In silico evaluation of S-adenosyl-L-homocysteine analogs as inhibitors of nsp14-viral cap N7 methyltranferase and PLpro of SARS-CoV-2: synthesis, molecular docking, physicochemical data, ADMET and molecular dynamics simulations studies.

A series of S-adenosyl-L-homosysteine (SAH) analogs, with modification in the base and sugar moiety, have been designed, synthesized and screened as nsp14 and PLpro inhibitors of severe acute respiratory syndrome corona virus (SARS-CoV-2). The outcomes of ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) studies demonstrated that the physicochemical properties of all analogs were permissible for development of these SAH analogs as antiviral agents. All molecules were screened against different SARS-CoV-2 targets using molecular docking. The docking results revealed that the SAH analogs interacted well in the active site of nsp14 protein having H-bond interactions with the amino acid residues Arg289, Val290, Asn388, Arg400, Phe401 and π-alkyl interactions with Arg289, Val290 and Phe426 of Nsp14-MTase site. These analogs also formed stable H-bonds with Leu163, Asp165, Arg167, Ser246, Gln270, Tyr274 and Asp303 residues of PLpro proteins and found to be quite stable complexes therefore behaved as probable nsp14 and PLpro inhibitors. Interestingly, analog 3 showed significant in silico activity against the nsp14 N7 methyltransferase of SARS-CoV-2. The molecular dynamics (MD) and post-MD results of analog 3 unambiguously established the higher stability of the nsp14 (N7 MTase):3 complex and also indicated its behavior as probable nsp14 inhibitor like the reference sinefungin. The docking and MD simulations studies also suggested that sinefungin did act as SARS-CoV-2 PLpro inhibitor as well. This study's findings not only underscore the efficacy of the designed SAH analogs as potent inhibitors against crucial SARS-CoV-2 proteins but also pinpoint analog 3 as a particularly promising candidate. All the study provides valuable insights, paving the way for potential advancements in antiviral drug development against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

HighlightsSAH analogs bearing modified bases and sugar moiety have been synthesized as antivirals against SARS-CoV-2.Molecular dynamics simulation established the stability of ligand-protein complex of analog 3 with nsp14 (N7-MTase) protein of SARS-CoV-2.Molecular docking studies of SAH analogs indicated them as nsp14 N7 methyltranferase as well as the PLpro inhibitors of SARS-CoV-2.The in silico antiviral activity of SAH analogs has been found comparable to the reference drug Sinefungin.

Exploring antiviral potency of N-1 substituted pyrimidines against HIV-1 and other DNA/RNA viruses: Design, synthesis, characterization, ADMET analysis, docking, molecular dynamics and biological activity.

A novel series of pyrimidine derivatives, bearing modified benzimidazoles at N-1 position, has been designed, synthesized and screened as NNRTIs against HIV and as broad-spectrum antiviral agents. The molecules were screened against different HIV targets using molecular docking experiment. The docking results indicated that the molecules interacted well with the residues Lys101, Tyr181, Tyr188, Trp229, Phe227 and Tyr318 present in NNIBP of HIV-RT protein, formed quite stable complexes and, thus, behaved as probable NNRTIs. Among these compounds, 2b and 4b showed anti-HIV activity with IC50 values as 6.65 µg/mL (SI = 15.50) and 15.82 µg/mL (SI = 14.26), respectively. Similarly, compound 1a showed inhibitory property against coxsackie virus B4 and compound 3b against different viruses. Molecular dynamics simulation results unequivocally demonstrated the higher stability of the complex HIV-RT:2b than the HIV-RT:nevirapine complex. The MM/PBSA-based binding free energy (-) 114.92 kJ/mol of HIV-RT:2b complex in comparison to that of HIV-RT:nevirapine complex (-) 88.33 kJ/mol, further demonstrated the higher binding strength of 2b and thus, established the potential of compound 2b as a lead molecule as an HIV-RT inhibitor.

Ag-Doped WO3 Nanoplates as Heterogenous Multifunctional Catalyst for Glycerol Acetylation, Electrocatalytic and Enhanced Photocatalytic Hydrogen Production.

