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Histone deacetylase (HDAC) is one of the therapeutically relevant target for the treatment of various types of cancer. To establish a correlation between biological potency and their structural features using a combined approach of Hypogen pharmacophore and five different 3D QSAR models. Hypogen model (Hypo1) for HDAC inhibitors was developed on the basis of existing one, having good correlation coefficient (R= 0.76), lowest root mean square deviation (RMSD) of 0.91, maximum fit value of 9.77 and highest cost difference value of 66.86. Quality validation of Hypo1 through cost analyses, test set prediction and Fischer’s randomization test suggested that the model can reliably detect HDAC inhibitors. The five different 3D QSAR models i.e., Recursive Partitioning Classification Model (pkRP model), Multiple Linear Regression (MLR) analysis, Partial Least Square (PLS), Genetic Function Approximation (GFA) models and Field based (or Grid Based) QSAR models were created and validated. Furthermore, top scored compounds were filtered through the virtual screening and after that, molecular dynamic (MD) simulation and MM-GBSA studies were used to validate the stability, binding energy and electrostatics of best HDAC receptor-ligand complex. The outcome of findings indicated that the best Field based model has R2=0.970and Q2=0.842, the best pkRP model has R2= 0.883 and Q2= 0.813, the best PLS model has R2= 0.856 and Q2= 0.746,the best MLR model has R2= 0.766 and Q2= 0.752, and the best GFA model has R2= 0.706 and Q2= 0.663. Cross-validated coefficient, (rcv2) of 0.968, 0.827, 0.743, 0.810 and 0.552 was found for Field/Grid based, pkRP, MLR, PLS and GFA model, respectively indicating the satisfied correlativity and prediction. The outcome of these studies will be a focal paradigm for designing of novel lead molecules as HDAC inhibitors with improved anticancer activity.

Background: The severe acute respiratory syndrome coronavirus-2 is causing a disaster through coronavirus disease-19 (COVID-19), affecting the world population with a high mortality rate. Although numerous scientific efforts have been made, we do not have any specific drug for COVID-19 treatment. Objective: Aim of the present study was to analyse the molecular interaction of nitrogen heterocyclic based drugs (hydroxychloroquine, remdesivir and lomefloxacin) with various SARSCoV- 2 proteins (RdRp, PLPro, Mpro and spike proteins) using a molecular docking approach. Methods: We have performed docking study using PyRx software, and Discovery Studio Visualizer was used to visualise the molecular interactions. The designed nitrogen heterocyclic analogues were checked for Lipinski’s rule of five, Veber's Law and Adsorption, Distribution, Metabolism, and Excretion (ADME) threshold. After obtaining the docking results of existing nitrogen heterocyclic drugs, we modified the selected drugs to get molecules with better affinity against SARS-CoV-2. Results: Hydroxychloroquine bound to RdRp, spike protein, PLPro and Mpro at -5.2, -5.1, -6.7 and -6.0 kcal/mol, while remdesivir bound to RdRp, spike protein, PLPro, and Mpro at -6.1, -6.9, -6.4 and -6.9 kcal/mol, respectively. Lomefloxacin bound to RdRp, spike protein, PLPro and Pro at -6.4, -6.6, -7.2 and -6.9 kcal/mol. ADME studies of all these compounds indicated lipophilicity and high gastro intestine absorbability. The modified drug structures possess better binding efficacy towards at least one target than their parent compounds. Conclusion: The outcome reveals that the designed nitrogen heterocyclics could contribute to developing the potent inhibitory drug SARS-CoV-2 with strong multi-targeted inhibition ability and reactivity

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are commonly allied with hypertension, renin-angiotensin-aldosterone system pathway, and other cardiovascular system disorders. The recent pandemic of COVID-19 has attracted the attention of numerous researchers on ACE2 receptors, where the causative viral particle, SARS-CoV-2, is established to exploit these receptors for permitting their entry into the human cells. Therefore, studies on the molecular origin and pathophysiology of the cell response in correlation to the role of ACE2 receptors to these viruses are bringing novel theories. The varying level of manifestation and importance of ACE proteins, underlying irregularities and disorders, intake of specific medications, and persistence of assured genomic variants at the ACE genes are potential questions raising nowadays while observing the marked alteration in response to the SARS-CoV-2-infected patients. Therefore, the present review has focused on several raised opinions associated with the role of the ACE2 receptor and its impact on COVID-19 pathogenesis.

