Anti-Infective Agents - Volume 18, Issue 4, 2020

Antibiotic resistance is one of the most prevalent, complex and serious global health issues, and needs to be monitored and controlled with medicine. Many approaches have been used to reduce the emergence and impact of resistance to antibiotics. The antimicrobial adjuvant approach is considered as novel, more effective and less expensive. The said approach not only suppresses the emergence of resistance but also conserves the activity of existing antibiotics by offering a promising strategy that is also complementary to the discovery of new antibiotics. This review contains an outline of the basic types of antibiotic adjuvant, their structure, the basis of their operation, their substrate antibiotics and the challenges in this field, as well as the role of potential compounds, namely β-lactamase inhibitors, efflux pump inhibitors and permeability enhancers in antibiotic resistance and their possible solutions.

Japanese encephalitis virus (JEV) is an arthropod-borne flavivirus that belongs to the Flaviviridae family affecting millions of people worldwide. There is no specific drug approved for the treatment of this infection and also available vaccines are not effective against all the clinical isolates. Thus, the exploration of novel mechanistic pathways of existing molecules may help to develop more effective anti-JEV agents. Abscisic acid is a naturally occurring phytohormone released particularly in stress conditions, which controls leaf abscission. Recent studies have shown that the abscisic acid has the potential to inhibit the virus by inhibiting protein disulfide isomerase enzyme, which is important for the formation of viral proteins. Apart from this, abscisic acid could also reduce the neuroinflammation (a major hallmark of JEV infection) through the stimulation of PPAR gamma. Thus, abscisic acid thereof could have the potential to develop as an anti-JEV agent.

Background: A series of Triazine Chalcone derivatives were synthesized by the condensation of 1-(4-((4,6-dimethoxy-1,3,5-triazin-2-yl)amino)phenyl)ethanone with substituted benzaldehyde in methanol solvent. Methods: All the synthesized derivatives (3a-l) were screened for their anti-bacterial evaluation against Gram negative bacteria Escherichia coli (NCIM 2137) and Pseudomonas aeruginosa (NCIM 2036); Gram positive bacteria Staphylococcus aureus, Bacillus subtilis (NCIM 2250) and four fungal stains. Candida albicans (MTCC 227), Aspergillus niger (NCIM 545), Candida tropicalis (NCIM 3110) and Candida glabrata (NCIM 3236). Results and Conclusion: Several target molecules throughout the series showed good antibacterial and antifungal activity against tested stains.

Introduction: Synthesis of new coordination complexes has gained a great interest of the inorganic chemists as well as researchers. Methods: A literature survey has revealed that main group elements as well as transition metals with ligand like Schiff’s base and many drug have the ability to form a coordinate bond. 3d-series of metal complex with chloroquine as a ligand was synthesized (ML2) stoichiometrically and characterized by conductivity, melting point, UV-spectra, TGA and X-ray analysis of coordination complexes and anti-microbial activity. Results: The synthesized metal complex was evaluated for in vitro antibacterial and antifungal activity against the bacterial strains such as Plasmodium falciparum, Pseudomonas aeruginosa, E. coli, Streptococcus, Bacillus, Staphylococcus aureus and Aspergillus niger. Conclusion: The metal complex shows very potential antibacterial as well as antifungal activity like a commercial drug. Inorganic chemistry gives us good opportunities to use metal complexes as Pharmacological agents.

