Synthesis, in silico Studies and Pharmacological Evaluation of a New Series of Indanone Derivatives as Anti-Parkinsonian and Anti-Alzheimer's Agents.

OBJECTIVE: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders. METHODS: A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects. RESULTS: The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents. CONCLUSION: The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases.

Isolation & identification of anti-inflammatory constituents of Randia dumetorum lamk. fruit: Potential beneficial effects against acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Randia dumetorum Lamk. is an Indian traditional medicinal plant that has been used for the treatment of various disorders including respiratory ailments. AIM OF THE STUDY: In continuation of our recent report that the Ethanol soluble fraction (ESF) of Randia dumetorum fruit had potent anti-inflammatory activity against acute lung injury (ALI) in mice, the present work was undertaken to unveil the key bioactive constituents possessing anti-inflammatory action against ALI by employing bioactivity-guided fractionation of ESF. MATERIAL AND METHODS: Different fractions/sub-fractions obtained by column chromatography of ESF were subjected to bioactivity studies by analyzing total and differential count, and protein content in broncho-alveolar lavage fluid (BALF) procured from mice. The most bioactive sub-fraction F3.2 was analyzed for the assessment of various inflammatory mediators using molecular techniques like ELISA, PCR, and western blotting. Further, an attempt was made to separate the key compounds in F3.2 using solvents of differential polarities; and isolated compounds were validated for their anti-inflammatory activity followed by their characterization using spectral techniques like 1HNMR, 13CNMR, FT-IR, and ESIMS Mass Spectrometry. RESULTS: The column chromatography of ESF yielded four fractions (F1, F2, F3, and F4) and data revealed that maximum activity resides in F3. Further fractionation of F3 yielded sub-fractions F3.1, F3.2, F3.3, and F3.4 which when tested for anti-inflammatory potential, showed F3.2 as the most active one. Moreover, the effect of F3.2 on oxidative stress parameters and inflammatory mediators analyzed via biochemical assays, PCR, and ELISA revealed the proficiency of this fraction in amelioration of ALI. F3.2 was then subjected to recrystallization using different solvents and two pure compounds were isolated which were characterized as D-Mannitol and Oleanolic acid (OA). D-Mannitol did not display any bioactivity, but OA showed potent anti-inflammatory activity. CONCLUSION: Considering the ethnopharmacological role of R. dumetorum in respiratory ailments, OA as an aglycone moiety seems to be the main active principle possessing anti-inflammatory potential against ALI.

Synthesis of deoxy-Andrographolide Triazolyl Glycoconjugates for the Treatment of Alzheimer's Disease.

A new andrographolide-based terminal alkyne 3 was synthesized in good yield from deoxy-andrographolide 2, obtained from a natural compound andrographolide 1, which in turn was isolated from the leaves of the plant Andrographis paniculata. Copper(I)-catalyzed azide-alkyne cycloaddition reaction of alkyne 3 with azido-sugars 4a-f furnished a library of andrographolide-fastened triazolyl glycoconjugates 5a-f in good yields. The structures of these semisynthetic andrographolide derivatives were established by Fourier transform infrared, NMR, and mass spectroscopy. The compounds 5a-f were further evaluated against Alzheimer's disease (AD) using a scopolamine (SCOP)-induced memory impairment mice model. It was observed that antioxidant and anticholinesterase properties of these compounds contribute significantly toward their remarkable potential to improve cognitive functioning.

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery.