Abstract: Multi-targeted agents can interact with multiple targets sequentially, resulting in synergistic and more effective therapies for several complicated disorders, including cancer, even with relatively modest activity. Histone deacetylase (HDAC) inhibitors are low molecular weight small compounds that increase the acetylation of histone and nonhistone proteins, altering gene expression and thereby impacting angiogenesis, metastasis, and apoptosis, among other processes. The HDAC inhibitors affect multiple cellular pathways thus producing adverse issues, causing therapeutic resistance, and they have poor pharmacokinetic properties. The designing of HDAC-based dual/multi-target inhibitor is an important strategy to overcome adverse effects, drug resistance and increase the effectiveness in controlling cancer. The selection of target combinations to design multitarget HDAC inhibitor is generally accomplished on the basis of systematic highthroughput screening (HTS), network pharmacology analysis methods. The identification of the pharmacophore against individual targets is performed using rational or computation methods. The identified pharmacophore can combine with merged, fused, or linked with the cleavable or non-cleavable linker to retain the interaction with the original target while being compatible with the other target. The objective of this review is to elucidate the potential targets' design strategies, biological activity, and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. This review elucidates the designing strategies of the potential target along with biological activity and the recent development of dual/multi-targeting HDAC inhibitors as potential anticancer agents. The development of HDAC-based dual/multi-target inhibitors is important for overcoming side effects, drug resistance, and effective cancer control.

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.

Background: The management of Alzheimer’s disease is challenging due to its complexity. However, the currently approved and marketed treatments for this neurodegenerative disorder revolves around cholinesterase inhibitors and glutamate regulators or the combination of these agents. Despite the prompt assurance of many new drugs, several agents were unsuccessful, especially in phase II or III trials, not meeting efficacy endpoints. Objective: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer’s disease. Method: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, Sciencedirect, and Pubmed) using the keywords Alzheimer’s disease, amyloid-β, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis. Result and Discussion: The researcher's intent for either developing a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimizing the available symptomatic treatments principally committed to the more advanced stages of Alzheimer’s. Since Alzheimer possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression. Conclusion: The combination approach may even allow for providing individual agents in lower doses, with reducible cost and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The below literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat the cognitive disorder.

Abstract: Histone deacetylases (HDACs) are essential for maintaining homeostasis by catalyzing histone deacetylation. Aberrant expression of HDACs is associated with various human diseases. Although HDAC inhibitors are used as effective chemotherapeutic agents in clinical practice, their applications remain limited due to associated side effects induced by weak isoform selectivity. HDAC1 displays unique structure and cellular localization as well as diverse substrates and exhibits a wider range of biological functions than other isoforms. HDAC1 displays a unique structure primarily found in the nucleus and involved in epigenetic and transcriptional regulation. HDAC1 is ubiquitously expressed and associated with Sin3, NuRD, and CoRest transcription repressive complexes responsible for distinct cellular processes like cell proliferation and survival. HDAC1 inhibitors have been effectively used to treat various cancers such as gastric, breast, colorectal, prostate, colon, lung, ovarian, pancreatic, and inflammation without exerting significant toxic effects. In this review, we summarize four major structural classes of HDAC1 inhibitors (i.e., hydroxamic acid derivatives, benzamides, hydrazides, and thiols) with their structural activity relationship. This review is a comprehensive work on HDAC1 inhibitors to achieve deep insight of knowledge about the structural information of HDAC1 inhibitors. It may provide up-to-date direction for developing new selective HDAC1 inhibitors as anticancer agents.

HDAC inhibitors (HDACi) play an essential role in various cellular processes, such as differentiation and transcriptional regulation of key genes and cytostatic factors, cell cycle arrest and apoptosis that facilitates the targeting of epigenome of eukaryotic cells. In the majority of cancers, only a handful of patients receive optimal benefit from chemotherapeutics. Additionally, there is emerging interest in the use of HDACi to modulate the effects of ionizing radiations. The use of HDACi with radiotherapy, with the goal of reaching dissimilar, often distinct pathways or multiple biological targets, with the expectation of synergistic effects, reduced toxicity and diminished intrinsic and acquired resistance, conveys an approach of increasing interest. In this review, the clinical potential of HDACi in combination with radiotherapy is described as an efficient synergy for cancer treatment will be overviewed.

