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Candidates generated from unsaturated ketone (chalcone) demonstrated as strong, reversible and specific monoamine oxidase-B (MAO-B) inhibitory activity. For the research on MAO-B inhibition, our team has synthesized and evaluated a panel of aldoxime-chalcone ethers (ACE) and hydroxylchalcones (HC). The MAO-B inhibitory activity of several candidates is in the micro- to nanomolar range in these series. The purpose of this research was to develop predictive QSAR models and look into the relation between MAO-B inhibition by aldoxime and hydroxyl-functionalized chalcones. It was shown that the molecular descriptors ETA Shape P, MDEO-12, ETA dBetaP, SpMax1 Bhi and ETA EtaP B are significant in the inhibitory action of the MAO-B target. Using the current 2D QSAR models, potential chalcone-based MAO-B inhibitors might be created. The lead molecules were further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex. Communicated by Ramaswamy H. Sarma.

A novel esterase (est3S) gene, 1026 bp in size, was cloned from a metagenomic library made of uncultured microorganisms from the contents of cow rumen. The esterolytic enzyme (Est3S) is composed of 342 amino acids and shows the highest identity with EstGK1 (71.7%) and EstZ3 (63.78%) esterases from the uncultured bacterium. The Est3S did not cluster in any up-to-date classes (I to XVIII) of esterase and lipase. Est3S protein molecular weight was determined to be 38 kDa by gel electrophoresis and showed optimum activity at pH 7.0 and 40 °C and is partially resistant to organic solvents. Est3S activity was enhanced by K+, Na+, Mg2+, and Ca2+ and its highest activity was observed toward the short-chain p-nitrophenyl esters. Additionally, Est3S can degrade chlorpyrifos (CP) and methyl parathion (70% to 80%) in an hour. A mutated Est3S (Ser132-Ala132) did not show any activity toward CP and ester substrates. Notably, the GHS132QG motif is superimposed with the homolog esterase and cutinase-like esterase. Therefore, Ser132 is the critical amino acid like other esterases. The Est3S is relatively stable with ester compounds, and the methyl parathion complex was confirmed by molecular dynamics simulation. Novelty statement A novel esterase gene (est3S) expressing esters and organophosphorus insecticide degradation traits was isolated from the uncultured bacterium in the contents of cow rumen. The Est3S protein did not cluster in any up-to-date classes (I to XVIII) of esterase/lipase proteins. Est3S was stable with the ligands up to 100 ns during the molecular dynamic simulations.

Diabetes mellitus (DM) is a group of metabolic disorders characterised by chronic hyperglycaemia. DM is currently one of the top ten causes of death in humans. Chronic hyperglycaemia in DM leads to long-term damage and failure of different organs in the body. Type 2 DM (T2D) is the most common DM form, characterised by peripheral insulin resistance, relative insulin deficiency, impaired hepatic glucose production regulation and pancreatic β cell dysfunction. The human pancreatic α-amylase (HPA) inhibitor is currently one of the most effective methods developed to inhibit hyperglycaemia in T2D patients. However, the current standard drug available, acarbose, has been associated with severe side effects following prolonged use in patients. Therefore, an alternative drug capable of effectively inhibiting HPA with minimal side effects is required. Based on our previous study, we further explored the therapeutic potential of quercetin and ombuin

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease that is characterized by memory and cognitive impairments that predominantly affects the elderly and is the most common cause of dementia. As is known, the AChE enzyme consists of two parts. In this work, 10 new hydrazones (

The nsp3 macrodomain is implicated in the viral replication, pathogenesis and host immune responses through the removal of ADP-ribosylation sites during infections of coronaviruses including the SARS-CoV-2. It has ever been modulated by macromolecules including the ADP-ribose until Ni and co-workers recently reported its inhibition and plasticity enhancement unprecedentedly by remdesivir metabolite, GS-441524, creating an opportunity for investigating other biodiverse small molecules such as β-Carboline (βC) alkaloids. In this study, 1497 βC analogues from the HiT2LEAD chemical database were screened, using computational approaches of Glide XP docking, molecular dynamics simulation and pk-CSM ADMET predictions. Selectively, βC ligands, 129, 584, 1303 and 1323 demonstrated higher binding affinities to the receptor, indicated by XP docking scores of -10.72, -10.01, -9.63 and -9.48 kcal/mol respectively than remdesivir and GS-441524 with -4.68 and -9.41 kcal/mol respectively. Consistently, their binding free energies were -36.07, -23.77, -24.07 and -17.76 kcal/mol respectively, while remdesivir and GS-441524 showed -21.22 and -24.20 kcal/mol respectively. Interestingly, the selected βC ligands displayed better stability and flexibility for enhancing the plasticity of the receptor than GS-441524, especially 129 and 1303. Their predicted ADMET parameters favour druggability and low expressions for toxicity. Thus, they are recommended as promising adjuvant/standalone anti-SARS-CoV-2 candidates for further study.Key words: SARS-CoV-2, nsp3 macrodomain, ADP-ribose, β-carboline, bioinformatics, drug design.

