Indole derivatives (2010-2020) as versatile tubulin inhibitors: synthesis and structure-activity relationships.

Tubulin inhibitors are conjugates that interfere with the dynamic equilibrium of the polymerization and depolymerization of microtubules. Among all the reported conjugates, indole moiety is one of the most significant classes for the development of new drug candidates for cancer therapy. Due to their presence in a wide range of natural as well as synthetic antitubulin agents, indole has become a versatile scaffold in research, and various synthetic and semisynthetic indole-based antitubulin agents have been identified and reported. The present article focuses on the reported indole-based tubulin inhibitors of synthetic origin from last the decade. Synthesis, structure-activity relationships and biological activities of synthetic indole derivatives along with brief updates on their antitubulin activity are presented.

Current Quest in Natural Bioactive Compounds for Alzheimer's Disease: Multi-Targeted-Designed-Ligand Based Approach with Preclinical and Clinical Based Evidence.

Alzheimer's disease is a common and most chronic neurological disorder (NDs) associated with cognitive dysfunction. Pathologically, Alzheimer's disease (AD) is characterized by the presence of ß-amyloid (Aß) plaques, hyper-phosphorylated tau proteins, and neurofibrillary tangles, however, persistence oxidative-nitrative stress, endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory cytokines, pro-apoptotic proteins along with altered neurotransmitters level are common etiological attributes in its pathogenesis. Rivastigmine, memantine, galantamine, and donepezil are FDA approved drugs for symptomatic management of AD, whereas tacrine has been withdrawn because of hepatotoxic profile. These approved drugs only exert symptomatic relief and exhibit poor patient compliance. In the current scenario, the number of published evidence shows the neuroprotective potential of naturally occurring bioactive molecules via their antioxidant, anti-inflammatory, antiapoptotic and neurotransmitter modulatory properties. Despite their potent therapeutic implications, concerns have arisen in context to their efficacy and probable clinical outcome. Thus, to overcome these glitches, many heterocyclic and cyclic hydrocarbon compounds inspired by natural sources have been synthesized and showed improved therapeutic activity. Computational studies (molecular docking) have been used to predict the binding affinity of these natural bioactive as well as synthetic compounds derived from natural sources for the acetylcholine esterase, α/ß secretase Nuclear Factor kappa- light-chain-enhancer of activated B cells (NF-kB), Nuclear factor erythroid 2-related factor 2(Nrf2) and other neurological targets. Thus, in this review, we have discussed the molecular etiology of AD, focused on the pharmacotherapeutics of natural products, chemical and pharmacological aspects and multi-targeted designed ligands (MTDLs) of synthetic and semisynthetic molecules derived from the natural sources along with some important on-going clinical trials.

Free radical scavengers: An overview on heterocyclic advances and medicinal prospects.

In the present scenario, there has been a lot of consideration toward the field of free radical chemistry. Free radicals responsive oxygen species are produced by different endogenous frameworks, exposure to various physicochemical conditions, radiation, toxins, metabolized drug by-product, and pathological states. On the off chance that free radical overpowers the body's capacity, it generates a condition known as oxidative stress, which can alter physiological conditions of the body and results in several diseases. For appropriate physiological function, it is necessary to have a proper balance between free radicals and antioxidants. Antioxidants chemically inhibit the oxidation process; they are also known as free radical scavengers. For tackling the problem of oxidative stress application of an external source of antioxidant is helpful. A lot of antioxidants of natural, semi-synthetic and synthetic origin are in use, with time search of more effective, nontoxic, safe antioxidant is intensified. The present review, discuss different synthetic derivatives bearing various heterocyclic scaffolds as radical scavengers.

Design, synthesis, and biological evaluation of imidazopyridine-linked thiazolidinone as potential anticancer agents.

In this study, two series of imidazopyridine-linked thiazolidinone rings (5a-h and 6a-h) constituting 16 new compounds were synthesized and tested for their antiproliferative activity against a panel of three human cancer cell lines, that is, MCF-7 (human breast cancer), A549 (human lung cancer), and DU145 (human prostate cancer). Three compounds, 5h, 6f, and 6h, exhibited remarkable results against all three cell lines, but compound 6h was found to be the most active one against the breast cancer cell line. Among all the synthesized compounds, 6h displayed the highest antioxidant results. Furthermore, the potent compounds 5h, 6f, and 6h showed no signs of toxicity at doses ranging from 50 to 500 mg/kg of animal body weight. The biochemical parameters (SGOT and SGPT) of compound 6h nearly matched the control in hepatotoxicity studies. The molecular docking and MM-GBSADG binding studies are in agreement with the in vitro anticancer and antioxidant activity results. The most promising compound 6h was found to have the highest docking score and binding energy, and its absorption, distribution, metabolism, and excretion (ADME) parameters are in the acceptable range. Thus, it can be concluded that 6h, an imidazopyridine derivative endowed with a thiazolidinone ring system, has the potential to be developed as an anticancer agent.