Herein, we report a hydrothermal method to synthesize pristine and Ag-doped WO3 nanoplates and study their multifunctional competence in the accomplishment of enhanced catalytic organic conversion and highly efficient photocatalytic and electrocatalytic H2 evolution reactions. The as-synthesized nanoplates were characterized by using various techniques including X-ray diffraction, field emission scanning electron microscopy-energy-dispersive X-ray analysis, transmission electron microscopy, UV-vis diffuse reflectance spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and BET surface area studies. The significant catalytic performance was shown by 1% Ag-doped WO3 nanoplates with 100% glycerol conversion and 90% triacetin selectivity. The photocatalytic activity was also examined toward water splitting H2 evolution reaction which demonstrates the highest H2 evolution of 12.06 mmol g-1 catalyst for 1% Ag-doped WO3 nanoplates in a time span of 8 h. Moreover, the electrocatalytic hydrogen evolution reaction was also monitored in acidic media (0.1 M H2SO4) which demonstrates good results for 1% Ag-doped WO3 nanoplates with a low overpotential of 0.53 V and a low Tafel slope of 40 mV dec-1.

Organochalcogen substituted dimesityl borane-imidazoles as fluorogenic fluoride and cyanide sensors in aqueous media.

Natural and anthropogenic activities leading to excessive toxic biological anions in water have warranted the development of anion sensors, especially for cyanide (CN-) and fluoride (F-) ions in aqueous media. Herein, a contemporary synthetic route to embed organochalcogen compounds (-SPh and -SePh) in a boron-functionalized imidazole scaffold via metal halogen exchange is reported. Upon methylation, fluorogenic compounds 5-dimesitylboryl-2-phenylthio-1-methylimidazole (7) and 5-dimesitylboryl-2-phenylselone-1-methylimidazole (8) form the corresponding imidazolium salts, 5-dimesitylboryl-2-phenylthio-1-methylimidazolium iodide (9) and 5-dimesitylboryl-2-phenylselone-1-methylimidazolium iodide (10), which are non-luminescent. All of the compounds are thoroughly characterized, and their utility in sensing F-, CN-, and various other biologically relevant halides has been studied through UV-vis and fluorescence spectroscopy. The substrates and products of 1 : 1 binding of anions (F-/CN-) with the compounds have been established by spectroscopy, spectrometry, single-crystal X-ray crystallography, and first principles quantum mechanical theoretical calculations. The superior binding ability and micromolar sensitivity towards CN- ions over other anions in aqueous media were elucidated. The reversibility of compound 7 was also tested and it was found that fluoride binding was reversible while cyanide binding was not.

Hydroxyalkynyl uracil derivatives as NNRTIs against HIV-1: in silico predictions, synthesis, docking and molecular dynamics simulation studies.

To improve rationally the efficacy of the non-nucleoside human immunodeficiency virus (HIV-1) inhibitors, it is important to have a precise and detailed understanding of the HIV-1 reverse transcriptase (RT) and inhibitor interactions. For the 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) type of nucleoside reverse transcriptase inhibitors (NNRTIs), the H-bond between the N-3H of the inhibitor and the backbone carbonyl group of K101 represents the major hydrophilic interaction. This H-bond contributes to the NNRTI binding affinity. The descriptor analyses of different uracil derivatives proved their good cell internalization. The bioactivity score reflected higher drug likeness score and the ligands showed interesting docking results. All molecules were deeply buried and stabilized into the allosteric site of HIV-1 RT. For majority of molecules, residues Lys101, Lys103, Tyr181 and Tyr188 were identified as key protein residues responsible for generation of H-bond and major interactions were similar to all known NNRTIs while very few molecules interacted with residues Phe227 and Tyr318. The TOPKAT protocol available in Discovery Studio 3.0 was used to predict the pharmacokinetics of the designed uracil derivatives in the human body. The molecular dynamics (MD) and post-MD analyses results reflected that the complex HIVRT:5 appeared to be more stable than the complex HIVRT:HEPT, where HEPT was used as reference. Different uracil derivatives have been synthesized by using uracil as starting material and commercially available propargyl bromide. The N-1 derivative of uracil was further reacted with sodamide and different aldehydes/ketones bearing alkyl and phenyl ring to obtain hydroxyalkynyl uracil derivatives as NNRTIs.Communicated by Ramaswamy H. Sarma.