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.

Background The World Health Organization (WHO) announced the COVID-19 occurrence as a global pandemic in March 2020. The treatment of SARS-CoV-2 patients is based on the experience gained from SARS-CoV and MERS-CoV infection during 2003. There is no clinically accepted therapeutic drug(s) accessible yet for the treatment of COVID-19. Main body Corticosteroids, i.e., dexamethasone, methylprednisolone, hydrocortisone and prednisone are used alone or in combination for the treatment of moderate, severe and critically infected COVID-19 patients who are hospitalized and require supplemental oxygen as per current management strategies and guidelines for COVID-19 published by the National Institutes of Health. Corticosteroids are recorded in the WHO model list of essential medicines and are easily accessible worldwide at a cheaper cost in multiple formulations and various dosage forms. Corticosteroid can be used in all age group of patients, i.e., children, adult, elderly and during pregnancy or breastfeeding women. Corticosteroids have potent anti-inflammatory and immunosuppressive effects in both primary and secondary immune cells, thereby reducing the generation of proinflammatory cytokines and chemokines and lowering the activation of T cells, monocytes and macrophages. The corticosteroids should not be used in the treatment of non-severe COVID-19 patients because corticosteroids suppress the immune response and reduce the symptoms and associated side effects such as slow recovery, bacterial infections, hypokalemia, mucormycosis and finally increase the chances of death. Conclusion Intensive research on corticosteroid therapy in COVID-19 treatment is urgently needed to elucidate their mechanisms and importance in contributing toward successful prevention and treatment approaches. Hence, this review emphasizes on recent advancement on corticosteroid therapy for defining their importance in overcoming SARS-CoV-2 pandemic, their mechanism, efficacy and extent of corticosteroids in the treatment of COVID-19 patients.

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.

The novel coronavirus disease-19 (COVID-19) is a global pandemic that emerged from Wuhan, China, and has spread all around the world, affecting 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 updates of August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine exists. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID- 19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in clinical uses or studies on COVID-19 and also focuses on the mode of action of drugs being repositioned against COVID-19.

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.

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.

Cancer is a very risky life-threatening disease having most formidable afflictions in the world. Several anticancer agents are commercially accessible, however, the emergence of acquired drug resistance along with extreme adverse effects of these clinically used anticancer medications are major barriers to the effective chemotherapy. Thus, it is recommended to rationally design the newer drugs with few side effects. Fluoroquinolone derivatives are of pivotal interest for researchers due to their admirable pharmacological and pharmacokinetic profiles. They exhibit several favourable characteristics including, higher bioavailability, excellent tissue penetration and relatively low prevalence of adverse and toxic effects. Due to their potential interventions in carcinogenesis and mutagenesis, the focus of the area of research is nowadays shifting towards anticancer aspects of these compounds. This review shows the recent advancements in the development of novel fluoroquinolones as potential anticancer and cytotoxic agents and structure-activity relationships along with the possible modes of action for further development and recent patents filed/granted related to anticancer activity from the last few years have also been tabulated. Also, this review is an attempt to focus on the various upcoming aspects of fluoroquinolones and provides a newer outlook on the possible roles of fluoroquinolones in the treatment of cancer. Scientific information identified in this paper is expected to be useful for aspiring researchers working on the anticancer activity of fluoroquinolones.

Objective: To establish immunomodulatory potential of aqueous extract of Polygonum minus (P. minus) leaves, the haematological effects and lysozyme activity of aqueous extract of P. minus leaf on Clarias gariepinus was studied. Methods: The fish were grouped and administered with the P. minus aqueous leaf extract intraperitoneally. Blood and serum samples were collected from each group and examined for various blood parameters. The turbidimetric assay for lysozyme activity using M. luteus and the survival rate of fish against A. hydrophila was carried out. Results: There was no significant impact (P>0.05) on white blood cell count, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and lysozyme activity was significantly (P

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.