The third-generation EGFR (epidermal growth factor receptor) inhibitors selectively and irreversibly target EGFR-T790M and other activating EGFR mutations. Osimertinib is the only FDA-approved third-generation inhibitor, which has a good potency against the EGFR-T790M mutant with minimal toxicities and excellent selectivity for wild-type EGFR. EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after the treatment of osimertinib, which is an undruggable mutation to all three existing generation drugs. Recently, trisubstituted imidazoles were reported based on an off-target hit of a p38α MAPK (mitogen-activated protein kinase) inhibitor as the fourth-generation EGFR-TKIs to overcome the C797S resistance by inhibiting the clinically relevant triple mutant kinase L858R/T790M/C797 EGFR. Here, we are reporting the clinical trial p38α MAPK kinase inhibitors SD-06, Amgen 16, RWJ67657 and SCIO-323 as L858R/T790M/C797S EGFR TK inhibitors to overcome the problem of drug resistance in non-small cell lung cancer (NSCLC).Communicated by Ramaswamy H. Sarma.

Four different simple, accurate and precise UV-spectrophotometric methods have been developed for the estimation of palbociclib (PB) in bulk and in-house capsule dosage form by zero order (Method I), zero order AUC (Method II), ‘first order derivative UV-spectrophotometric (Method III), and first order AUC (Method IV) methods. The drug was dissolved in methanol (AR-Grade) and further dilution was made in double distilled water. Zero order was performed at λ max 220.00 nm of PB (Method I) and AUC was calculated between 215.40 nm - 228.20 nm wavelength (Method II). In Method-III zero-order spectra were derivatized into first-order and amplitude measured at 231.00 nm and the AUC was recorded between 224.00 nm - 240.60 nm (Method IV). PB followed linearity in the concentration range of 4.08-20.40 µg/mL with correlation coefficient (r2 )> 0.99 for PB.

TB is the 9th leading cause of death worldwide above HIV/AIDS. Tuberculosis (TB) management remains challenging due to the emergence of drug-resistant tuberculosis such as MDR-TB and XDR-TB. To improvise therapeutic results for MDR/XDR-TB, 89 nations had started utilizing bedaquiline and 54 had utilized delamanid by June 2017. Unfortunately, cardiac arrhythmia was found to be the most serious side effect associated with the both drugs restricting their use for the management of MDR- and XDR-TB. The current review discussed the clinically trialed and approved drug for the treatment of XDR-TB, recently reported compounds against XDR-TB, their synthesis and activity spectrum. This information could be helpful to the medicinal chemist in synthesizing the best XDR-TB inhibitors free from resistance and toxicity.

In this study, two novel derivatives of naphthalene-2-sulfonic acid: 6-(((1S,5R)-3,5-dichloro-2,4,6-triazabicyclo [z3.1.0]hex-3-en-1-yl)amino)-5-((E)-phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS1) and (E)-6-((4,6-dichloro-1,3,5-triazine2-yl)amino)-4-hydroxy-3-(phenyldiazenyl)naphthalene-2-sulfonic acid (DTPS2) have been synthesized and characterized using FT-IR, UV-vis, and NMR spectroscopic techniques. Applying density functional theory (DFT) at the B3LYP, APFD, PBEPBE, HCTH, TPSSTPSS, and ωB97XD/aug-cc-pVDZ level of theories for the electronic structural properties. In-vitro analysis, molecular docking, molecular dynamic (MD) simulation of the compounds was conducted to investigate the anti-inflammatory potential using COXs enzymes. Docking indicates binding affinity of −9.57, −9.60, −6.77 and −7.37 kcal/mol for DTPS1, DTPS2, Ibuprofen and Diclofenac which agrees with in-vitro assay. Results of MD simulation, indicates sulphonic group in DTPS1 has > 30% interaction with the hydroxyl and oxygen atoms in amino acid residues, but > 35% interaction with the DTPS2. It can be said that the DTPS1 and DTPS2 can induce inhibitory effect on COXs to halt biosynthesis of prostaglandins (PGs), a chief mediator of inflammation and pain in mammals. Communicated by Ramaswamy H. Sarma

