Current trends in development and manufacturing of higher-valent pneumococcal polysaccharide conjugate vaccine and its challenges.

Pneumococcal conjugate vaccines (PCVs) have been developed to protect against pneumococcal diseases caused by the more than 100 serotypes of the bacterium Streptococcus pneumoniae. PCVs primarily prevent pneumococcal infections such as sepsis, bacteraemia, meningitis, otitis media, pneumonia, septicaemia, and sinusitis among infants, adults, elderly, and immunocompromised individuals. The current available PCVs only cover a limited number of serotypes, and there is an immense need for developing higher-valent PCVs that can protect against non-vaccine serotypes to overcome challenges like serotype replacement and antibiotic resistance. The main challenges for developing higher valent PCVs are the complexity of the manufacturing process comprising polysaccharide fermentation, purification, modification or sizing of multiple polysaccharides and conjugation between polysaccharides and carrier proteins, the stability of the conjugates, and the immunogenicity of the vaccine. Different manufacturing processes have been explored to produce higher valent PCVs using different serotypes of S. pneumoniae and conjugation with different carrier proteins. The global coverage of higher valent PCVs are still low, mainly due to the high cost and limited supply of the vaccine. This review focuses on the existing and emerging manufacturing processes and challenges associated with higher-valent pneumococcal PCV development.

Synthesis, biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors.

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC50 value = 51.2 µM) and 5a (IC50 value = 66.2 µM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC50 = 40.0 µM). Two compounds 5a (MIC = 94.2 µg/mL) and 5f (MIC = 98.8 µg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC = 50.0 µg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.

Bioinspired Carbon Quantum Dots: An Antibiofilm Agents.

Carbon dots, very tiny carbon material with various surface passivations, have emerged as a new class of nanomaterials for various applications. Herein, we describe a simple, economical, and green approach for the synthesis of colloidal luminescent carbon dots (C-dots) by solvothermal method from fruit juice of Citrus limetta, an abundantly available plant in Asian countries. The existence of C-dots was confirmed by X-ray Diffraction and High Resolution Transmission Electron Microscopy studies. The C-dots size was observed to be 2-4 nm. We further evaluated the efficacy of C-dots to inhibit the attachment of Candida albicans MTCC 227, and biofilm formation on the polystyrene surfaces. The C-dots have effectively inhibited the attachment and formation of biofilm in Candida albicans at very low concentrations, which is hitherto unattempted. The ability of C-dots to inhibit biofilm formation may contribute to diverse applications of C-dots in biomedical field.

Microwave-assisted synthesis of novel 5-substituted benzylidene amino-2-butyl benzofuran-3-yl-4-methoxyphenyl methanones as antileishmanial and antioxidant agents.

A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50 = 52.0 ±â€¯0.09 µg/ml), 4h (IC50 = 56.0 ±â€¯0.71 µg/ml) and 4l (IC50 = 59.3 ±â€¯0.55 µg/ml) were shown significant antileishmanial when compared with standard sodium stibogluconate (IC50 = 490.0 ±â€¯1.5 µg/ml). Antioxidant study revealed that compounds 4i (IC50 = 2.44 ±â€¯0.47 µg/ml) and 4l (IC50 = 3.69 ±â€¯0.44 µg/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC50 = 3.31 ±â€¯0.34 µg/ml). Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and 4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour.

Fungal biofilm inhibition by piperazine-sulphonamide linked Schiff bases: Design, synthesis, and biological evaluation.

We report the synthesis of some new piperazine-sulphonamide linked Schiff bases as fungal biofilm inhibitors with antibacterial and antifungal potential. The biofilm inhibition result of Candida albicans proposed that the compounds 6b (IC50 = 32.1 µM) and 6j (IC50 = 31.4 µM) showed higher inhibitory activity than the standard fluconazole (IC50 = 40 µM). Compound 6d (MIC = 26.1 µg/mL) with a chloro group at the para position was found to be the most active antibacterial agent of the series against Bacillus subtilis when compared with the standard ciprofloxacin (MIC = 50 µg/mL). Compound 6j (MIC = 39.6 µg/mL) with an OH group at the ortho position showed more potent antifungal activity as compared to that of the standard fluconazole (IC50 = 50 µM) against C. albicans. Thus, the synthesized compounds 6a-k were found to be potent biofilm inhibitors as well as active antibacterial and antifungal agents. The molecular docking study of the synthesized compounds against the secreted aspartyl protease (SAP5) enzyme of C. albicans exhibited good binding properties. The in silico ADME properties of the synthesized compounds were also analyzed and showed their potential to be developed as potential oral drug candidates.