Modified, Solvothermally Derived Cr-doped SnO2 Nanostructures for Enhanced Photocatalytic and Electrochemical Water-Splitting Applications.

Cr-doped SnO2 nanostructures with a dopant concentration ranging from 1 to 5% have been successfully prepared using low-temperature modified solvothermal synthesis. The as-prepared nanoparticles showed a rutile tetragonal structure with a rough undefined morphology having no other elemental impurities. The particle shape and size, band gap, and specific surface area of the samples were investigated by scanning electron microscopy, transmission electron microscopy (TEM), high-resolution TEM, UV-visible diffused reflectance spectroscopy, and Brunauer-Emmett-Teller surface area studies. The optical band gap was found in the range of 3.23-3.67 eV and the specific surface area was in the range of 108-225 m2/g, which contributes to the significantly enhanced photocatalytic and electrochemical performance. Photocatalytic H2 generation of as-prepared Cr-doped SnO2 nanostructures showed improved effect of the increasing dopant concentration with narrowing of the band gap. Electrochemical water-splitting studies also stressed upon the superiority of Cr-doped SnO2 nanostructures over pristine SnO2 toward hydrogen evolution reaction and oxygen evolution reaction responses.

A Significant Role of Chemistry in Drug Development: A Systematic Journey from Traditional to Modern Approaches with Anti-HIV/AIDS Drugs as Examples.

BACKGROUND: Traditionally, various plant extracts having interesting biological properties were the main source of new drugs. In the last 30 years, the role of chemistry in combination with new technologies, like various computational techniques in chemistry, has witnessed a major upsurge in drug discovery and targeted drug delivery. OBJECTIVE: This article provides a succinct overview of recent techniques of chemistry that have a great impact on the drug development process in general and also against HIV/AIDS. It focuses on new methods employed for drug development with an emphasis on in silico studies, including identifying drug targets, especially the proteins associated with specific diseases. METHODS: The rational drug development process starts with the identification of a drug target as the first phase, which helps in the computer-assisted design of new drug molecules. Synthetic chemistry has a major impact on the drug development process because it provides new molecules for future study. Natural products based semisynthesis or microwave assisted synthesis is also involved in developing newly designed drug molecules. Further, the role of analytical chemistry involves extraction, fractionation, isolation and characterization of newly synthesized molecules. RESULTS: Chemistry plays a key role in drug discovery and delivery by natural process or with the help of synthetic nanoparticles or nanomedicines. So, nanochemistry is also deeply involved in the development of new drugs and their applications. CONCLUSION: The previous era of drug discovery was dominated only by chemistry, but the modern approaches involve a comprehensive knowledge of synthetic chemistry, medicinal chemistry, computational chemistry and the concerned biological phenomenon.

Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2.

A new series of quinoline derivatives has been designed and synthesized as probable protease inhibitors (PIs) against severe acute respiratory syndrome coronavirus 2. In silico studies using DS v20.1.0.19295 software have shown that these compounds behaved as PIs while interacting at the allosteric site of target Mpro enzyme (6LU7). The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with His41, His164, Glu166, Tyr54, Asp187, and showed π-interaction with His41, the highly conserved amino acids in the target protein. Toxicity Prediction by Komputer Assisted Technology results confirmed that the compounds were found to be less toxic than the reference drug. Further, molecular dynamics simulations were performed on compound 5 and remdesivir with protease enzyme. Analysis of conformational stability, residue flexibility, compactness, hydrogen bonding, solvent accessible surface area (SASA), and binding free energy revealed comparable stability of protease:5 complex to the protease: remdesivir complex. The result of hydrogen bonding showed a large number of intermolecular hydrogen bonds formed between protein residues (Glu166 and Gln189) and ligand 5, indicating strong interaction, which validated the docking result. Further, compactness analysis, SASA and interactions like hydrogen-bonding demonstrated inhibitory properties of compound 5 similar to the existing reference drug. Thus, the designed compound 5 might act as a potential inhibitor against the protease enzyme.Communicated by Ramaswamy H. SarmaHighlightsQuinoline derivatives have been designed as protease inhibitors against SARS-CoV-2.The compounds were docked at the allosteric site of SARS-CoV-2-Mpro enzyme (PDB ID: 6LU7) to study the stability of protein-ligand complex.Docking studies indicated the stable ligand-protein complexes for all designed compounds.The Toxicity Prediction by Komputer Assisted Technology protocol in DS v20.1.0.19295 software was used to evaluate the toxicity of the designed quinoline derivatives.Molecular dynamics studies indicated the formation of stable ligand-Mpro complexes.

