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Background: COVID-19, first reported in China, from the new strain of severe acute respiratory syndrome coronaviruses (SARS-CoV-2), poses a great threat to the world by claiming uncountable lives. SARS-CoV-2 is a highly infectious virus that has been spreading rapidly throughout the world. In the absence of any specific medicine to cure COVID-19, there is an urgent need to develop novel therapeutics, including drug repositioning along with diagnostics and vaccines to combat the COVID-19. Many antivirals, antimalarials, antiparasitic, antibacterials, immunosuppressive anti-inflammatory, and immunoregulatory agents are being clinically investigated for the treatment of COVID-19. Objectives: The earlier developed one parameter regression model correlating the dock scores with in vitro anti-SARS-CoV-2 main protease activity well predicted the six drugs viz remdesivir, chloroquine, favipiravir, ribavirin, penciclovir, and nitazoxanide as potential anti-COVID agents. To further validate our earlier model, the biological activity of nine more recently published SARS-CoV-2 main protease inhibitors has been predicted using our previously reported model. Methods: In the present study, this regression model has been used to screen the existing antiviral, antiparasitic, antitubercular, and anti pneumonia chemotherapeutics utilizing dock score analyses to explore the potential including mechanism of action of these compounds in combating SARS-CoV-2 main protease. Results: The high correlation (R=0.91) explaining 82.3% variance between the experimental versus predicted activities for the nine compounds is observed. It proves the robustness of our developed model. Therefore, this robust model has been further improved, taking a total number of 15 compounds to formulate another model with an R-value of 0.887 and the explained variance of 78.6%. These models have been used for high throughput screening (HTS) of the 21 diverse compounds belonging to antiviral, antiparasitic, antitubercular, and anti pneumonia chemotherapeutics as potential repurpose agents to combat SARS-CoV-2 main protease. The models screened that the drugs bedaquiline and lefamulin have higher binding affinities (dock scores of -8.989 and -9.153 Kcal/mol respectively) than the reference compound N-[2-(5-fluoranyl-1~H-indol-3-yl)ethyl]ethanamide (dock score of -7.998 Kcal/Mol), as well as higher predicted activities with pEC50 of 0.783 and 0.937 μM and the 0.611 and 0.724 μM respectively. The clinically used repurposed drugs dexamethasone and cefixime have been predicted with pEC50 values of -0.463 and -0.622 μM and -0.311 and -0.428 μM respectively for optimal inhibition. The drugs such as doxycycline, cefpodoxime, ciprofloxacin, sparfloxacin, moxifloxacin, and TBAJ-876 showed moderate binding affinity corresponding to the moderate predicted activity (-1.540 to -1.109 μM). Conclusion: In the present study, validation of our previously developed dock score-based one parametric regression model has been carried out by predicting 9 more SARS-CoV-2 main protease inhibitors. Another model has been formulated to explore the model's robustness. These models have been taken as a barometer for the screening of more potent compounds. The HTS revealed that the drugs such as bedaquiline and lefamulin are highly predicted active compounds, whereas dexamethasone and cefixime have optimal inhibition towards SARS-CoV-2 main protease. The drugs such as doxycycline, cefpodoxime, ciprofloxacin, sparfloxacin, moxifloxacin, and TBAJ-876 have moderately active compounds towards the target inhibition.

Present work can be used to calibrate inductance standards by utilizing the error evaluated at the same nominal value of reactance of a capacitance standard. Inductance can be determined in terms of capacitance standard by direct measurement of capacitive reactance on the LCR meter. The conventional Maxwell–Wien bridge is currently used at CSIR-NPL to determine traceability to the inductance standard through capacitance and two resistance standards. However, proposed technique defines inductance in terms of one capacitance only. Measurement results of 100 mH inductors at 1 kHz are evaluated and validated with the inductor's previously assigned values with Maxwell–Wien bridge. Preliminary results obtained from both techniques were found within 50 ppm; hence this technique can be used as an alternative to Maxwell–Wien bridge.

