limit their use as clinical anticancer agents. To overcome these shortcomings, numerous water soluble amino analogs, amino acid derivative, phosphate prodrug (CA - 4P) and cis-locked CA - 4 have been developed with distinctive attributes of antitubulin and antivascular properties in a wide variety of preclinical tumor models. Subsequently, several heterocycle based cis restricted CA - 4 analogs are being reported for antitumor activity against collection of cancer cell lines. This review recapitulates the rational design, structure activity relationship, pharmacokinetic and pharmacodynamic profile of synthesized cis restricted CA - 4 analogs.

Quinazolinone scaffold has been considered as a magic moiety possessing myriad spectrum of medicinal activities. Diversity of biological response profile has attracted considerable interest of several researchers across the globe to explore this skeleton for its assorted therapeutic significance. Various novel classes of structurally different quinazolinones have been designed and synthesized depicting potential interventions such as antibacterial, antifungal, antiviral, anticonvulsant, CNS depressant, antiinflammatory, antihistaminic, anticancer and so on. Moreover, the nucleus constitutes an integral structural component in a number of drugs currently employed in several clinical therapies. The present paper is an earnest attempt to provide an insight view on the current medicinal aspects of quinazolinone heterocycles alongwith brief discussion of their chemistry.