Molecular interactions of vinclozolin metabolites with human estrogen receptors 1GWR-α and 1QKM and androgen receptor 2AM9-ß: Implication for endocrine disruption.

Background: Vinclozolin (VCZ) is a widely used antifungal agent with capability to enter into the human food chain. VCZ metabolizes into seven metabolites M1-M7. Several studies have shown its effects on reprotoxicity. However, there is limited information available on the interaction of VCZ metabolites with nuclear receptors. In silico studies aimed at identifying interaction of endocrine disruptor with nuclear receptors serve a prescreening framework in risk assessment.Methods: We studied interactive potential of VCZ and its metabolites with human estrogen (ER) and androgen receptor (AR) using molecular docking method. Binding potential of VCZ and its metabolites with estrogen receptors 1GWR-α, 1QKM and androgen receptor 2AM9-ß was checked by using Schrodinger Maestro 10.5. Estradiol (E2), a natural ligand of ER and AR was taken as a reference.Results: VCZ and its metabolites showed higher or similar binding efficiency on interaction with target proteins when compared with E2. VCZ and its metabolites also exhibited agonistic effect against 1GWR-α, 1QKM and 2AM9-ß with strong binding potential to them.Conclusion: Some VCZ metabolites such as M4 and M5 showed higher binding potencies with 1GWR-α, 1QKM and 2AM9-ß than E2. Toxicity data of VCZ is well endowed. However, endocrine disrupting potential of VCZ via nuclear receptor mediated pathway is less understood. This in silico study revealing that not only VCZ but its metabolites have potential to interact with 1GWR-α, 1QKM and 2AM9-ß offers a platform for further exploration of VCZ in this direction.

Synthetic strategy and SAR studies of C-glucoside heteroaryls as SGLT2 inhibitor: A review.

Gliflozins constitute an important class of compounds useful as sodium glucose co-transporter (SGLT2) inhibitors to treat type-II diabetes. They act by blocking sodium-glucose transport protein 2 which is responsible for re-absorption of glucose in the proximal convoluted tubule (PCT) of kidney and thus its inhibition reduces blood glucose level. There are a number of gliflozins which have been approved by drug regulatory bodies like FDA, EMA and PMDA whereas some others are in pipeline in their late developmental phases. The present review article offers a detailed account of synthetic strategies employed for the synthesis, alternate synthetic routes along with Structure Activity Relationship (SAR) studies of well-established as well as newly developed SGLT2 inhibitors.

Medicinal prospects of antioxidants: A review.

Free radicals generated due to exposure of radiation, environmental pollutants and as by-products of metabolised drugs. These free radicals are antagonized by molecules which are antioxidant in nature. Antioxidants are the substances which inhibit oxidation. They are moreover acknowledged as "free radical scavengers" as they form minor reactive species via radicals. Based on origin, they are categorised into two types: exogenous and endogenous antioxidants. An Antioxidant reduces the occurrence of different disorders like: aging, cancer, diabetes, inflammation, liver disease, cardiovascular disease, cataract and nephrotoxicity and neurodegenerative disorders. Dietary antioxidants are thought to have potential capacities to avert oxidative anxiety induced diseases. This review figures the various researches on pharmacological activity of natural along with synthetic antioxidant molecules.

Novel 9-(2-(1-arylethylidene)hydrazinyl)acridine derivatives: Target Topoisomerase 1 and growth inhibition of HeLa cancer cells.

A series of 9-(2-(1-arylethylidene)hydrazinyl)acridine and its analogs were designed, synthesized and evaluated for biological activities. Various biochemical assays were performed to determine the free radical scavenging capacity of synthesized compounds (4a-4j). Anticancer activity of these compounds was assessed against two different human cancer cell lines viz cervical cancer cells (HeLa) and liver cancer cells (HepG2) as well as normal human embryonic kidney cell line (HEK 293). Compounds 4b, 4d and 4e showed potential anti-proliferative effects on HeLa cells. Based on results obtained from antioxidant and cytotoxicity studies, 4b, 4d and 4e were further studied in detail for different biological activities. 4b, 4d and 4e reduced the cell growth, inhibited metastatic activity and declined the potential of cell migration in HeLa cell lines. Topoisomerase1 (Top1) treated with compounds 4b, 4d and 4e exhibited inhibition of Top1 and prevented DNA replication. Molecular docking results validate that interaction of compounds 4b, 4d and 4e with Top1-DNA complex, which might be accountable for their inhibitory effects. Further it was concluded that compounds 4b, 4d and 4e arrests the cells at S phase and consequently induces cell death through DNA damage in HeLa cells.

Anti-tubulin agents of natural origin: Targeting taxol, vinca, and colchicine binding domains.