Background: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis. As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR & XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines have been reported with their antitubercular and ATP synthase inhibitory activity. Methods: To understand the role of physicochemical parameters like hydrophobicity, electronic and steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR) studies have been carried out using the computed parameters as independent variable and activity (-log IC50/MIC) as the dependent variable. Results: The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters have high predictivity as also shown on external data set and the mean value of the computed 3D parameters of enantiomers may be used in QSAR analysis for racemic compounds. Conclusion: These results are also substantiated by pharmacophore modeling. The similar dependence of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as the main target for antitubercular activity and the QSAR models may be useful in the identification of novel antitubercular agents.

Tuberculosis (TB) is a devastating disease responsible for millions of humans’ deaths worldwide. It is caused by a mycobacterial organism, the tubercle bacillus or Mycobacterium tuberculosis. Although TB can be treated, cured and can be prevented if patients take prescribed medicines, scientists have never come close to wiping it out due to a sharp rise in the incidence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) mycobacterium strains. Due to long regimen treatment and emergence of MDR and XDR-TB, it is urgent to re-engineer and reposition old drugs for developing new antimycobacterial entities with novel mechanisms of action to achieve effective TB control even against the resistant forms of TB. To combat the dreadful MDR and XDR-TB, potential targets are being extensively searched for the last couple of years for the design and discovery of active potential antitubercular chemotherapeutics. To explore the disease virulence, potential new tubercular target enzymes such as InhA, MmpL3, ATP synthase, DprE1, QcrB and MenA have been taken into consideration in the present study and the structure-based design of the corresponding target inhibitors which are under clinical investigation has been attempted to identify structural features for the discovery of new chemical entities (NCEs) having specificity towards MDR and XDR Mycobacterium tuberculosis (M. tuberculosis).

Streptomyces is genetically and functionally diverse genus known to produce a wide array of phenolics and flavonoids with significant biotechnological applications. 52 isolates belonging to 26 species of Streptomyces collected from Meghalaya, India were analyzed for their genetic diversity using BOX-PCR. Significant inter- and intra- generic diversity was observed among the Streptomyces isolates especially those belonging to S. cacaoi, S. lavendulae, S. olivochromogenes, S. aureus, S. flavovirens. During bioactivity screening of the isolates, S. rectiviolaceus MJM72 recorded the highest DPPH activity (77.13 ± 0.91%) whereas S. antimycoticus MSCA162 showed excellent ABTS radical scavenging activity (99.65 ± 0.41%). On the other hand, S. novaecaesareae MJM58 had the highest (756.4 ± 7.38 μg GAE g

Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) has been a global challenge as 1.4 million deaths were reported in 2019, which included deaths attributed to HIV-TB co-infection. It is curable by the prescribed Directly Observed Treatment Short (DOTS) course, but the situation becomes critical and alarming due to multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Hence there has been an urgent need to develop novel M.tb chemotherapeutics to overcome this situation. Areas covered This review provides an overview and update on recent developments on the novel therapeutics for the treatment of TB from the important published and granted patents (2018-present). Expert opinion The discovery of potent chemotherapeutics with reduced toxicity to combat M.tb particularly MDR and XDR-TB is a major challenge in antitubercular drug development. The missing of any doses during the DOTS treatment and poor immunity particularly in HIV patients has been a major cause for the development of drug resistance. Hence the major focus has to be on novel targets with their inhibitors and novel molecules both of natural and synthetic origins along with repurposed drugs for the complete eradication of tuberculosis.

In the present case study, a QSAR model has been developed to identify CCK2 receptor antagonists. The earlier reported 3D pharmacophore modeling of these molecules involved commercial software. Since the reduction in the cost involved in the drug discovery phase is very crucial, in the present study, QSAR models based on the structural indices including 1D, 2D and 3D indices computed from the structures of CCK2 receptor antagonists has been developed utilizing NanoBRIDGES software which is openly accessible (http://nanobridges.eu/software/). This QSAR model is not only comparable to the earlier reported model, but it also reasonably predicts the external set of nine compounds including the drug benzotript and the most active 6a described in earlier work on structure-based homology model CCK2 receptor antagonists as antiulcer agents and thus may be useful in virtual screening for the identification of new CCK2 receptor antagonists.