Microfluidics-based generation of cell encapsulated microbeads in the presence of electric fields and spatio-temporal viability studies.

Microfluidics based techniques for generation of cell-laden microbeads are emerging as an attractive route to 3D cell encapsulation due to the precise control provided by microfluidics. However, existing microfluidics based cell encapsulation methods are restricted to 2D planar devices and use of passive methods for droplet generation. In this work, we report the development of a 3D glass-PDMS (polydimethylsiloxane) hybrid device for complete on-chip generation of cell-laden alginate beads in the presence of electric fields. The 3D hybrid device allows application of electric fields for active control of droplet (sodium alginate) size without the need for electrode patterning or liquid electrodes. Chemical gelation is achieved through on-chip coalescence of sodium alginate droplets and calcium chloride plugs, generated using coflow and T-junction geometries respectively. Using this approach, we successfully encapsulate E. coli cells (with viability ∼90 %) into alginate microbeads and perform comprehensive spatio-temporal growth and viability studies. The active control of droplet size coupled with complete on-chip gelation demonstrated here is a promising technology for cell encapsulation with applications such as cell therapy, organ repair, biocatalysis, and microbial fuel cells.

Ligand sensing enhances bacterial flagellar motor output via stator recruitment.

It is well known that flagellated bacteria, such as Escherichia coli, sense chemicals in their environment by a chemoreceptor and relay the signals via a well-characterized signaling pathway to the flagellar motor. It is widely accepted that the signals change the rotation bias of the motor without influencing the motor speed. Here, we present results to the contrary and show that the bacteria is also capable of modulating motor speed on merely sensing a ligand. Step changes in concentration of non-metabolizable ligand cause temporary recruitment of stator units leading to a momentary increase in motor speeds. For metabolizable ligand, the combined effect of sensing and metabolism leads to higher motor speeds for longer durations. Experiments performed with mutant strains delineate the role of metabolism and sensing in the modulation of motor speed and show how speed changes along with changes in bias can significantly enhance response to changes in its environment.

Anti-HIV potential of diarylpyrimidine derivatives as non-nucleoside reverse transcriptase inhibitors: design, synthesis, docking, TOPKAT analysis and molecular dynamics simulations.

In view of the low toxicity of NNRTIs in comparison to NRTIs, a new series of diarylpyrimidine derivatives has been designed as NNRTIs against HIV-1. In silico studies using DS 3.0 software have shown that these compounds behaved as NNRTIs while interacting at the allosteric site of HIV-RT. The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Tyr181, Tyr318 and π- interactions with Tyr181, Tyr188, Phe227 and Trp229 amino acid residues located in the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-RT protein. The intended molecules have shown high binding affinity with HIV-1 RT, analogous to standard drug molecule-etravirine. TOPKAT results confirmed that the designed compounds were found to be less toxic than the reference drug. Further, employing molecular dynamics simulations, the complexes of the best screened compound 6 and etravirine with the HIV-1 RT protein were analyzed by calculating the RMSD, RMSF, Rg, number of hydrogen bonds, principal components of the coordinates, molecular mechanics-Poisson-Boltzmann surface area-based binding free energy and their decomposition for different interactions. The analysis demonstrated the higher stability of compound 6 than the standard drug etravirine with HIV-1 RT. The interactions like hydrogen-bonding, van-der-Waals, electrostatic and the solvent accessible surface energy have favorable contributions to the complex stability. Thus, the shortlisted designed compound has great promise as a potential inhibitor against HIV-1 RT.

Multifunctional Efficacy of Environmentally Benign Silver Nanospheres for Organic Transformation, Photocatalysis, and Water Remediation.

