Anti-Infective Agents - Volume 18, Issue 2, 2020

Leishmaniasis is a major tropical disease. There is no effective vaccine against leishmaniasis and chemotherapy is still the most effective treatment for the disease. However, most of the common drugs have many disadvantages such as toxicity and high cost. Most important of all is the development of resistance against these drugs. Many studies have tried to provide new pharmaceutical agents and formulations in various ways to overcome these problems. In recent years, medical plants have been widely considered for leishmaniasis treatment. Besides, various drug delivery strategies have been studied for the treatment of leishmaniasis in order to increase activity and reduce the side effects of the drugs. Accordingly, nanotechnology will play an important role in the preparation of new pharmaceutical formulations. In this review, we focused on various therapeutic approaches for leishmaniasis.

Background: A series of 2-aminothiazole schiff’s bases (1-24) were synthesized and screened against a few neglected tropical disorders (NTDs). Compounds 12 and 14 were found to have antitrypanosidal activity, whereas compound 14 was found to be more effective than standard benznidazole. The antiplasmodial assay provided three specific and effective compounds (9, 12 and 24) than standard chloroquine. Compound (21) inhibited Leishmania infantum, almost similar to Miltefosine. Methods: All the compounds were subjected to cytotoxicity assay and none of the compounds were found to be cytotoxicity. Molecular docking simulations revealed that four compounds (1, 9, 12 and 21) were found to similarly occupy the hydrophobic active site of trans-2-enoyl acyl carrier protein reductase of P. falciparum (PfENR) as triclosan and outcomes were closely related to their anti-malarial potencies. Results and Conclusion: The screening results against T. cruzi, T. brucei, L. donovani, L. infantum, P. falciferum and cytotoxicity assays provided a few significant to most potent compounds; two variant class of NTDs.

Background: The prevalence of anti-drug resistance by disease causing microorganisms has necessitated the search for alternative sources of drugs for the treatment of the ailments caused by these microorganisms. This study examines the biological properties of extracts from the leaves of Irvingia gabonensis (bush mango). Objective: The objective of this study is to determine the anti-microbial activity of chloroform fraction of the leaf extract and compare it with that of clinical reference. Methods: Antimicrobial activity of the chloroform fraction of the leaf extract of Irvingia gabonensis was evaluated against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Shigella dysenteriae, Salmonella typhi, Klebsiella pneumonia, Salmonella paratyphi, Candida albicans and Trichophyton rubrum by using the agar well diffusion method and Mycobacterium tuberculosis using agar proportion method on Lowenstein–Jensen medium. Preliminary phytochemical screening of the chloroform leaf fraction was done using qualitative standard methods. Results: This showed the presence of saponins, flavonoids, tannins, coumarin, phenol and alkaloids. Organisms were susceptible to chloroform fraction at different concentrations. The lowest MIC value obtained was 0.625mg/mL for S. aureus and S. typhi. While, five out of seven mycobacterial strains that were used, were susceptible. Conclusion: The antimicrobial activity is a result of the phytochemicals present in leaf. Therefore, we conclude that Irvingia gabonensis leaves can be used in the development of new pharmaceuticals research activities such as drug production.

Background: Nosocomial infection is a serious threat to hospitalized patients in healthcare when last-resort antibiotics do not act against pathogenic bacteria. Aims: The aim of this study was to study the effect of Polypropylene imine nanocomposite (PPI/CNT) on Gram-Positive and Gram-Negative bacteria. Methods: PPI/CNT component was produced. Surface morphology and structure of PPI/CNT were analyzed by Fourier-transform infrared (FTIR), Scanning Electron Microscopy (SAM) and Transmission Electron Microscopy (TEM). Minimum Inhibitory Concentration (MIC) of PPI/CNT was determined against various bacteria. Results: FTIR showed strong and wider peak binding molecules in the CNT/COOH and PPI/CNT component. PPI/CNT component was denser in comparison to low carbon nanotube according to SAM test. TEM images showed that carbon nanotube was covered by PPI dots. The lowest MIC concerns polymer particles for Staphylococcus epidermidis were 0.0025 μM/ml and Mycobacterium smegmatis 0.005 μM/ml. Conclusion: Our result indicated that PPI/CNT nanocomposite had good activity against Gram-positive and Gram-negative bacteria. Some of the gram-negative bacteria were tolerant up to highest concentration. With more investigations, it can be used as a new antibacterial component.

Background: High-throughput screening (HTS) of large-compound libraries is a convenient and cost-effective tool for novel drug discovery. However, in many cases, HTS platforms are not well adapted to perform cell-based screening assay with simultaneous identification of the mechanism of action for active compounds. Methods: Previously, we have described a unique double-reporter system that can be used to reveal compounds having antibacterial activity. This construction is based on two genes of Katushka2S and RFP that encode proteins with different imaging signature. The upregulated expression of the first gene attributes directly to translation inhibition in prokaryotes while the high expression of the second one is unambiguously associated with DNA biosynthesis restriction (SOS-response). Results: In the current work, we have applied this system for the identification of novel smallmolecule compounds with antibacterial activity in HTS scale. Compounds were selected from the ChemDiv in-house collection (of total 47K molecules) following the maximum diversity in structure. Based on the obtained results, we have revealed a small series of tetrahydrocarbazole derivatives with antibacterial activity. The hit compound inhibited bacterial growth with a MIC value of 21 μg/ml and blocked DNA biosynthesis. No activity towards translation has been observed. In spite of a relatively moderate potency, as compared to the control sample (erythromycin, MIC=3 μg/ml), this molecule provides good selectivity index (SI>333, HEK239). Conclusion: Tetrahydrocarbazole derivatives can be properly regarded as an attractive starting point for further development and optimization.