Ever increasing unmet medical requirements of the human race and the continuous fight for survival against variety of diseases give birth to novel molecules through research. As diseases evolve, different strategies are employed to counter the new challenges and to discover safer, more effective, and target-specific therapeutic agents. Among several novel approaches, bioconjugation, in which two chemical moieties are joined together to achieve noticeable results, has emerged as a simple and convenient technique for a medicinal chemist to obtain potent molecules. The steroid system has been extensively used as a privileged scaffold gifted with significantly diversified medicinal properties in the drug discovery and development process. Steroidal molecules are preferred for their rigidness and good ability to penetrate biological membranes. Slight alteration in the basic ring structure results in the formation of steroidal derivatives with a wide range of therapeutic activities. Steroids are not only active as such, conjugating them with various biologically active moieties results in increased lipophilicity, stability, and target specificity with decreased adverse effects. Thus, the steroid nucleus prominently behaves as a biological carrier for small molecules. The steroid bioconjugates offer several advantages such as synergistic activity with fewer side effects due to reduced dose and selective therapy. The steroidal bioconjugates have been widely explored for their usefulness against various disorders and have shown significant utility as anticancer, anti-inflammatory, anticoagulant, antimicrobial, insecticidal/pesticidal, antioxidant, and antiviral agents along with several other miscellaneous activities. This work provides a comprehensive review on the therapeutic progression of steroidal bioconjugates as medicinally active molecules. The review covers potential biological applications of steroidal bioconjugates and would benefit the wider scientific community in their drug discovery endeavors.

Quantitative analysis of doxorubicin hydrochloride and arterolane maleate by mid IR spectroscopy using transmission and reflectance modes.

BACKGROUND: Environment-friendly fast and accurate mid-infrared spectroscopic methods have been developed for the quantitative analysis of doxorubicin hydrochloride (DOX) and arterolane maleate (ALM) in bulk and marketed formulations. Both transmittance and reflectance modes have been used for the analysis and a comparison has been drawn for better accuracy. The analytical methods were validated in accordance with International Council for Harmonisation (ICH) guidelines RESULTS: The proposed methods have been successfully developed and validated for the quantification of doxorubicin and arterolane maleate in solid bulk and dosage form. High recovery values in both the modes, while analysing DOX and ALM, indicated good accuracy of the methods. The methods showed excellent repeatability and intermediate precision [% RSD (Relative Standard Deviation < 2.0%]. The assay values of the drugs in solid dosage forms were also found close to the labelled claim. CONCLUSION: The proposed Fourier transform infrared (FT-IR) spectroscopic methods were found to be specific, reproducible, valid and could be used as general methods for the quantification of most of the solid drug preparations such as tablets, capsules and powders.

16-Substituted steroids alleviate LPS-induced neurodegenerative disorders in rats.

The neuroprotective effects of some 16-substituted steroidal derivatives against the locomotive impairment and cognitive deficits in the lipopolysaccharide (LPS)-induced neuroinflammation model of rats have been investigated. The in vivo and in vitro evaluations include behavioural tests (actophotometer, block tests, Morris water maize and elevated plus maize), estimation of the biochemical parameters such as acetylcholinesterase, lipid peroxide, reactive oxygen, and nitric oxide species and molecular assays for the key proinflammatory mediators like Tumour Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL- 1ß) after 21 days of the treatment with the steroids. Behavioural and biochemical studies indicated impairment in the locomotor activity and cognitive dysfunction in rats after LPS treatment. In addition, higher levels of TNF-α and IL-1ß in the blood serum of the rats were also noticed. However, significant alleviation of LPS-induced movement and memory disorders was observed in LPS-injected rats after treatment with 16-substituted steroidal derivatives 1-11. Furthermore the biochemical and molecular studies revealed suppression of oxidative and nitrosative stress, decreased acetylcholinesterase activity, and reduction of TNF-α and IL-1ß levels after treatment with compounds 1-11. Among all the 16-substituted steroidal derivatives, the compounds 8 and 11 were found to be the most active neuroprotective agents and produced effects marginally better than standard drug dexamethasone.

A New Series of 1,3-Dimethylxanthine Based Adenosine A2A Receptor Antagonists as a Non-Dopaminergic Treatment of Parkinson's Disease.

BACKGROUND: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson's disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson's disease due to their potent A2A AR antagonistic properties. OBJECTIVE: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. METHODS: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. RESULTS: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly long-lasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. CONCLUSION: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Therapeutic progression of quinazolines as targeted chemotherapeutic agents.