Considering the current dramatic and fatal situation due to the high spreading of SARS-CoV-2 infection, there is an urgent unmet medical need to identify novel and effective approaches for prevention and treatment of Coronavirus disease (COVID 19) by re-evaluating and repurposing of known drugs. For this, tomatidine and patchouli alcohol have been selected as potential drugs for combating the virus. The hit compounds were subsequently docked into the active site and molecular docking analyses revealed that both drugs can bind the active site of SARS-CoV-2 3CLpro, PLpro, NSP15, COX-2 and PLA2 targets with a number of important binding interactions. To further validate the interactions of promising compound tomatidine, Molecular dynamics study of 100 ns was carried out towards 3CLpro, NSP15 and COX-2. This indicated that the protein-ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. Post dynamic MM-GBSA analysis of molecular dynamics data showed promising mean binding free energy 47.4633 ± 9.28, 51.8064 ± 8.91 and 54.8918 ± 7.55 kcal/mol, respectively. Likewise, in silico ADMET studies of the selected ligands showed excellent pharmacokinetic properties with good absorption, bioavailability and devoid of toxicity. Therefore, patchouli alcohol and especially, tomatidine may provide prospect treatment options against SARS-CoV-2 infection by potentially inhibiting virus duplication though more research is guaranteed and secured.

The evolution of microbial resistance necessitates the development of new antimicrobial drugs that are more effective than those currently on the market. To address this problem, we have prepared a series of novel 4-(biphenyl-4-yl)-1,4-dihydropyridine and 4-(biphenyl-4-yl)pyridine derivatives via Hantzsch reaction using nine different compounds containing active methylene group. IR, NMR, and mass spectra were used to determine the structures. Using ampicillin and griseofulvin as standards, the titled compounds were investigated for their antibacterial activity against different bacteria and fungi. Compounds 1f, 1g, 2f, and 2g have the best antibacterial activity against Gram-negative bacteria (minimum inhibitory concentration = 50 μg/ml), while 1f, 1h, 2g, and 2h have high antifungal activity against Candida albicans (minimum inhibitory concentration = 100 μg/ml). To gain a better understanding of the binding process and affinity for the bacterial Staphylococcus epidermidis protein, researchers used molecular docking and molecular mechanics, as well as the generalized Born model and solvent accessibility-based binding free energy. The active compounds 1g, 1h, and 2f have good docking scores of -5.575, -5.949, and -5.234, respectively, whereas compound 2c has the greatest docking score (-6.23). The HOMO-LUMO energy gap and molecular electrostatic potential were used to evaluate the reactivity of promising compounds, which were then associated with antibacterial efficacy.

The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.

Quinazoline is the six-membered heterocyclic ring system reported for its versatile biological activities. This characteristic feature of quinazoline makes it a good template for a lead generation library. Ring opening is one of the major concerns in the synthesis of quinazolin-4(3H)-one that results in diamide formation. Here, alternative fusion strategy is reported, which is a time-saving and costeffective method to overcome the ring opening problem associated with the synthesis of benzo[ d][1,3]oxazin-4-one and quinazolin-4(3H)-one.

Thymol (2-isopropyl-5-methylphenol) is an important monoterpene phenol occurring in the essential oils isolated from Thymus vulgaris, Thymus zygis, Thymus hyemalis, etc. Thymol and its derivatives show various activities such as antioxidant, antiinflammatory, antibacterial, and antifungal effects. In the present study, a set of new benzamide derivatives (4a–e), which are structurally similar to paracetamol, were synthesized from thymol using a green synthetic approach and characterized by Fourier-transform infrared (FT-IR) and 1H and 13C nuclear magnetic resonance (NMR) spectroscopies, liquid chromatography–mass spectrometry (LC–MS), and X-ray single-crystallographic analysis for derivative 4c. These derivatives were subjected to antioxidant testing by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and antibacterial testing against five microorganisms. Molecular docking studies of all the compounds indicated that they are good inhibitors of heme oxygenase-1. These results extend the development of thymol-based benzamide scaffolds as promising antioxidant agents.