Tuberculosis (TB) still continues to be a major killer disease worldwide. Unlike other bacteria Mycobacterium tuberculosis (Mtb) has the ability to become dormant within the host and to develop resistance. Hence efforts are being made to overcome these problems by searching for new antitubercular agents which may be useful in the treatment of multidrug-(MDR) and extensively drugresistant (XDR) M. tuberculosis and shortening the treatment time. The recent introduction of bedaquiline to treat MDR-TB and XDR-TB may improve the status of TB treatment. The target enzymes in anti-TB drug discovery programs play a key role, hence efforts have been made to review the work on molecules including antiTB drugs acting on different enzyme targets including ATP synthase, the target for bedaquiline. Literature searches have been carried out to find the different chemical molecules including drugs and their molecular targets responsible for their antitubercular activities in recent years. This review provides an overview of the chemical structures with their antitubercular activities and enzyme targets like InhA, ATP synthase, Lip Y, transmembrane transport protein large (MmpL3), and decaprenylphospho-β-D-ribofuranose 2-oxidase, (DprE1). The major focus has been on the new target ATP synthase. Such an attempt may be useful in designing new chemical entities (NCEs) for specific and multi-drug targeting against Mtb.

The virtual screening (VS) is an important tool used in the modern drug discovery process to identify new leads and drug-like molecules for therapeutic interventions. With the rapid advancements in the computational hardware supported by advanced algorithmic progress and comprehensive data, the VS has gained fast momentum in drug discovery paradigm. The VS protocol is performed predominantly by using the ligand-based (LB) and structure-based (SB) VS methods with each one having its own merits and demerits. The LBVS method works on the similarity approach based on the physicochemical parameters, chemical functionality, and shape similarity of the ligands. The SBVS method works on the complementarity of the ligand with the target binding site and is more preferred than LBVS due to the consideration of both ligand and target information. Further in the SBVS, the available conformational information of the active chemical space helps in making reasonable decisions for the ligand selection. However, the limitations in scoring functions and incorrect pose prediction may result in the inaccurate SB models of limited performance in VS experiments. Various factors interplay in the development of successful VS models and the fine tuning of these factors leads to the efficient VS models with high sensitivity. In this chapter, some of the recent ligand- and structure-based approaches for virtual screening in drug discovery are described.

The molecular mechanisms of mitotic cell cycle progression involve very tightly restricted types of machinery which are highly regulated by a fine balance between the positive and negative accelerators (or regulators). These regulators include several checkpoints that have proteins acting as enzymes and their activating partners. These checkpoints incessantly monitor the external as well as internal environments such as growth signals, favorable conditions for growth, cell size, DNA integrity of the cell and hence function to maintain the highly ordered cell cycle progression by sustaining cell homeostasis and promoting error-free DNA replication and cell cycle division. To progress through the mitotic cell cycle, the cell has to successfully drive past the cell cycle checkpoints. Due to the abnormal behavior of some cell cycle proteins, the cells tend to divide continuously overcoming the tight regulation of cell cycle checkpoints. Such anomalies may lead to unwanted cell division, and this deregulation of cell cycle events is considered as one of the main reasons behind tumor development, and thus, cancer progression. So the understanding of the molecular mechanisms in cancer progression might be insightful for designing several cancer treatment strategies. The deregulation in the checkpoints is caused due to the changes in the tyrosine residues of TPKs via PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways. Therefore, the inhibitors of PDGFR, EGFR, FGFR, and VEGFR-mediated signaling pathways could be potential anticancer agents. The resistance and toxicity in the existing synthetic anticancer chemotherapeutics may decrease the life span of a patient. For long, natural products have played an essential alternative source of therapeutic agents due to having least or no side effect and toxicity. The present study is an attempt to promote natural anticancer drug development focusing on the updated structural information of PDGFR, EGFR, FGFR, and VEGFR inhibitors isolated from the plant sources. The data used in this review has been collected from internet resources, viz. GOOGLE Web, GOOGLE SCHOLAR, and PubMed Central. The citation of each report was first checked, after which the articles were selected as an authentic reference for the present study. Around 200 journal articles were initially selected, of which around 142 were finally chosen for presenting the study on the natural sourced inhibitors of EGFR, PDGFR, FGFR, and VEGFR-mediated signaling pathways which may help to enhance the potential cancer treatment.