Presently cancer is a grave health issue with predominance beyond restrictions. It can affect any organ of the body. Most of the available chemotherapeutic drugs are highly toxic, not much selective and eventually lead to the development of resistance. Therefore, a target specific palliative approach for the treatment of cancer is required. Remarkable advancements in science have illuminated various molecular pathways responsible for cancer. This has resulted in abundant opportunities to develop targeted anticancer agents. Quinazoline nucleus is a privileged scaffold with significant diversified pharmacological activities. Numerous established anticancer quinazoline derivatives constitute a new class of chemotherapeutic agents which are found to act by inhibiting various protein kinases as well as other molecular targets. A recent update on various quinazoline derivatives acting on different types of molecular targets for the treatment of cancer has been compiled in this review. Brief SAR studies of quinazoline derivatives acting through different mechanisms of action have been highlighted. The comprehensive medicinal chemistry aspects of these agents in this review provide a panoramic view to the biologists as well as medicinal chemists working in this area and would assist them in their efforts to design and synthesize novel quinazoline based anticancer compounds.

Steroidal pyrazolines as a promising scaffold in drug discovery.

Steroidal pyrazolines constitute an interesting and promising scaffold for drug discovery as they display diverse chemical reactivity and a wide range of biological activities. Literature reports indicate potent anticancer potential of steroidal pyrazolines along with broad-spectrum antimicrobial activities. Strong neuroprotective effects with steroids possessing pyrazoline moiety have also been observed. Among all the therapeutically active steroidal pyrazolines, D-ring-substituted derivatives are highly potent and the least toxic. The current and futuristic research approaches in this area are focused towards the exploration of this promising scaffold to develop molecules with widespread pharmacological activities. This review article mainly covers the synthetic and pharmacological aspects of steroidal pyrazolines, which will assist the medicinal chemists working in this area in their scientific endeavors.

16,17-N'-(alky/arylsulfonyl)pyrazoline substituted neuroprotective heterosteroids: Synthesis, molecular docking and preclinical efficacy/toxicity studies in rodents.

The synthesis and neuroprotective efficacy and toxicity studies of a new series of 16,17-N'-(alkyl/arylsulfonyl)pyrazolinyl steroids is presented. Significant suppression of the overexpressed acetylcholinesterase and lipid peroxidation, marked reduction of nitrite, oxidative stress and TNF-α levels and noticeable improvement in cognitive and locomotor functions were observed after treatment with the newly synthesized steroids 2-4a-d in the LPS-treated animal models. Higher neuroprotective effects were produced by some of the pyrazolinyl steroids in comparison to the reference drugs celecoxib and dexamethasone. N'-(4-fluorobenzenesulfonyl) derivative 4c showed the most promising effects on all the analyzed parameters and is the most potent molecule among all compounds of this series. Acute toxicity studies on the most active steroids 2-4c at 50 mg/kg did not reveal any toxic effects on animals, however hepatitis and chronic nephritis were observed in histological examination of liver and kidney of mice after 28 days of treatment. The pyrazolinyl steroids 2-4a-d could be considered as promising candidates for the designing of novel multitarget-directed neuroprotectives for an effective therapy of AD and PD.

Synthesis, biological evaluation and molecular modelling studies of 1,3,7,8-tetrasubstituted xanthines as potent and selective A2A AR ligands with in vivo efficacy against animal model of Parkinson's disease.

In the present study, an attempt has been made to develop a new series of 1,3,7,8-tetrasubstituted xanthine based potent and selective AR ligands for the treatment of Parkinson's disease. Antagonistic interactions between dopamine and A2A adenosine receptors serve as the basis for the development of AR antagonists as potential drug candidates for PD. All the synthesized compounds have been evaluated for their affinity toward AR subtypes using in vitro radioligand binding assays. 1,3-Dipropylxanthine 7a with a methyl substituent at N-7 position represents the most potent compound of the series and displayed highest affinity (A2A, Ki = 0.108 µM), however incorporation of a propargyl group at 7-positon of the xanthine nucleus seems to be the most appropriate substitution to improve selectivity towards the A2A subtype along with reasonable potency. Antiparkinsonian activity has been evaluated using perphenazine induced catatonia in rats. Most of the synthesized xanthines significantly lowered the catatonic score as compared to control and displayed antiparkinsonian effects comparable to standard drug. All the synthesized compounds were subjected to grid-based molecular docking studies to understand the key structural requirements for the development of new molecules well-endowed with intrinsic efficacy and selectivity as adenosine receptor ligands. In silico studies carried out on newly synthesized xanthines provided further support to the pharmacological results.