Antileishmanial evaluation of clubbed bis(indolyl)-pyridine derivatives: One-pot synthesis, in vitro biological evaluations and in silico ADME prediction.

A new series of bis(indolyl)-pyridine derivatives 6(a-m) were synthesized by Chichibabin reaction process and evaluated for antileishmanial and antibacterial activities to establish structure-activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, and ammonium acetate in the presence of camphor-10-sulfonic acid as a catalyst. The compounds 6d (IC50=102.47µM) and 6f (IC50=99.49µM) had shown promising antileishmanial against L. donovani promastigotes when compared with standard sodium stibogluconate (IC50=490.00µM). All the synthesized compounds (MIC range=41.35-228.69µg/mL) had shown potent antibacterial activity than standard ampicillin (MIC range=100.00-250.00µg/mL) against all the tested bacterial strains. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.

Antileishmanial potential of fused 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiols: Synthesis, biological evaluations and computational studies.

A series of newer 1,2,4-triazole-3-thiol derivatives 5(a-m) and 6(a-i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC50=79.0µM) and 6f (IC50=79.0µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50=490.0µM). Compounds 5b (IC50=13.96µM) and 6b (IC50=13.96µM) showed significant antioxidant activity. After performing molecular docking study and analyzing overall binding modes it was found that the synthesized compounds had potential to inhibit L. donovani pteridine reductase 1 enzyme. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives.

Novel amalgamation of phthalazine-quinolines as biofilm inhibitors: One-pot synthesis, biological evaluation and in silico ADME prediction with favorable metabolic fate.

A facile and highly efficient one-pot synthesis of phthalazine-quinoline derivatives is reported via four component reaction of phthalic anhydride, hydrazine hydrate, 5,5-dimethyl 1,3 cyclohexanedione and various quinoline aldehydes using PrxCoFe2-xO4 (x=0.1) nanoparticles as a catalyst. The synthesized compounds have been evaluated for anti-biofilm activity against Pseudomonas aeruginosa and Candida albicans. The compounds 12a (IC50=30.0µM) and 12f (IC50=34.5µM) had shown promising anti-biofilm activity against P. aeruginosa and C. albicans, respectively, when compared with standards without affecting the growth of cells (and thus behave as anti-quorum sensing agents). Compounds 12a (MIC=45.0µg/mL) and 12f (MIC=57.5µg/mL) showed significant potent antimicrobial activity against P. aeruginosa and C. albicans, respectively. Thus, the active derivatives were not only potent biofilm inhibitors but also efficient antimicrobial agents. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antimicrobial drug discovery initiatives.

Antileishmanial activity of novel indolyl-coumarin hybrids: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction.

In present work we have designed and synthesized total twelve novel 3-(3-(1H-indol-3-yl)-3-phenylpropanoyl)-4-hydroxy-2H-chromen-2-one derivatives 13(a-l) using Ho(3+) doped CoFe2O4 nanoparticles as catalyst and evaluated for their potential antileishmanial and antioxidant activities. The compounds 13a, 13d and 13h were found to possess significant antileishmanial activity (IC50 value=95.50, 95.00 and 99.00µg/mL, respectively) when compared to the standard sodium stibogluconate (IC50=490.00 µg/mL). The compounds 13a (IC50=12.40 µg/mL), 13d (IC50=13.49 µg/mL), 13g (IC50=13.24 µg/mL) and 13l (IC50=13.74 µg/mL) had shown good antioxidant activity when compared with standards butylated hydroxy toluene (IC50=16.5 µg/mL) and ascorbic acid (IC50=12.8 µg/mL). After performing molecular docking studies, it was found that compounds 13a and 13d had potential to inhibit pteridine reductase 1 enzyme. In silico ADME pharmacokinetic parameters had shown promising results and none of the synthesized compounds had violated Lipinski's rule of five. Thus, suggesting that compounds from the present series can serve as important gateway for the design and development of new antileishmanial as well as antioxidant agent.

Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction.

Herein, we report the synthesis and screening of cyano substituted biaryl analogs 5(a-m) as Peptide deformylase (PDF) enzyme inhibitors. The compounds 5a (IC50 value=13.16µM), 5d (IC50 value=15.66µM) and 5j (IC50 value=19.16µM) had shown good PDF inhibition activity. The compounds 5a (MIC range=11.00-15.83µg/mL), 5b (MIC range=23.75-28.50µg/mL) and 5j (MIC range=7.66-16.91µg/mL) had also shown potent antibacterial activity when compared with ciprofloxacin (MIC range=25-50µg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF, the synthesized compounds 5(a-m) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Bacterial Peptide Deformylase Inhibition of Tetrazole-Substituted Biaryl Acid Analogs: Synthesis, Biological Evaluations, and Molecular Docking Study.

