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A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC 50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC 50 values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity ( in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a , was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. [ABSTRACT FROM AUTHOR]

Monoamine oxidase inhibitors (MAOIs) are potential drug candidates for the treatment of various neurological disorders like Parkinson’s disease, Alzheimer’s disease and depression. In the present study, two series of 4-substituted phenylpiperazine and 1-benzhydrylpiperazine ( 1 – 21 ) derivatives were synthesized and screened for their MAO-A and MAO-B inhibitory activity using Amplex Red assay. Most of the synthesized compounds were found selective for MAO-B isoform except compounds 3 , 7 , 8 , 9 and 13 (MAO-A selective) while compound 11 was non-selective. In the current series, compound 12 showed most potent MAO-B inhibitor activity with IC 50 value of 80 nM and compound 7 was found to be most potent MAO-A inhibitor with IC 50 value of 120 nM and both the compounds were found reversible inhibitors. Compound 8 was found most selective MAO-A inhibitor while compound 20 was found most selective inhibitor for MAO-B isoform. In the cytotoxicity evaluation, all the compounds were found non-toxic to SH-SY5Y and IMR-32 cells at 25 µM concentration. In the ROS studies, compound 8 (MAO-A inhibitor) reduced the ROS level by 51.2% while compound 13 reduced the ROS level by 61.81%. In the molecular dynamic simulation studies for 30 ns, compound 12 was found quite stable in the active cavity of MAO-B. Thus, it can be concluded that phenyl- and 1-benzhydrylpiperazine derivatives are promising MAO inhibitors and can act as a lead to design potent, and selective MAO inhibitors for the treatment of various neurological disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel series of substituted- N -(5,6-diphenyl-1,2,4-triazin-3-yl) benzamide (R: 1 - R: 10) were designed and synthesized. • Two compounds (R:5 and R: 9) showed most potent MAO-A inhibition activity. • Compounds R: 5 and R: 9 showed noteworthy antidepressant-like effect. • In ADME studies none of the compounds violated the lipinski rule and all other parameters were also within the acceptable ranges. The novel series of substituted- N -(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides (R: 1 – 12) were designed, synthesized and evaluated for in-vitro and in-vivo antidepressant-like activity. In MAO-A inhibition assay, compound R: 5 and R: 9 displayed most potent activity with IC 50 = 0.12 and 0.30 µM. R: 5 and R: 9 were also evaluated for in-vivo antidepressant using FST and TST. In both models, the test samples R: 5 and R: 9 showed noteworthy antidepressant effect. R: 5 showed 46.48 % and 45.96 % reduction in immobility in FST and TST respectively at dosage of 30 mg/kg (p.o). Whereas compound R: 9 reduced the immobility time by 52.76 % and 47.14 % as compared to control in FST and TST, respectively at same dosage. Both the compounds were also tested for behavioural study using actophotometer and grip tests. None of compounds exhibited decrease in locomotor activity. Further, these compounds were subjected to in silico studies to determine their ADME properties along with binding energies and binding orientions. In ADME studies none of the compounds violated the Lipinski rule and all other parameters were also within the acceptable ranges. In docking study R: 5 (-10.7) and R: 9 (-10.4) were also displayed highest docking score. These encouraging results present the pharmacophoric features of substituted- N -(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides as interesting lead for further development of new antidepressant drug molecules. [ABSTRACT FROM AUTHOR]

Abstract: The thermodynamic behaviour of imidazolium based ionic liquids (ILs), 1-butyl-3-methylimidazolium chloride [C4mim][Cl]; 1-octyl-3-methylimidazolium chloride [C8mim][Cl], and 1-butyl-3-methylimidazolium methylsulfate [C4mim][C1OSO3] in ethylene glycol [HOCH2CH2OH] (EG) have been investigated over the whole composition range at T =(298.15 to 318.15)K to probe the interactions in bulk. For the purpose, volumetric properties such as excess molar volume, , apparent molar volume, Vϕ , i , and its limiting values at infinite dilution, , have been calculated from the experimental density measurements. The molecular scale interactions between ionic liquids and EG have been investigated through Fourier transform infrared (FTIR) and 1H NMR spectroscopy. The shift in the vibrational frequency for C–H stretch of aromatic ring protons of ILs and O–H stretch of EG molecules has been analysed. The NMR chemical shifts for various protons of RTILS or EG molecules and their deviations show multiple hydrogen bonding interactions of varying strengths between RTILs and EG in their binary mixtures. [Copyright &y& Elsevier]