Background: Plethora of literature reported hitherto, depicts impending biological activities for spirochromones. This fact encouraged us for the exploration of the synthesis of new substituted spirochromones and their evaluation of their bioactivities. Objectives: To synthesize different substituted spirochromones derivatives from a spirochromones salt using (R)-pyroglutamic acid as catalyst and their evaluation for antimicrobial and antioxidant activities. Methods: Herein, Aldol cascade method was used for the syntheses of spirochromone derivatives from its salt. A mild protocol is developed for the syntheses of spirochromones derivatives by using (R)-pyroglutamic acid as catalyst. Further, the derivatives and its precursor salt were screened for antimicrobial and antioxidant activity. The antioxidant potentials of the synthesized compounds were checked by DPPH and hydroxyl free radical scavenging assay. Consequently, in vitro antimicrobial activities were performed by well diffusion assay against gram negative bacterium (E. coli) and gram positive bacterium (S. aureus). Results: In the present work, 10 synthesized derivatives are obtained in harmonious yield from a precursor spirochromones salt using (R)-pyroglutamic acid as catalyst. Amongst the studied compounds, 6a depicted maximum antimicrobial activity against the screened microorganisms along with maximum antioxidant activity. Albeit, the synthesized motifs showed moderate to good antioxidant and antimicrobial activities. Conclusion: A mild protocol was developed for the synthesis of spirochromone derivatives from their precursor spirochromones salt by using (R)-pyroglutamic acid as catalyst, which showed moderate to good antimicrobial and antioxidant activity.

Background: Benzothiazoles possess a vast sphere of biological activities including anti- inflammatory, antibacterial activities whereas triazoles display various pharmacological properties including antimicrobial and antitubercular activities. Hence, triazole conjugated benzothiazole side-chain anticipating their interesting biological properties has been focused upon. Objective: The objective of the current work is synthesis and biological evaluation of a new series of benzothiazole appended triazole derivatives. Methods: The target compounds were prepared via a multi-step method involving the treatment of 2-amino benzothiazole with hydrazine followed by cyclization with carbon disulfide to give the corresponding triazol-2-thiol derivatives and then alkylation of these derivatives. All the synthesized compounds were characterized by FT-IR, Mass, ¹;H and ¹³C NMR spectra and were screened for their antibacterial, antioxidant, anti-inflammatory and anti-tubercular (anti-TB) activities in vitro. These molecules were also docked into the enoyl acyl carrier reductase (Inha, PDB ID-1ZID) in silico. Results: While all the synthesized compounds were active against M. tuberculosis at 50 μg/ml, the pyrrolidine and piperidine appended benzothiazolyltriazoles showed the superior activity (MIC values 12.5 to 1.6 μg/ml). Compound 5a (5-CH3 with piperidine), 5b (7-CH3 with piperidine) and 7b (7-CH3 with pyrrolidine) showed good antibacterial activity against Staphylococcus aureus with MIC value 31.25μ g/ml, while compounds 7a (5-CH3 with pyrrolidine), 6b (7-CH3 with morpholine) and 8c (7-Br with pyridine) exhibited good antibacterial activity against E-coli with MIC value 62.5μg/ml. Compounds 7b (7-CH3 with pyrrolidine) and 5c (7-Br with piperidine) showed good anti-oxidant activities with IC50 values 93.25 and 82.25, respectively. Notably, these compounds were non-toxic to the normal cells even at high concentrations with IC50 value 238μg/ml. Conclusion: The compound 7b, a benzothiazolyltriazole having a pyrrolidine group (five membered ring) attached to two CH2 groups and methyl substituent at 7th position of the benzothiazole ring emerged as a novel and promising hit molecule that showed anti-TB, antimicrobial and antiinflammatory activities in vitro.