The synthesis and screening of tetrazole-substituted biaryl acid analogs 7a-l as bacterial peptide deformylase (PDF) enzyme inhibitors is reported. The compounds 7e (IC50 value = 5.50 µM) and 7g (IC50 value = 7.25 µM) showed good PDF inhibition activity. The compounds 7e (MIC range = 10.75-11.66 µg/mL) and 7g (MIC range = 8.91-12.83 µg/mL) also showed potent antibacterial activity when compared with the standard ciprofloxacin (MIC range = 25-50 µg/mL). Thus, the active derivatives were not only potent PDF enzyme inhibitors but also efficient antibacterial agents. In order to gain more insight into the binding mode of the compounds with the PDF enzyme, the most active compounds 7e and 7g, the moderately active compound 7k, and the least active compound 7h were docked against the PDF enzyme of Escherichia coli. The docking study of the most active compounds 7e and 7g against the PDF enzyme exhibited good binding properties. Hence, we believe our synthesized compounds 7a-l could serve as reservoir for bacterial PDF inhibitor development.

Biosurfactant/s from Lactobacilli species: Properties, challenges and potential biomedical applications.

Lactic acid bacteria are generally believed to have positive roles in maintaining good health and immune system in humans. A number of Lactobacilli spp. are known to produce important metabolites, among which biosurfactants in particular have shown antimicrobial activity against several pathogens in the intestinal tract and female urogenital tract partly through interfering with biofilm formation and adhesion to the epithelial cells surfaces. Around 46 reports are documented on biosurfactant production from Lactobacillus spp. of which six can be broadly classified as cell free biosurfactant and 40 as cell associated biosurfactants and only approximately 50% of those have reported on the structural composition which, in order of occurrence were mainly proteinaceous, glycolipidic, glycoproteins, or glycolipopeptides in nature. Due to the proteinaceous nature, most biosurfactant produced by strains of Lactobacillus are generally believed to be surlactin type with high potential toward impeding pathogens adherence. Researchers have recently focused on the anti-adhesive and antibiofilm properties of Lactobacilli-derived biosurfactants. This review briefly discusses the significance of Lactobacilli-derived biosurfactants and their potential applications in various fields. In addition, we highlight the exceptional prospects and challenges in fermentation economics of Lactobacillus spp.-derived biosurfactants' production processes.

Biofilm inhibition of linezolid-like Schiff bases: synthesis, biological activity, molecular docking and in silico ADME prediction.

Herein, we report the synthesis and screening of linezolid-like Schiff bases as inhibitors of biofilm formation. The result of biofilm inhibition of Pseudomonas aeruginosa suggested that compounds 5h (IC50 value=12.97±0.33µM) and 5i (IC50 value=15.63±0.20µM) had more inhibitory activity when compared with standard linezolid (IC50=15.93±0.18µM) without affecting the growth of cells (and thus behave as anti-quorum sensing agents). The compounds 5h (MIC range=2.5-10µg/mL) and 5i (MIC range=3.5-10µg/mL) with 2-chloroquinolinyl and 2-chloro-8-methylquinolinyl motif, respectively, showed antibacterial activity in comparable range of linezolid (MIC range=2-3µg/mL) and were more potent when compared with ciprofloxacin (MIC range=25-50µg/mL). Thus, the active derivatives were not only potent inhibitors of P. aeruginosa biofilm growth but also efficient antibacterial agents. The docking study of most active compounds 5h and 5i against PqsD enzyme of P. aeruginosa exhibited good binding properties. In silico ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Synthesis, antileishmanial activity and docking study of N'-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazides.

A series of N'-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives is synthesized and evaluated for antileishmanial activity against Leishmania donovani promastigotes. Compounds 9a and 9i were shown significant antileishmanial when compared with standard sodium stilbogluconate. Antimicrobial study revealed that compound 9b has potent as well as broad spectrum antibacterial activity when compared with ampicillin and compound 9e showed promising antifungal activity when compared with miconazole. Also, none of the synthesized compounds showed cytotoxicity up to tested concentration. Further, docking study against pteridine reductase 1 enzyme of L. donovani showed good binding interactions. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Exploring antibiofilm potential of some new imidazole analogs against C. albicans: synthesis, antifungal activity, molecular docking and molecular dynamics studies.

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein.Communicated by Ramaswamy H. Sarma.

Silver-decorated orthorhombic nanotubes of lithium vanadium oxide: an impeder of bacterial growth and biofilm.