[Display omitted] • Sodium channel inhibitors are the promising target for the management of convulsions. • Detailed pharmacology of sodium channel. • Development of anticonvulsant drugs as voltage gated sodium channel inhibitors. • Detailed pharmacological activity, SAR and possible mechanisms is discussed. Voltage-gated sodium channel blockers are one of the vital targets for the management of several central nervous system diseases, including epilepsy, chronic pain, psychiatric disorders, and spasticity. The voltage-gated sodium channels play a key role in controlling cellular excitability. This reduction in excitotoxicity is also applied to improve the symptoms of epileptic conditions. The effectiveness of antiepileptic drugs as sodium channel depends upon the reversible blocking of the spontaneous discharge without blocking its propagation. There are number of antiepileptic drug(s) which are in pipeline to flour the market to conquer abnormal neuronal excitability. They inhibit the seizures through the inhibition of complex voltage- and frequency-dependent ionic currents through sodium channels. Over the past decade, the sodium channel is one of the most explored targets to control or treat the seizure, but there has not been any game-changing discovery yet. Although there are large numbers of drugs approved for the treatment of epilepsy, however they are associated with several acute to chronic side effects. Many research groups have tirelessly worked for better therapeutic medication on this popular target to treat epileptic seizures. The review quotes briefly the developments of the approved examples of sodium channel blockers as anticonvulsant drugs. Medicinal chemists have tried the design and development of some more potent anticonvulsant drugs to minimize the toxicity that are discussed here, and an emphasis is given for their possible mechanism and the structure–activity relationship (SAR). [ABSTRACT FROM AUTHOR]

Abstract: The interactions of alkoxyalkanols with the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim][Br] as a function of temperature were investigated by combination of volumetric and acoustic methods. The density, ρ, and speed of sound, u, of ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, and triethylene glycol monomethyl ether (0.00–1.01mol·kg−1) in aqueous 1-butyl-3-methylimidazolium bromide solutions ranging from pure water to 0.29mass% of ionic liquid have been measured at T =(288.15, 298.15 and 308.15)K and atmospheric pressure. The apparent molar volume (Vϕ ) and adiabatic compressibility (Kϕ , S ) of alkoxyalkanols in aqueous ionic liquid solution were determined at the measured temperatures. The partial molar volume and partial molar adiabatic compressibility of alkoxyalkanols at infinite dilution were evaluated. Transfer volumes and transfer adiabatic compressibility () at infinite dilution from water to aqueous ionic liquid solution were also calculated. The temperature dependence of the apparent molar volume was used to calculate apparent molar expansivity () and the Hepler’s constant values, . The results were explained on the basis of competing patterns of interactions of co-solvent and the solute. [Copyright &y& Elsevier]

[Display omitted] • A new series of oxadiazole clubbed benzhydrylpiperazines (AP1-12) was designed, synthesized and evaluated for MAO inhibitory potential. • In this series, compounds AP3 and AP12 displayed most potent, selective and reversible inhibition of MAO-A enzyme. • In FST and TST studies, AP3 and AP12 exhibited potential antidepressant-like behaviour similar to standard drug fluoxetine. • Both potent compounds displayed good binding affinity and stability at binding pocket of MAO-A in in silico studies. Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC 50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule. [ABSTRACT FROM AUTHOR]

[Display omitted] • A new series of oxadiazole clubbed piperazines (5a-j) was designed, synthesized and evaluated for MAO inhibitory potential. • In this series, compounds 5f and 5 g displayed most potent, selective and reversible inhibition of MAO-A enzyme. • These compounds also exhibited neuroprotective and free radical scavenging potential without toxicity against SH-SY5Y cells. • In FST and TST studies, 5f and 5 g exhibited potential antidepressant-like behaviour similar to standard drug fluoxetine. Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC 50 values of 0.96 ± 0.04 µM µM and 0.81 ± 0.03 µM, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations. [ABSTRACT FROM AUTHOR]