Bedaquiline was approved by USFDA in 2012 for pulmonary MDR-TB. The IC50 value of bedaquiline was reported to be remarkably low (25 nM), effectively inhibiting mycobacterial ATP synthase. In addition to these obvious assets of bedaquiline, the potential disadvantages of bedaquiline include inhibition of the hERG (human Ether-a-go-related gene; KCNH2) potassium channel (concurrent risk of cardiac toxicity), hepatic toxicity and possibly phospholipidosis. The current review focuses primarily on the structural part of bedaquiline for the activity-toxicity optimization. This critical analysis of the structure of bedaquiline will help medicinal chemists to synthesize the better modified analouge of bedaquiline with reduced cardiotoxicity, hepatotoxicity potential and improved pharmacokinetics.

The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5 mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50 mM/kg/day dose for 5 days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30 min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1β production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Tuberculosis is considered as a leading health issue globally. Even though, the todays first line anti-mycobacterial treatments used in the hospital have low deaths, multidrug-resistance forms of the ailment have now spread globally and become a major issue. The wide-ranging biodiversity of medicinal plants, ocean animals have gained considerable attention for drug discovery in previous spans, and the emergence of TB drug resistance has inspired interest in judging natural products (NPs) to cure this disease. Till now, several compounds have been isolated from natural sources with anti-mycobacterial activity, few of which demonstrate significant activity and have the potential for further development. Worldwide huge natural flora and fauna are existing, this flora and fauna must be investigated for new potent lead against infectious TB. This review systematically surveys various classes of terpenoid molecules obtained from different medicinal plants, fungi, sponges, and sea plumes with anti-TB activity, which could be useful for further optimization and development in this field.

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (− 5.636 kcal/mol) and highest binding free energy (ΔG bind − 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00086-x.

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.

Drug resistance tuberculosis is one of the challenging tasks that dictates the desperate need for the development of new antitubercular agents which operate via novel modes of action. Here, we are reporting on 4-aminoquinazolines as M. tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMTB ) inhibitors to overcome the problem of the MDR-TB. Amongst the synthesized compounds, two of them were observed to be the effective compounds of the series (IC50 =6.4 μM (H37Rv), MIC=25 μM (MDR-TB) and IC50 =2.9 μM (H37Rv), MIC=6.25 μM (MDR-TB), respectively).

Background: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. Methods: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. Results: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. Conclusion: These compounds also showed less inclination towards WT-EGFR.

Mycobacterium tuberculosis (MTB) infection has become a growing health risk as multi-drug resistant strain (MDR-MTB) has emerged worldwide. The development of isoniazid (INH)-resistant M. tuberculosis strains dictate the need to re-design this old drug to create effective analogs against the resistant INH strains. Synthesis and the biological activity of isoniazid and pyridine derivatives were successfully carried out with elaborated characterization by spectral data. Amongst the synthesized compounds; 1 and 2 displayed encouraging antimycobacterial activity with IC50 of 3.2 µM and 1.5 µM against the H37Rv strain. The MIC of test compounds 1 and 2 were also assessed against the 5 drug resistant isolates (FQ-R1, INH-R1, INH-R2, RIF-R1 and RIF-R2) of MTB strains under aerobic conditions and compound 1 [MIC = 3.2 µM for FQ-R1; MIC = 140 µM for INH-R1; MIC = 160 µM for INH-R2; MIC = 2.4 µM towards RIF-R1; MIC = 4.2 µM for RIF-R2] and 2 [MIC = 3.3 µM for FQ-R1; MIC = 170 µM for INH-R1; MIC = 190 µM for INH-R2; MIC = 1.8 µM for RIF-R1; MIC = 8.4 µM for RIF-R2] have shown significant activity at non-cytotoxic concentration in comparison to the standard drug.

Drug resistance tuberculosis is one of the challenging tasks that dictates the desperate need for the development of new antitubercular agents which operate via novel modes of action. Here, we are reporting on 4-aminoquinazolines as M. tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmU

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. In this work, we have reported the novel T790M/C797S-EGFR Tyrosine Kinase inhibitors using BREED based de novo hybridization approach. BREED generates novel inhibitors from structures of known ligands bound to a common target. Among the generated hybridised breed compounds, the top best scorer breed molecules were breed 436, breed 530, breed 450, breed 562 and breed 313. Molecular Dynamics simulation of breed 436 for 10 ns further suggested that docked compound was stable into the pocket of the T790M/C797S-EGFR Tyrosine Kinase. In silico pharmacokinetic predictions of the breed hybridised compounds were within the defined range described for human use. Communicated by Ramaswamy H. Sarma