Reoccurrence of infectious diseases and ability of pathogens to resist antibacterial action has raised enormous challenges which may possibly be confronted by nanotechnology routes. In the present study, uniformly embedded silver nanoparticles in orthorhombic nanotubes of lithium vanadium oxide (LiV2O5/Ag) were explored as an impeder of bacterial growth and biofilm. The LiV2O5/Ag nanocomposites have impeded growth of Gram-positive Bacillus subtilis NCIM 2063 and Gram-negative Escherichia coli NCIM 2931 at 60 to 120 µg/mL. It also impeded the biofilm in Pseudomonas aeruginosa NCIM 2948 at 12.5 to 25 µg/mL. Impedance in the growth and biofilm occurs primarily by direct action of the nanocomposites on the cell surfaces of test organisms as revealed by surface perturbation in scanning electron microscopy. As the metabolic growth and biofilm formation phenomena of pathogens play a central role in progression of pathogenesis, LiV2O5/Ag nanocomposite-based approach is likely to curb the menace of reoccurrence of infectious diseases. Thus, LiV2O5/Ag nanocomposites can be viewed as a promising candidate in biofabrication of biomedical materials.

Evaluation of anti-quorum sensing activity of silver nanowires.

A menace of antimicrobial resistance with growing difficulties in eradicating clinical pathogens owing to the biofilm has prompted us to take up a facile aqueous-phase approach for the synthesis of silver nanowires (SNWs) by using ethylene glycol as a reducing agent and polyvinylpyrrolidone (PVP) as a capping agent. This synthesis is a reflux reaction seedless process. The obtained SNWs were about 200-250 nm in diameter and up to 3-4 µm in length. The SNWs were characterized by field emission scanning electron microscopy, transmission electron microscopy, UV-Vis spectroscopy, and X-Ray powder diffraction, and the chemical composition of the sample was examined by energy dispersive X-ray spectrum. The SNWs did not show an antibacterial activity against test organisms, Bacillus subtilis NCIM 2063 and Escherichia coli NCIM 2931; however, it showed a promising property of a quorum sensing-mediated inhibition of biofilm in Pseudomonas aeruginosa NCIM 2948 and violacein synthesis in Chromobacterium violaceum ATCC 12472, which is hitherto unattempted, by polyol approach.

Exploring the interaction of Valsartan and Valsartan-Zn(ll) complex with DNA by spectroscopic and in silico methods.

Belonging to the Sartan family, antihypertensive drug - Valsartan (Val) had been found to possess antioxidant properties. Also, the zinc complex of Valsartan (VZn) has been recently recognized as inducing agents of the reductive stress effects thus possessing anticancer activity. Hence, in this work an attempt has been made to understand the interaction of Val and VZn with DNA using spectroscopic and in silico methods as DNA has been identified as the target for many anticancer drugs. VZn has been prepared in 2:1 M ratio and characterised by absorbance, FTIR, HRMS, NMR and Job's continuous variation method. VZn has been tested against human lungs cancer cell line which exhibited good anticancer activity (IC50 = 89 µg/mL). Interaction of Val and VZn with ct-DNA under physiological conditions has been studied by spectroscopic techniques such as fluorescence, absorbance, FTIR, circular dichroism (CD) and in silico methods. Fluorescence quenching, DNA melting and viscometric studies confirmed that both ligand and complex bind to the grooves of the ct-DNA. The experimental results have revealed that VZn strongly bind with DNA compared to Val. Docking study suggested that, Val binds at major groove while VZn binds to both minor and major grooves of B-DNA.

Identification of potential antileishmanial 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-ones, in vitro metabolic stability, cytotoxicity and molecular modeling studies.

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC50 values range from 55.0 to 77.0 µg/ml, with 3m (IC50 55.75 µg/ml) being equipotent with amphotericin B (IC50 50.0 µg/ml, used as standard). The most active compound 3m, is metabolically stable in rat liver microsomes. Furthermore, the molecules are highly specific against leishmania as shown by their weak antibacterial and antifungal activity. In vitro cytotoxicity studies show the compounds lack any cytotoxicity. Furthermore, molecular modeling studies show plausibility of binding to Leishmania donovani topoisomerase 1 (LdTop1). Structure activity relationships reveal bulky substitutions on the pyridone nitrogen are well-tolerated, and such compounds have better binding affinity. Intramolecular hydrogen bonds confer some rigidity to the molecules, rendering a degree of planarity akin to topotecan. Taken together, we emphasis the merits of molecules possessing the 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one skeleton as potential antileishmanial agents warranting further investigation.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.