Chlorpyrifos (CP) and its highly electrophilic intermediates are principal toxic metabolites. The active form of CP i.e. chlorpyrifos oxon (CP-oxon) is responsible for both the insecticidal activity and is also of greater risk when present in the atmosphere. Thus, the combined effects of both CP, CP-oxan, and other metabolites enhance our understanding of the safety and risk of the insecticide CP. They cause major toxicities such as AChE inhibition, oxidative stress, and endocrine disruption. Further, it can have adverse hematological, musculoskeletal, renal, ocular, and dermal effects. Excessive use of this compound results in poisoning and potentially kills a non-target species upon exposure including humans. Several examples of reactive metabolites toxicities on plants, aquatic life, and soil are presented herein. The review covers the general overview on reactive metabolites of CP, chemistry and their mechanism through toxic effects on humans as well as on the environment. Considerable progress has been made in the replacement or alternative to CP. The different strategies including antidote mechanisms for the prevention and treatment of CP poisoning are discussed in this review. The approach analyses also the active metabolites for the pesticide activity and thus it becomes more important to know the pesticide and toxicity dose of CP as much as possible. [Display omitted] • Chlorpyrifos and its electrophilic intermediates are highly toxic metabolites. • The degradation of chlorpyrifos mainly involves the oxidation, hydrolysis and diarylation. • The reactive metabolites induce toxicities via oxidative stress, AChE inhibition, and endocrine disruption. • The degradation products were toxic on humans, plants, aquatic life, and soil. • The different treatment strategies including antidote mechanism alleviates the symptoms of poisoning. [ABSTRACT FROM AUTHOR]

[Display omitted] • Total 12 indole-3-subtituted pyrazoline and oxazole derivatives were synthesized. • These compounds were evaluated for in vivo and in vitro anti-inflammatory activity. • Compound 15c and 15f presented more promising and comprehensive NSAID-like profile. • Oxadiazole derivatives were found more potent than pyrazoline derivatives. There are several potential side and adverse effects are found to be associated with the anti-inflammatory drugs in clinical practice. The long-term use of these clinical agents highly unsafe. It encouraged the development of novel heterocyclic compounds with potential anti-inflammatory activity and low to no toxicity. In present investigation, a total of 12 indole functionalized pyrazole and oxadiazole derivatives were designed, synthesized and evaluated for the in-vivo anti-inflammatory and analgesic potential. These compounds displayed comparable anti-inflammatory and analgesic potential to the reference drugs. Finally, molecular docking analysis was performed considering different anti-inflammatory targets to determine the mechanistic target of the designed molecules. Detailed analysis suggested that the molecules inhibit COX-2, preferably over other anti-inflammatory targets. The results suggested that two compounds (15c and 15f) were found promising candidates for the development of novel anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

• COVID-19 created an unprecedented medical and economic crisis all over the world. • Spike protein, RNA dependent RNA polymerase and Mpro Protease are major targets for COVID-19. • Similarity and key amino acid interactions of these are compared with SARS-CoV. • It will help to understand key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2. SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19. [ABSTRACT FROM AUTHOR]

• Three different series of new 1,5-benzodiazepines were synthesized. • All the compounds were screened in vivo to evaluate their CNS depressant and antiepileptic activity. • Compound 11b exhibited most potent CNS depressant activity whereas 10c displayed significant antiepileptic activity. • In silico studies were performed. Benzodiazepines (BZDs) represent a class of privilege scaffold in the modern era of medicinal chemistry as CNS active agents and BZD based drugs are used to treat different psychotic disorders. Inspired from the therapeutic potential of BZDs as promising CNS active agents, in the present work three different series of 1,5-benzodiazepines bearing various substitutions at position 2 and 4 of the benzodiazepine core were synthesized by condensing different substituted chalcones with o -phenylenediamine in the presence of piperidine as a base catalyst. Structural characterization of title compounds was done by using various analytical techniques such as IR, NMR, elemental analysis and mass spectral data. All the synthesized compounds (9a-d , 10a-e and 11a-c) were subjected to in vivo neuropharmacological studies to evaluate their CNS depressant and antiepileptic activity. Results of in vivo evaluation data showed that analogue 11b exhibited potent CNS depressant activity which was comparable to the standard drug diazepam. Compounds 10b and 10c displayed significant antiepileptic activity however they were less potent than the standard drug phenobarbitone. Molecular docking studies were performed using MOE software to find the interaction pattern and binding mode at the GABAA receptor (PDB Id: 6HUP). The results of the docking studies were in good agreement with the observed in vivo activity and revealed the satisfactory binding mode of the compounds within the binding site of the protein. The docking scores for the most promising candidates 10c , 11b and Diazepam were found to be −9.18, −9.46 and −9.88, respectively. Further, the compounds showed compliance with the Lipinski's 'rule of five' and exhibited favourable drug-likeness scores. The identified leads can be explored further for the design and development of new BZD based psychotropic agents. [ABSTRACT FROM AUTHOR]