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. Recently, EAI045 fourth-generation allosteric EGFR inhibitor has been reported, which binds away from the ATP-binding site and not rely on Cys 797 binding. Here, we are reporting compound ZINC20531199 by virtual based screening studies as allosteric inhibitor to overcome the EGFR T790M/C797S Tyrosine Kinase (TK) mutation problem. Molecular Dynamics simulation for 10 ns further suggested that docked compound ZINC20531199 was stable into the allosteric pocket of the C797S EGFR tyrosine kinase. In silico pharmacokinetic predictions of the virtually screened compounds are within the defined range described for human use. Results indicate that the virtual screened compounds could be potential leads for the further development of new allosteric EGFR T790M/C797S inhibitors to overcome the problem of drug resistance. Communicated by Ramaswamy H. Sarma

In the current research, methaqualone derivatives were synthesized and assessed for their anti-convulsant activity. Among them, compounds 3, 4, 6, 7 and 11 exhibited significant anti-convulsant activities with ED50 values of 132.23 mg/kg, 120.34 mg/kg, 100.78 mg/kg, 145.89 mg/kg, and 148.46 mg/kg, respectively. The toxicity profiling (TD50) of these compounds (3, 4, 6, 7 and 11) demonstrated that these drugs caused only a minor neurological impairment. The PI scores of these compounds (3, 4, 6, 7 and 11) were higher than the reference drug (methaqualone PI: 1.99). The acetylcholinesterase enzyme level is significantly reduced in these compounds, indicating the enhancement of cognition activity. Pharmacophoric modelling and molecular docking studies against the human GABA-A receptor are in close agreement with each other. Molecular dynamic simulation of compound 6 indicates that it remains stable with the human GABA-A receptor for a 100 ns time span.

Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to delineate the design, synthesis, in vitro biological analysis of a series of novel reversible selective T790M inhibitors with minimal cardiotoxicity. Amongst the virtually sorted compounds; compound 18 and 74 have been located to be the foremost active compounds of the series with IC50 value of 0.88, 0.92 μM in cellular assay and 0.56, 0.62 μM in enzymatic assay, against double mutant L858R/T790M EGFR. Additionally, they showed much less affinity toward wild-type (WT)-EGFR with minimal cardiotoxicity.

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle. EGFR C797S mutation was accounted to be a main mechanism of resistance to the third-generation inhibitors. The C797S mutation gives off an impression of being an ideal target for conquering the acquired resistance to the third generation inhibitors. We have performed structure based-virtual screening strategies for binding of glucokinase activator to EGFR C797S, which can overcome EGFR resistance impediment with mutant-selective allosteric inhibition towards all kinds of mutant EGFR (T790M, L858R, TMLR) and WT EGFR. The final filter of Lipinski's Rule of Five, Jargan's Rule of Three and in silico ADME predictions gave 23 hits, which conform to Lipinski's rule and Jorgensen's rule and all their pharmacokinetic parameters are inside the appropriate range characterized for human use, in this manner demonstrating their potential as a drug-like molecule.

In the present research, we report the synthesis and in vitro antimicrobial activity of a new series of novel quinazolino-thiadiazoles as fused pharmacophore (3–20). In general, the results of the in vitro antibacterial activity are encouraging, as out of 18 compounds tested, Compounds 3 and 8 with a 4-chlorophenyl and 4-nitro phenyl at C-2 of thiadiazole and chloromethyl substituent at C-2 of quinazolinone displayed a broad spectrum antimicrobial activity against all the strains, while compounds 13 and 16 again with a 4-chlorophenyl and 4-nitrophenyl at C-2 of thiadiazole and ethyl substituent at C-2 of quinazolinone showed the same potency but with a narrower spectrum (Bacterial and Fungal strains) with MIC values of 62.5 µg/ml. The structures of the compounds were confirmed by IR, 1H NMR, 13C NMR and Mass analysis. It is worth to mention that the combination of two biologically active moieties quinazoline and thiadiazole profoundly influences the biological activity.

COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has threatened the whole world affecting almost 243 million people globally. Originating from China, it has now spread worldwide with USA and India being the two most affected countries which emphasizes the immense potential of the coronaviruses to cause severity in the human population. This study validates the efficacy of some marine antiviral agents to target the viral main protease (Mpro) of SARS-CoV-2 by in silico studies. A total of 14 marine-derived antiviral agents were screened from several databases including PubChem and DrugBank and docked against the crystallised 3D structure of SARS-CoV-2 Mpro. MD simulation of the top two ligands was carried out for 100 ns to validate the protein-ligand stability. Later, their physicochemical, pharmacokinetics, and drug-likeness properties were evaluated and toxicity prediction was performed using eMOLTOX webtool. We found that all the 14 compounds are acting as a good target for Mpro. Among them, avarol and AcDa-1 procured the best docking results with the estimated docking score of −8.05 and −7.74 ​kcal/mol respectively. MD simulation revealed good conformational stability. The docked conformation was visualised and subsequent ligand-amino acid interactions were analysed. Avarol revealed good pharmacokinetic properties with oral bioavailability. The overall finding suggested that these marine compounds may have the potential to be used for the treatment of COVID-19 to tackle this pandemic., Graphical abstract Image 1