Isolation of a new flavonoid and waste to wealth recovery of 6-O-Ascorbyl Esters from Seeds of Aegle marmelos (family- Rutaceae).

Aegle marmelos is a plant species native to India. Commercially available food products such as jam, jelly, candy, squash etc. are prepared from ripe fruit pulp of A. marmelos. Ripe fruit processing accounts for 60% of whole fruit mass while 40% remains unutilized and generates waste (hard shell, pomace, fiber and seeds) on a massive scale which do not have high value applications. A new flavone 3,5,7-trihydroxy-2-(4'-hydroxy-3'-isopentyloxyphenyl-4H-chromen-4-one (5) in addition to the known compounds 1-4, has been isolated from seeds of A. marmelos. Also, compound 7-(3'-methylbut-2'-enyloxy)-2H-chromen-2-one (2) has been isolated for the first time from A. marmelos. The structure of compounds 1-5 was determined by spectral analysis (UV, IR, NMR, etc.). Additionally, the non-edible oil obtained from seeds was investigated for waste to wealth recovery of 6-O-ascorbyl esters in high regioselectivity via one step semi-synthetic approach in the presence of ascorbic acid and H2SO4 at ambient temperature.

An Overview of Discovery of Thiazole Containing Heterocycles as Potent GSK-3ß Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine (ser/thr) kinase that was originally identified as a regulator of glycogen metabolism and coupled with insulin signaling. Due to multifunctionality of this enzyme, it is found to play an important role in the onset and progression of various human diseases. Thiazole nucleus has received special attention by medicinal chemists because of its wide therapeutic potential. The objective of this review is to cover all the aspects of GSK-3ß enzyme including its clinical implications, types of inhibitors with special reference to thiazole as GSK-3ß inhibitor. Literature search was performed using Pubmed/Medline and Google Scholar to search for articles published in English language.

Hybrids of Steroid and Nitrogen Mustard as Antiproliferative Agents: Synthesis, In Vitro Evaluation and In Silico Inverse Screening.

Hybrids of 16E-arylidene steroids and nitrogen mustard have been synthesized and evaluated for their in vitro cytotoxic activity to develop tissue specific antineoplastic agents from steroids. These hybrids displayed specificity towards leukemia cell lines, however somewhat reduced potency was observed in comparison with the earlier reported 16E-arylidene steroids. The in silico reverse screening experiments were employed to find out the probable pharmacological mechanism of these hybrids. Molecular docking studies suggested glucocorticoid receptors as a probable target for the antileukemic action of these steroid-nitrogen mustard hybrids.

Microwave Mediated Synthesis and Analytical Method Development for the Estimation of Novel 1,4-Dihydropyridines in Bulk by RP-HPLC.

The present work describes a rapid and green microwave mediated method for the synthesis and a simple and precise isocratic reverse phase HPLC method for the estimation of the biologically significant dihydropyridines. The conventional synthesis of these dihydropyridines has been previously reported from our lab. The analysis of a standard solution (1 mg/ml) was accomplished on a symmetry (4.6 mm I.D x 250 mm) C-18 column using mobile phase acetonitrile:water:triethylamine (TEA) (70:30:0.1 v/v/v) at a flow rate of 0.7 ml/min. Detection was monitored at 354 nm. The retention time for all the compounds was accomplished as less than 10 min. The compounds showed the linear response over the concentration range 10-100 µg/ml. The study is aimed to develop a rapid method for the quantification of these potent molecules. Various parameters like linearity (10-100 µg/ml), USP tailing and plate count were found to be satisfactory. The investigated parameters were studied with the freshly prepared solutions.