Microtubules are a protein which is made of α- and ß-heterodimer. It is one of the main components of the cell which play a vital role in cell division especially in G2/M-phase. It exists in equilibrium dynamic of polymerization and depolymerization of α- and ß-heterodimer. It is one of the best targets for developing anti-cancer drugs. Various natural occurring molecules are well known for their anti-tubulin effect such as vinca, paclitaxel, combretastatin, colchicine etc. These microtubule-targeted drugs are acted through two processes (i) inhibiting depolymerization of tubulin (tubulin stabilizing agents) and (ii) inhibiting polymerization of tubulin (tubulin destabilizing agents). Now days, various binding domains have been explore through which these molecules are binding to tubulin but the three major binding domain of tubulin are taxol, vinca and colchicine binding domain. The present article mainly focus on the classification of various naturally occurring compounds on the basis of their inhibition processes (depolymerization and polymerization) and the site of interaction (targets taxol, vinca and colchicine binding domain) which has been hitherto reported. By placing all the naturally occurring taxol, vinca and colchicine binding site analogues at one place makes a better understanding of the tubulin interactions with known natural tubulin binders that would helps in the discovery of new and potent natural, semi-synthetic and synthetic analogues for treating cancer.

DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective.

Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of ß-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aß 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors.

Design and synthesis of quinazoline-3,4-(4H)-diamine endowed with thiazoline moiety as new class for DPP-4 and DPPH inhibitor.

New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-quinazoline-3,4-(4H)-diamine derivatives were design and synthesized by a sequence of reactions starting from appropriate 6-methyl anthranilic acid. The title compounds were screened for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity and diphenyl-2-picryl-hydrazyl (DPPH) assay and results showed significant to good activity in compared to Linagliptin for antidiabetic activity and Ascorbic acid for antioxidant activity. Compound 7g (IC50=0.76nM) exhibited most promising DPP-4 inhibitory activity and also showed good antioxid and result. Docking study was also performed to provide an insight about the binding mode into binding sites of DPP-4 enzyme. Hopefully in future, compound 7g could be used as a lead compound for developing new antidiabetic agent with good antioxidant property.

Recent Advances in the Synthesis and Anticancer Activity of Some Molecules Other Than Nitrogen Containing Heterocyclic Moeities.

OBJECTIVE: The present review article presented a detailed account of the design strategies and the structure activity relationship of different derivatives apart from the nitrogen containing ring. These scaffolds play an important part in the drug discovery which showed anticancer activity against different human cancer cell lines through apoptosis, cell cycle arrest, inhibiting kinases, angiogenesis, disruption of cell migration, modulation of nuclear receptor responsiveness and others. Naphthalenes amides/amidines, furan, podophyllotoxin, platinum compounds, steroids, and urea, which forms the core part or along with other N-heterocyclic rings are enclosed. Some of these compounds e.g. podophyllotoxin and platinum based drugs displayed anticancer activity at nanomolar range. Various substitutions from the earlier and latest information are prerequisite in the drug synthesis process. CONCLUSION: The review focused on the recent development of these derivatives, design and anticancer properties, thus providing with the most profound knowledge for the development of targeted based anticancer drugs.

Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder.

The present work discusses the preparation, characterization and in vivo evaluation of thiolated chitosan nanoparticles (TCS-NPs) of buspirone hydrochloride (BUH) for brain delivery through intranasal route. TCS NPs were prepared by ionic gelation method and characterized for various parameters. The NPs formed were having particle size of 226.7±2.52nm with PDI 0.483±0.031. Drug entrapment efficiency (EE) and loading capacity (LC) were found to be 81.13±2.8 and 49.67±5.5%. The cumulative percentage drug permeation through nasal mucosa was 76.21%. Bioadhesion study carried out on porcine mucin and showed a bioadhesion efficiency of 90.218±0.134%. Nose-to-brain delivery of placebo NPs was investigated by confocal laser scanning microscopy (CLSM) technique using rhodamine-123 as a marker. The brain concentration achieved after intranasal administration of TCS-NPs was 797.46±35.76ng/ml with tmax 120min which was significantly higher than achieved after intravenous administration on BUH solution 384.15±13.42ng/ml and tmax of 120min and intranasal administration of BUH solution 417.77±19.24ng/ml and tmax 60min.

A review on anticancer potential of bioactive heterocycle quinoline.

The advent of Camptothecin added a new dimension in the field anticancer drug development containing quinoline motif. Quinoline scaffold plays an important role in anticancer drug development as their derivatives have shown excellent results through different mechanism of action such as growth inhibitors by cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. The anti-cancer potential of several of these derivatives have been demonstrated on various cancer cell lines. In this review we have compiled and discussed specifically the anticancer potential of quinoline derivatives, which could provide a low-height flying bird's eye view of the quinoline derived compounds to a medicinal chemist for a comprehensive and target oriented information for development of clinically viable anticancer drugs.