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

Tuberculosis (TB) transmitted by Mycobacterium tuberculosis (Mtb) is one of the top 10 causes of death globally. Currently, the widespread occurrence of resistance toward Mtb strains is becoming a significant concern to public health. This scenario exaggerated the need for the discovery of novel targets and their inhibitors. Targeting the “Mtb cell wall peptidoglycan synthesis” is an attractive strategy to overcome drug resistance. Mur enzymes (MurA-MurF) play essential roles in the peptidoglycan synthesis by catalyzing the ligation of key amino acid residues to the stem peptide. These enzymes are unique and confined to the eubacteria and are absent in humans, representing potential targets for anti-tubercular drug discovery. Mtb Mur ligases with the same catalytic mechanism share conserved amino acid regions and structural features that can conceivably exploit for the designing of the inhibitors, which can simultaneously target more than one isoforms (MurC-MurF) of the enzyme. In light of these findings in the current review, we have discussed the recent advances in medicinal chemistry of Mtb Mur enzymes (MurA-MurF) and their inhibitors, offering attractive multi-targeted strategies to combat the problem of drug-resistant in M. tuberculosis.

T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.

EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

Novel analogs of 3-(4-substituted benzylideneamino)-N-(6-substituted-1,3-benzo[d]thiazol-2-yl)-4,5-dihydro-5-oxo-pyrazole-1-carboxamide (5a–s) were designed and synthesized by reacting 3-amino-N-(6-substituted-1,3-benzo[d]thiazol-2-yl)-4,5-dihydro-5-oxo-pyrazole-1-carboxamide (4a–d) with p-substituted benzaldehydes. The Infrared Spectroscopy, 1H-Nuclear Magnetic Resonance, 13C-Nuclear Magnetic Resonance, and High Resolution Mass Spectra spectral data confirmed the structures of all the novel synthesized compounds. Among the series tested, two compounds 5k and 5o displayed promising antibacterial activity especially against Staphylococcus aureus (MIC = 3.14 and 1.57 µg/mL) and Bacillus subtilis (MIC = 3.12 and 1.84 µg/mL) respectively. Further, these title compounds were also assessed for their cytotoxic activity (IC50) against mammalian Vero cell line using 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-tetrazolium bromide assay, indicating that the compounds exhibit antibacterial activity at non-cytotoxic concentrations. Field based three-dimensional quantitative structure–activity relationships were also discussed based on the antimicrobial screening data. Synthesis, spectral studies, antibacterial evaluation and QSAR studies of nineteen novel Schiff bases of pyrazol-5-one derivatives derived from 2-aminobenzothiazole nucleus are described.

The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.

Mycobacterium tuberculosis (MTB) infection has become an increasing health threat due to the worldwide emergence of multidrug-resistant MTB (MDR-MTB) strain. Isoniazid (pyridine) resistance problem is a complex process and is associated with mutations in several genes. However, the emergence of isoniazid (INH) resistant M. tuberculosis strains dictates the necessity for redesigning this old drug in order to create analogs effective against INH-resistant strains by using rational approach. In light of these findings, the present review discusses the synthesis, structural optimization, and modification in pyridine structure to combat the problem of multidrug-resistant tuberculosis.

N,N,N-trimethyl chitosan (TMC), a quaternized hydrophilic derivative of chitosan (CHT), outperformed the well-known solubility issues raised by CHT. The excellent properties offered by TMC provide it a significant edge for nanoparticle (NP) formation over other nanocarrier materials. Recently, TMC NPs have been applied to various fields like pharmaceutical, biomedical, biomaterials, and biotechnological field. The aim of this review is, therefore, to bring the TMC into the limelight so as to appraise it as an attractive functional polymer for nanomedicine applications which is facing oversight, at present, by regulatory agencies and manufacturers. The versatility of surface-tailoring, the capability of further chemical modifications, and the feasibility of ligand-conjugations in TMC polymer will further assist the scientists for reaching new dimensions in the nano-assembly of novel structures based on TMC.