Background: To overcome one of the resistance mechanisms of Isoniazid (INH), there is a need for an antitubercular agent that can inhibit InhA enzyme by circumventing the formation of INH-NAD+ adduct. Objective: The objective of the study is the development of novel antitubercular agents that target Mycobacterium tuberculosis InhA (Enoyl Acyl Carrier Protein Reductase). Methods: A small-molecule chemical library was used for the identification of the novel InhA inhibitors using primary screening and molecular docking studies followed by the scaffold hopping approach. The designed molecules, 2-(2-(hydroxymethyl)-1H- benzo[d] imidazole-1-yl)- N- substituted acetamides were synthesized by reacting (1H- benzo[d]imidazole -2-yl)methanol with appropriate 2-chloro-N-substituted acetamides / dialkylamino carbonyl chlorides respectively in good yields (42-65%). The antitubercular activity of synthesized compounds was determined by Microplate Alamar Blue Assay (MABA) against Mycobacterium tuberculosis H37Rv strain. The selected compounds were screened for cytotoxicity on normal cell lines. Results: The antitubercular activity data revealed that the 4-chlorophenyl substituted derivative (3b) showed good MIC value at 6.25 μg/mL and, dimethylacetamide substituted derivative (3i) showed MIC at 25 μg/mL among the tested compounds. The substitution of dimethylacetamide (3i) group on the 1^st position of benzimidazole has good antitubercular activity (25μg/mL) in comparison to the diethyl acetamide group (3j, 100μg/mL). Conclusion: The antitubercular activity data indicated that the tested compounds exhibited well to moderate inhibition of the H37Rv strains. The compounds (3b) with electronegative substitution on the phenyl moiety exhibited better antitubercular activity than that of the other substitutions. The active compounds have displayed a good safety profile on normal cell lines.

Background: The resistance of Staphylococcus aureus to commonly used antibiotics is linked to their ability to acquire and disseminate antimicrobial-resistant determinants in nature. This study determined the antibiotic sensitivity profile of Staphylococcus aureus isolated from milk samples of mastitic and healthy dairy cattle. Isolation and Identification of S. aureus was done by Marphological and Biochemical characters. Methods: The primary purpose of this study was to determine Antibiotic Sensitivity of Staphylococcus aureus by using extracts of Prosopis juliflora, Cassia occidentalis and Tephrosia purpurea. Antimicrobial properties of plant extracts were analyzed by determining Zone of Inhibition (ZOI) and Minimum Inhibitory Concentration (MIC). Antibiogram pattern of the isolated Staphylococcus aureus was observed to be Susceptible, Intermediate and Slight resistant by Prosopis juliflora, Tephrosia purpurea and Cassia occidentalis respectively. Results: From the results, it has been indicated that the extracts of Tephrosia purpurea, Prosopis juliflora and Cassia occidentalis are having potential to use in the management of Staphylococcus aureus. Conclusion: Further phytochemical analysis is required to identify the active components of plant extracts showing antimicrobial activity.

Aims: 1,3- Oxazine-2-amines synthesized by sonochemical method using green catalyst lithium hydroxide monohydrate to enhance effect in reaction time when compared to traditional methods under acoustic energy. Background: Hostile to microbials accept a noteworthy activity in the treatment of infections to the individuals and at the same time, strange, medication of higher enemy of contamination changes protections in the quality level and may turn into the purpose for the anti-microbial opposition. Objective: In this assignment, an undertaking has been made to join a couple of auxiliaries of 1, 3- oxazine-2-amines by ultrasonic irradiation with shorter reaction time also their in vitro screening was coordinated against Mycobacterium tuberculosis, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Aspergillus niger and Candida albicans. Methods: Five compounds were produced by under ultrasonic illumination within the use of lithium hydroxide monohydrate (LiOH.H2O) as a catalyst, which gave the items in great yields after short response times under mellow conditions The proposed concoction structures were affirmed by various spectroscopic systems like FTIR, 1H NMR and Mass spectroscopy. TLC was utilized to realize that the reactants were depleted and the development of the item happened. Sharp melting point of the compounds concludes the purity. All the molecules assessed for in vitro antibacterial and antifungal exercises. Antibacterial and antifungal exercises were tried utilizing the agar dispersion technique. Results: From the screening thinks about it was seen that a large portion of the compounds have indicated moderate antibacterial and antifungal inhibition at 500 μg/mL and 100 μg/mL fixations individually. The MIC of the molecules like C (Chloro), N (Nitro) demonstrated promising activity at the conenctration of 1.6 μg/ml and F (Fluoro) – 3.12 μg/ml when appeared differently in relation to measures like Pyrazinamide-3.125μg/ml, Ciprofloxacin 3.125μg/ml, Streptomycin-6.25μg/ml against Mycobacterium tuberculosis. Conclusion: The results are extremely promising which on further assessments may provoke medicine particles against different microorganisms. Especially, C, N can be considered as a far reaching range master due to its solid development against different microorganisms like Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Candida albicans.