Background: Molecular docking is in regular practice to assess ligand affinity on a target protein crystal structure. In the absence of protein crystal structure, the homology modeling or comparative modeling is the best alternative to elucidate the relationship details between a ligand and protein at the molecular level. The development of accurate homology modeling (HM) and its integration with molecular docking (MD) is essential for successful, rational drug discovery. Objective: The G-protein coupled receptors (GPCRs) are attractive therapeutic targets due to their immense role in human pharmacology. The GPCRs are membrane-bound proteins with the complex constitution, and the understanding of their activation and inactivation mechanisms is quite challenging. Over the past decade, there has been a rapid expansion in the number of solved G-protein-coupled receptor (GPCR) crystal structures; however, the majority of the GPCR structures remain unsolved. In this context, HM guided MD has been widely used for structure-based drug design (SBDD) of GPCRs. Methods: The focus of this review is on the recent (i) developments on HM supported GPCR drug discovery in the absence of GPCR crystal structures and (ii) application of HM in understanding the ligand interactions at the binding site, virtual screening, determining receptor subtype selectivity and receptor behaviour in comparison with GPCR crystal structures. Results: The HM in GPCRs has been extremely challenging due to the scarcity in template structures. In such a scenario, it is difficult to get accurate HM that can facilitate understanding of the ligand-receptor interactions. This problem has been alleviated to some extent by developing refined HM based on incorporating active /inactive ligand information and inducing protein flexibility. In some cases, HM proteins were found to outscore crystal structures. Conclusion: The developments in HM have been highly operative to gain insights about the ligand interaction at the binding site and receptor functioning at the molecular level. Thus, HM guided molecular docking may be useful for rational drug discovery for the GPCRs mediated diseases.

Salt stress hampers plant growth and development. It is now becoming one of the most important threats to agricultural productivity. Rhizosphere microorganisms play key roles in modulating cellular responses and enable plant tolerant to salt stress, but the detailed mechanisms of how this occurs need in-depth investigation. The present study elucidated that the microbe-mediated restructuring of the cellular responses leads to ecological fitness and adaptiveness to the maize (Zea mays L.) grown in saline–sodic soil. In the present study, effects of seed biopriming with B. safensis MF-01, B. altitudinis MF-15, and B. velezensis MF-08 singly and in consortium on different growth parameters were recorded. Soil biochemical and enzymatic analyses were performed. The activity and gene expression of High-Affinity K+ Transporter (ZmHKT-1), Sodium/Hydrogen exchanger 1 (zmNHX1), and antioxidant enzymes (ZmAPX1.2, ZmBADH-1, ZmCAT, ZmMPK5, ZmMPK7, and ZmCPK11) were studied. The expression of genes related to lateral root development (ZmHO-1, ZmGSL-1, and ZmGSL-3) and root architecture were also carried out. Seeds bioprimed with consortium of all three strains have been shown to confer increased seed germination (23.34–26.31%) and vigor indices (vigor index I: 38.71–53.68% and vigor index II: 74.11–82.43%) as compared to untreated control plant grown in saline–sodic soil at 30 days of sowing. Results indicated that plants treated with consortium of three strains induced early production of adventitious roots (tips: 4889.29, forks: 7951.57, and crossings: 2296.45) in maize compared to plants primed with single strains and untreated control (tips: 2019.25, forks: 3021.45, and crossings: 388.36), which was further confirmed by assessing the transcript level of ZmHO-1 (7.20 folds), ZmGSL-1 (4.50 folds), and ZmGSL-3 (12.00 folds) genes using the qPCR approach. The uptake and translocation of Na+, K+, and Ca2+ significantly varied in the plants treated with bioagents alone or in consortium. qRT-PCR analysis also revealed that the ZmHKT-1 and zmNHX1 expression levels varied significantly in the maize root upon inoculation and showed a 6- to 11-fold increase in the plants bioprimed with all the three strains in combination. Further, the activity and gene expression levels of antioxidant enzymes were significantly higher in the leaves of maize subjected seed biopriming with bioagents individually or in combination (3.50- to 12.00-fold). Our research indicated that ZmHKT-1 and zmNHX1 expression could effectively enhance salt tolerance by maintaining an optimal Na+/K+ balance and increasing the antioxidant activity that keeps reactive oxygen species at a low accumulation level. Interestingly, up-regulation of ZmHKT-1, NHX1, ZmHO-1, ZmGSL-1, and ZmGSL-3 and genes encoding antioxidants regulates the cellular responses that could effectively enhance the adaptiveness and ultimately leads to better plant growth and grain production in the maize crop grown in saline–sodic soil.