Highly crystalline and monophasic silver nanospheres with a high specific surface area of 57 m2/g have been synthesized by an environmentally benign rapid chemical reduction using l-alanine for catalytic transformation, photocatalytic degradation, and bacterial disinfection, which can provide an ample strategy for water remediation. Electron microscopic analysis confirms the spherical morphology of as-prepared silver nanoparticles with an average grain size of 20 nm. Silver nanospheres showed excellent catalytic activity for the catalytic hydrogenation and conversion (95.6%) of 4-nitrophenol to 4-aminophenol. Significant photocatalytic degradation proficiency was also shown for methylene blue (94.5%) and rhodamine B (96.3%) dyes under solar irradiation. The antibacterial behavior of Ala-Ag nanospheres was demonstrated through the disk diffusion antibacterial assay against Gram-positive (Escherichia coli) and Gram-negative (Staphylococcus aureus) bacteria. Multifunctional efficiency of as-prepared Ala-Ag nanospheres for water remediation has also been established.

Alkylated benzimidazoles: Design, synthesis, docking, DFT analysis, ADMET property, molecular dynamics and activity against HIV and YFV.

A series of alkylated benzimidazole derivatives was synthesized and screened for their anti-HIV, anti-YFV, and broad-spectrum antiviral properties. The physicochemical parameters and drug-like properties of the compounds were assessed first, and then docking studies and MD simulations on HIV-RT allosteric sites were conducted to find the possible mode of their action. DFT analysis was also performed to confirm the nature of the hydrogen bonding interaction of active compounds. The in silico studies indicated that the molecules behaved like possible NNRTIs. The nature - polar or non-polar and position of the substituent present at fifth, sixth, and N-1 positions of the benzimidazole moiety played an important role in determining the antiviral properties of the compounds. Among the various compounds, 2-(5,6-dibromo-2-chloro-1H-benzimidazol-1-yl)ethan-1-ol (3a) showed anti-HIV activity with an appreciably low IC50 value as 0.386 × 10-5µM. Similarly, compound 2b, 3-(2-chloro-5-nitro-1H-benzimidazol-1-yl) propan-1-ol, showed excellent inhibitory property against the yellow fever virus (YFV) with EC50 value as 0.7824 × 10-2µM.

Synthesis, docking, ADMET prediction, cytotoxicity and antimicrobial activity of oxathiadiazole derivatives.

A series of molecules bearing oxathiadiazole, a five membered heterocyclic ring has been designed, synthesized and screened for antimicrobial activity. Molecules, 1a, 1b, 1d, 3a-b and 4a-b were found to be highly active (MIC value upto 1.5 µg/mL) against different human pathogens, namely S. aureus, B. cerus, P. aeruginosa and E. coli. Some of the compounds, 1a, 1b and 1d have also shown the antifungal activity (MIC value upto 6.2 µg/mL) against Candida albicans, Candida glubrate and Candida crusei. During in vitro cytotoxicity study, the oxathiadiazole derivatives showed less toxicity than the reference used against PBM, CEM and Vero (African green monkey kidney) cell lines. Docking studies suggested that all designed ligands interacted well within active site of PDF enzyme (PDB ID: 1G2A). Oxathiadiazole ring of all ligands formed H-bond with amino acid Leu91 at a distance ranging between 2.5-2.8 Å and also exhibited π - + and π - π interactions with amino acid residues Arg97 and His132, respectively. In silico ADMET evaluations of compounds showed more than 90% intestinal absorption for all compounds except 4b (87.45%), which too was greater than the reference drugs sulfamethoxazole (76.46%) and chloramphenicol (69.94%). TOPKAT results also supported the lower cytotoxicity of all compounds.

Deep Learning in Drug Discovery and Medicine; Scratching the Surface.

The practice of medicine is ever evolving. Diagnosing disease, which is often the first step in a cure, has seen a sea change from the discerning hands of the neighborhood physician to the use of sophisticated machines to use of information gleaned from biomarkers obtained by the most minimally invasive of means. The last 100 or so years have borne witness to the enormous success story of allopathy, a practice that found favor over earlier practices of medical purgatory and homeopathy. Nevertheless, failures of this approach coupled with the omics and bioinformatics revolution spurred precision medicine, a platform wherein the molecular profile of an individual patient drives the selection of therapy. Indeed, precision medicine-based therapies that first found their place in oncology are rapidly finding uses in autoimmune, renal and other diseases. More recently a new renaissance that is shaping everyday life is making its way into healthcare. Drug discovery and medicine that started with Ayurveda in India are now benefiting from an altogether different artificial intelligence (AI)-one which is automating the invention of new chemical entities and the mining of large databases in health-privacy-protected vaults. Indeed, disciplines as diverse as language, neurophysiology, chemistry, toxicology, biostatistics, medicine and computing have come together to harness algorithms based on transfer learning and recurrent neural networks to design novel drug candidates, a priori inform on their safety, metabolism and clearance, and engineer their delivery but only on demand, all the while cataloging and comparing omics signatures across traditionally classified diseases to enable basket treatment strategies. This review highlights inroads made and being made in directed-drug design and molecular therapy.