Background: Leishmania infantum causes the most lethal form of Leishmaniasis: Visceral leishmaniasis. Current therapy for this disease is related to the development of drug-resistant species and toxicity. Trypanothione Reductase (LiTR), a validated target for the drug discovery process, is involved with parasites' thiol-redox metabolism. Methods: In this study, through Virtual Screening employing two distinct Natural Products Brazilian databases, we aimed to identify novel inhibitor scaffolds against LiTR. Results: Thus, the “top 10” LiTR-ligand energies have been selected and their interaction profiles into LiTR sites through the AuPosSOM server have been verified. Finally, Pred-hERG, Aggregator Advisor, FAF-DRUGS, pkCSM and DataWarrior were employed and their results allowed us to evaluate, respectively, the cardiotoxicity, aggregation capacity, presence of false-positive compounds (PAINS) and their toxicities. Conclusion: Three molecules that overcame the in silico pharmacokinetic analysis and have a good interaction with LiTR, were chosen to use in vitro assays hoping that our computational results reported here would aid the development of new anti-leishmanial compounds.

Background: Polyhydroxy aromatic compounds are one of the most important classes of phenolic compounds with different biological activities. Some important and biologically active phenol-based compounds have also been isolated from nature. Methods: An efficient procedure for the synthesis of polyhydroxy aromatic compounds (phloroglucide analogs) is described. In this procedure, a reaction took place between different 4-substituted phenols and 2,6-bis(hydroxymethyl) phenols. The reactions proceed in the presence of catalytic amount of silica gel supported boric tri-sulfuric anhydride (SiO2-BTSA) in excellent yields. Results: 16 compounds were synthesized (I1-I16). Chemical structures of all the compounds were confirmed by spectroscopic methods. We optimized the chemical reactions in the presence of different acidic catalysts, different solvents and also different temperatures. A catalytic amount of SiO2-BTSA in dichloroethane (DCE) was the best condition. Some of the synthesized compounds were screened for their antimicrobial activities. Antifungal and antibacterial activities of the synthesized compounds were evaluated by broth microdilution method as recommended by CLSI. Some of the tested compounds showed good in vitro biological properties. Conclusion: Our active compounds could introduce as good candidates for further studies as antimicrobial agents.

Background: Carbapenem-resistant Enterobacteriaceae (CRE) has emerged as a global threat with mortality risk ranging from 48%-71% worldwide. The emergence of MBL resistance is threatening as carbapenem is one of the last line antibiotics. A total 24 variants of NDM resistance raises a concern to the clinicians and epidemiologists worldwide. Objective: The study aims at identifying MBL resistance (NDM, IMP, VIM, GIM, SPM, and SIM) and its coexistence in clinical isolates in a single tertiary care center. Methodology: Forty five clinical isolates characterized phenotypically for Carbapenem resistance obtained from PSG Institute of Medical Science and Research (PSG IMSR), Coimbatore, between February to March 2018 were taken for analysis. Results: Out of the 45 Clinical isolates, 38 isolates (84%) were detected as MBL carriers. VIM, NDM, GIM, and SPM were the predominant resistance genes, with detection rates of 48.8% , 28.8%, 24.4%, and 22.2% respectively. Fifteen isolates were observed to harbor more than one MBL gene in coexistence. Two isolates - U42 and R714 (K. pneumoniae) were found to harbor all 5 MBL variants in combination. Conclusion: 33% of clinical isolates harboring multiple MBL variants is a concern in clinical settings. The presence of SPM and GIM gene amongst isolates in this geographical location within India is an indicator demanding continuous monitoring of these resistance determinants.