Background: Depression is a mental illness caused by the imbalance of important neurotransmitters such as serotonin (5-HT) and norepinephrine (NE). It is a serious neurological disorder that could be treated by antidepressant drugs. Objective: There are two major classes such as TCAs and phenoxyphenylpropylamines which have been proven to be broad-spectrum antidepressant compounds. Several attempts were made to design, synthesize and discover potent antidepressant compounds having the least toxicity and most selectivity towards serotonin and norepinephrine transporters. But there is hardly any drug design based on quantitative structure-activity relationship (QSAR) and pharmacophore modeling attempted yet. Method: In the present study, many TCAs (dibenzoazepine) and phenoxyphenylpropylamine derivatives are taken into consideration for pharmacophore feature generation followed by pharmacophoric distant related descriptors based QSAR modeling. Further, several five new congeners have been designed which are subjected to the prediction of biological activities in terms of serotonin receptor affinity utilizing validated QSAR models developed by us. Results: An important pharmacophoric feature point C followed by the generation of a topography of the TCAs and phenoxyphenylpropylamine has been predicted. The developed pharmacophoric feature-based QSAR can explain 64.2% of the variances of 5-HT receptor antagonism. The best training model has been statistically validated by the prediction of test set compounds. This training model has been used for the prediction of some newly designed congeneric compounds which are comparable with the existed drugs. Conclusion: The newly designed compounds may be proposed for further synthesis and biological screening as antidepressant agents.

Agriculture is a multifarious interface between plants and associated microorganisms. In contemporary agriculture, emphasis is being given to environmentally friendly approaches, particularly in developing countries, to enhance sustainability of the system with the least negative effects on produce quality and quantity. Modern agricultural practices such as extensive tillage, the use of harmful agrochemicals, mono-cropping, etc. have been found to influence soil microbial community structure and soil sustainability. On the other hand, the question of feeding the ever-growing global population while ensuring system sustainability largely remains unanswered. Agriculturally important microorganisms are envisaged to play important roles in various measures to raise a healthy and remunerative crop, including integrated nutrient management, as well as disease and pest management to cut down agrochemicals without compromising the agricultural production. These beneficial microorganisms seem to have every potential to provide an alternative opportunity to overcome the ill effects of various components of traditional agriculture being practiced by and large. Despite an increased awareness of the importance of organically produced food, farmers in developing countries still tend to apply inorganic chemical fertilizers and toxic chemical pesticides beyond the recommended doses. Nutrient uptake enhancement, biocontrol of pests and diseases using microbial inoculants may replace/reduce agrochemicals in agricultural production system. The present review aims to examine and discuss the shift in microbial population structure due to current agricultural practices and focuses on the development of a sustainable agricultural system employing the tremendous untapped potential of the microbial world.

Objective: The world is under the grasp of dangerous post-antibiotics and antimicrobials attack where common infections may become untreatable, leading to premature deaths due to antimicrobial resistance (AMR). While an estimated 7,00,000 people die annually due to AMR, which is a public health threat to all communities in different parts of the world regardless of their economic status; however, this threat is serious in low- and middle-income countries having lack of sanitation and health infrastructure. The 68th World Health Assembly endorsed the Global Action Plan on antimicrobial resistance. Consequently, many countries started drafting and committing to National Action Plans against AMR. As strong as National Action Plans are in terms of prescribing rational use of antimicrobials, infection control practices, and related public health measures, without strong healthcare systems, these measures will have a limited impact on AMR in developing countries. Methods: The major reason for AMR is microbial quorum sensing (QS) that may strengthen the microbial community to generate inter-communication and virulence effects via quorum sensing mechanisms. Global stewardship to combat antimicrobial resistance aims to develop anti-quorum sensing compounds that can inhibit the biosynthetic pathway mediated different quorum sensing targets. Results: It may pave an effective attempt to minimize microbial quorum sensing mediated antimicrobial resistance. The present review describes QS mediated various potential target enzymes, their connection to AMR, and finds out the corresponding QS biosynthetic target inhibitors. Conclusion: These potential inhibitors can be derivatized to design and develop next-generation antimicrobial agents.

Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side-effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco-conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92 mmol/kg) than the standard drug PQ diphosphate (3.861 mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound.

The development of small molecule inhibitors targeting GPVI has promising therapeutic role, as they inhibit arterial thrombosis with limited risk of bleeding. Among the compounds showing in vivo antithrombotic activity, the most active compound 6b (ED50 = 28.36 μmol/kg po in mice) showed improved inhibition for collagen (IC50 = 6.7 μM), CRP-XL (IC50 = 53.5 μM), and convulxin (CVX) (IC50 = 5.7 μM) mediated platelet aggregation as compared to losartan (LOS) (collagen, IC50 = 10.4 μM; CRP-XL, IC50 = 158 μM; CVX, IC50 = 11 μM) than any of its enantiomers S (6c) (collagen, IC50 = 25.3 μM; CRP-XL, IC50 = 181.4 μM; CVX, IC50 = 9 μM) and R (6d) (collagen, IC50 = 126.3 μM; CRP-XL, IC50 > 500 μM; CVX, IC50 = 86.8 μM). Compound 6b also inhibited platelet P-selectin expression and thus may diminish atherosclerosis. The molecular interactions of both enantiomers 6c and 6d at the GPVI receptor have been explained through docking studies.

S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide] is a novel and potent antithrombotic agent developed by CSIR-CDRI, India. The present study was aimed to develop a sensitive LC–MS/MS method for the quantification of S002-333 in mice plasma and tissues. The extraction of S002-333 from relatively small amount of mouse biomatrices (50 μL) was accomplished using protein precipitation followed by liquid-liquid extraction and the separation of analytes was achieved on C18 reversed phase column using acetonitrile and triple distilled water (75:25, v/v) as mobile phase at a flow rate of 0.6 mL/min. The instrument was operated in the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive scan mode. For all the biomatrices, linear relationship was attained over the concentration range of 0.39–200 ng/mL with correlation coefficients ≥0.992. The lower limit of quantification for mouse plasma and tissue homogenates was 0.39 ng/mL. The bioanalytical method was reproducible and reliable for all the matrices with inter-day and intra-day variability in precision being less than 15% and accuracy within ±15%. The assay was successfully applied to pharmacokinetics and tissue distribution of S002-333 in mice. The pharmacokinetic study revealed adequate gastrointestinal absorption of S002-333 into the systemic circulation of mice with absolute oral bioavailability of 45.8%. Tissue distribution data showed rapid and wide distribution of S002-333 in the following order: small intestine > liver > kidney ≈ lungs > heart > spleen > brain. The present findings may provide meaningful basis for further clinical development of this new chemical entity.

A series of N-(2-(benzoyl/4-chlorobenzoyl)-benzofuran- 3-yl)-2-(substituted)-acetamide derivatives (4a-l, 5a-l) was synthesized in good yield. All synthesized compounds were in agreement with elemental and spectral data. The anticonvulsant activity of all synthesized compounds was assessed against the maximal electroshock induced seizures (MES) model in mice. Neurotoxicity was evaluated using the rotarod method. The majority of compounds exhibited anticonvulsant activity at a dose of 30 mg kg-1 body mass during 0.5-4 h, indicating their ability to prevent seizure spread at low doses. Relative to phenytoin, [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(cyclohexyl( methyl) amino)-acetamide] (5i) and [N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-methylpiperidin-1- yl)-acetamide] (5c) demonstrated comparable relative anticonvulsant potency of 0.74 and 0.72, respectively, whereas [(N-(2-(4-chlorobenzoyl)benzofuran-3-yl)-2-(4-(furan-2-carbonyl)-piperazin-1-yl)-acetamide] (5f) exhibited the lowest relative potency of 0.16. The ALD50 of tested compounds ranged from 1.604 to 1.675 mmol kg-1 body mass. The ED50 of synthesized compounds ranged from 0.055 to 0.259 mmol kg-1 (~23.4 to 127.6 mg kg-1) body mass. The pharmacophore mapping of the examined compounds on standard drugs (phenobarbital, phenytoin, ralitolin and carbamazepine) strongly suggests that these compounds may exert their anticonvulsant activity via the same established mechanism as that of known drugs.