Supervised learning reveals circulating biomarker levels diagnostic of hepatocellular carcinoma in a clinically relevant model of non-alcoholic steatohepatitis; An OAD to NASH.

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH) HCC manifests in the absence of cirrhosis. Given the sheer size of the ongoing non-alcoholic fatty liver disease (NAFLD) epidemic and the dismal prognosis associated with late-stage primary liver cancer there is an urgent need for HCC surveillance in the NASH population. Using serum levels of HCC biomarkers as vectors and biopsy-proven HCC or no HCC as outputs / binary classifier, a supervised learning campaign was undertaken to develop a minimally invasive technique for making a diagnosis of HCC in a clinically relevant model of NASH. Adult mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. In this training set, receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of ≥ 0.89. Serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) diagnostic for HCC were confirmed in a test set comprising mice on control diet or FFD and mice subjected to hepatic ischemia-reperfusion injury. These data suggest that levels of circulating OPN, AFP and DKK1 can be used to make a diagnosis of HCC in a clinically relevant model of NASH.

Synthesis, antibacterial activity, synergistic effect, cytotoxicity, docking and molecular dynamics of benzimidazole analogues.

A series of 2-Cl-benzimidazole derivatives was synthesized and assessed for antibacterial activity. Antibacterial results indicated that compounds 2d, 2e, 3a, 3b, 3c, 4d and 4e showed promising activity against B. cerus, S. aureus and P. aeruginosa (MIC: 6.2 µg/mL) and excellent efficacy against E. coli (MIC: 3.1 µg/mL). Furthermore, compounds 3d and 3e displayed better activity (MIC: 3.1 µg/mL) than the reference drugs chloramphenicol and cycloheximide against gram positive and gram negative bacterial strains. The compounds 3d-e also showed better activity than the reference drug paromomycin against B. cerus and P. aeruginosa and showed similar inhibition pattern against S. aureus and E. coli. (MIC: 3.1 µg/mL). Studies on fractional inhibitory concentration (FIC) determination of compounds 1a-e, 2a-c, 4a-c and the reference antibiotic via combination approach revealed a synergistic effect as the MIC values were lowered up to 1/8th to 1/33rd of the original MIC. In-vitro cytotoxicity study indicated that 2-Cl-benzimidazole derivatives showed less toxicity than the reference used against PBM, CEM and Vero cell lines. Docking studies and MD simulations of compounds on bacterial protein (eubacterial ribosomal decoding A site, PDB: 1j7t) have been conducted to find the possible mode of action of the molecules. In silico ADMET evaluations of compounds 3d and 3e showed promising results comparable to the reference drugs used in this study.

Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole.

A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50-3.1 µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination - varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4-32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.

Escherichia coli modulates its motor speed on sensing an attractant.

It is well known that Escherichia coli achieves chemotaxis by modulating the bias of the flagellar motor. Recent experiments have shown that the bacteria vary their swimming speeds as well in presence of attractants. However, this increase in the swimming speed in response to the attractants has not been correlated with the increase in the flagellar motor speed. Using flickering dark-field microscopy, we measure the head-rotation speed of a large population of cells to correlate it with the flagellar motor speed. Experiments performed with wild-type and trg-deletion mutant strains suggest that the cells are capable of modulating the flagellar motor speed via mere sensing of a ligand. The motor speed can be further correlated with the swimming speed of the cells and was found to be linear. These results suggest the existence of a hitherto unknown intra-cellular pathway that modulates the flagellar motor speed in response to sensing of chemicals, thereby making chemotaxis more efficient than previously known.