Studies on 16,17-Pyrazoline Substituted Heterosteroids as Anti-Alzheimer and Anti-Parkinsonian Agents Using LPS Induced Neuroinflammation Models of Mice and Rats.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common forms of neurodegenerative disorders. Dehydroepiandrosterone (DHEA) has been reported as a neuroprotective steroid useful in the therapeutic management of neurodegenerative disorders such as AD and PD. Herein we report the synthesis and evaluation of a new series of 16,17-pyrazolinyl DHEA analogues 2-4a-d as neuroprotective agents using LPS-induced neuroinflammation animal models. Treatment with the pyrazoline substituted steroids considerably improved the LPS-induced learning, memory and movement deficits in animal models. Suppression of biochemical parameters of oxidative and nitrosative stress, acetylcholinesterase activity, and TNF-α levels was also observed. 16,17-Pyrazolinyl steroids 2c-4c substituted with a 4-pyridyl moiety at the 5-position of the heterocyclic ring were found to be the most potent agents and produced neuroprotective effects better than standard drugs celecoxib and dexamethasone. Of these pyrazoline substituted steroids, the N-acetyl analogue 3c displayed neuroprotective effects better than N-phenyl (4c), which in turn showed potency more than N-unsubstituted analogue 2c.

Tuberculosis and its Treatment: An Overview.

Tuberculosis (TB) is a primordial infectious disease that mainly affects the lungs. M. tuberculosis (Mycobacterium tuberculosis) is the etiological agent of TB and currently more than one-third of the world population is suffering from TB. For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria. However, antibiotic resistance is an emerging problem in multiple drug-resistant tuberculosis (MDR-TB) infections. World Health Organization (WHO) has developed a novel strategy called DOTS (directly observed treatment, short-course), in which specific combination of anti-TB drugs is given to control TB. In this review article we have focused on the comprehensive management of TB and have provided the valuable information about first and second line anti-TB drugs, DOTS and novel drug delivery systems to be used against M. tuberculosis. Important aspects related to new anti-TB drugs and vaccines in various stages of clinical development are also covered in this article.

Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review.

Neurodegeneration is a complex process, which leads to progressive brain damage due to loss of neurons. Despite exhaustive research, the cause of neuronal loss in various degenerative disorders is not entirely understood. Neuroprotective steroids constitute an important line of attack, which could play a major role against the common mechanisms associated with various neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Natural endogenous steroids induce the neuroprotection by protecting the nerve cells from neuronal injury through multiple mechanisms, therefore the structural modifications of the endogenous steroids could be helpful in the generation of new therapeutically useful neuroprotective agents. The review article will keep the readers apprised of the detailed description of natural as well as synthetic neuroprotective steroids from the medicinal chemistry point of view, which would be helpful in drug discovery efforts aimed toward neurodegenerative diseases.

Synthesis of androstene oxime-nitrogen mustard bioconjugates as potent antineoplastic agents.

In the present study, synthesis and antineoplastic activity of phenylacetic acid and benzoic acid nitrogen mustard conjugates of various steroidal oximes are reported for the first time. The conjugation was achieved through a more stable oxime-ester linkage and the resulting newly synthesized conjugates were evaluated in vitro on various human cancer cell lines for cytotoxicity. The extent of their alkylating activity was investigated by the in vitro colorimetric 4-(p-nitrobenzyl)pyridine (NBP) assay. The 17E-steroidal oxime-benzoic acid mustard ester 3ß-acetoxy-17E-[p-(N,N-bis(2-chloroethyl)amino)]benzoyloxyimino-androst-5-ene (8) emerged as the most potent conjugate having significant cytotoxicity on most of the NCI 60-cell lines. Outstanding growth inhibition was observed on the IGROV1 ovarian cancer cell line with GI50=0.937µM. In general, the D-ring derived androstene oxime-nitrogen mustard conjugates were found to possess better antineoplastic activity over a variety of cancer cells in comparison to those derived from other rings of the steroid skeleton.