Background: In this study, synthesis of some novel 1-(3-(4-chlorophenylimino)-3,4- dihydroquinoxalin-2-yl)-3-substituted phenyl-1H-pyrazole-4-carbaldehyde were done by cyclization of dehydrated hemiketal using VilsmeierHaack reaction. The structures of synthesized compounds were in accordance of the basis of IR, 1HNMR, Mass spectral data and elemental analyses. The synthesized compounds had given good yields and high purity. Methods: The antimicrobial activity of the synthesized compounds was preliminarily screened by paper disc diffusion technique. The determination of minimum inhibitory concentrations (MIC) of the synthesized compounds were done by using tube dilution method. Results and Conclusion: All the screened compounds showed antibacterial and antifungal activity against selected strains of Gram positive and Gram negative bacteria and two strains of fungus, respectively but exhibited considerably less activity when compared to the reference drug ciprofloxacin and Fluconazole for antibacterial and antifungal activity, respectively. Among the synthesized compounds VV5 exhibited significant activity.

Background: A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole-pyrimidine derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. Objectives: The current research aimed to synthesize and evaluateed pyrazole-pyrimidine based antitubercular agents by an in vitro microbial study based on our previously reported 3D-QSAR. Methods: The designed molecules were synthesised via chalcone intermediate and cyclisation using guanidine and urea. The molecules were then characterized by various spectroscopic methods like IR, MASS, 1H-NMR, 13C-NMR and in vitro evaluation against M. tuberculosis H37Rv. They were further evaluated under anaerobic condition and their intracellular assay was studied. The compounds were further examined for cytotoxicity towards eukaryotic cells. Results: Compounds 3a, 3c and 3i were found to be the most effective against M. tuberculosis H37Rv, with IC50 of 16μM, 13μM and 15μM, respectively. Conclusion: The designed strategy, to enhance the antitubercular activity against M. tuberculosis H37Rv, was proved fruitful. On considering the overall data, the promising results would be useful to design the next target with improved efficacy and potency of compounds for further medicinal importance.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) causes infection in the wound leading to life-threatening bacteriemia. It causes recalcitrant infections because of being resistant to various antibiotics. The recent studies reported clindamycin to be effective against MRSA rather than inducible clindamycin resistance and decrease the incidence of new infections after clindamycin treatment. The study focused on assessing the efficacy and safety of clindamycin against MRSA infected rats. Methods: The rats become neutropenic by intraperitoneal administration of cyclophosphamide at a dose of 150 mg/kg and 100 mg/kg for 4 days and 5th day respectively. The neutropenic rats were infected with MRSA by subcutaneous administration of 106 CFU/ml of MRSA. The 3 groups of rats such as Normal, MRSA infected, MRSA infected rats that were administered clindamycin orally at a dose of 90 mg/kg/ thrice daily for 14 days were used in the study. The abscess size, weight, and bacterial load were measured at the end of the study. The blood and liver samples were collected for biochemical analysis and histopathological evaluation. Results: The MRSA was confirmed by Polymerase Chain Reaction (PCR) method. The clindamycin minimum inhibitory concentration was 0.125 - 0.5 μg/ml. The MRSA showed negative D test for clindamycin indicating the absence of inducible clindamycin resistance. The decreased abscess size, weight, bacterial count, Intestinal Alkaline Phosphatase (IAP), weight loss, alteration in hematological parameters, mild changes in cholesterol, ALT and liver histology, no significant (P > 0.05) change in triglycerides, AST, ALP, bilirubin, lactate, urea, and creatinine were seen in clindamycin treated MRSA infected rats. The MRSA infected clindamycin treated rats showed mild irritation and diarrhea. Conclusion: Our study concludes that the clindamycin showed better anti- MRSA activity and tolerable adverse effects such as anemia, weight loss, and mild irritation after oral treatment, but the intestinal dysbiosis is a severe adverse effect and causes diarrhea.

Background: Drug-phytochemical interactions sometimes result in various unpredictable outcomes. Objectives: The aim of this study was to evaluate the in vivo antiplasmodial activity of the aqueous leaf extract of Telfairia occidentalis and its potentiation of the activity of Amodiaquine (AQ) and dihydroartemisinin (DHA) on mice infected with Plasmodium berghei. Methods: Phytochemical screening of the extract was carried out using standard procedures. The extract prepared in 250 and 500 mg/kg/body weight together with amodiaquine and dihydroartemisinin were administered as a single dose and in combination to albino mice by oral gavage, adopting the standard procedures of prophylactic, suppressive and curative antiplasmodial assay models. Results: Phytochemical screening of the extract confirms the abundance of alkaloids, saponins and tannins. The analysis reveals a significant (p < 0.05) competitive reduction of parasitaemia by the conventional drugs and the extract in a dose-dependent order. The aqueous extract of T. occidentalis at 250 and 500 mg/kg gave a percentage parasitaemia reduction of 83.90 % and 85.00%, respectively when compared with the negative control. The concurrent administration of the extract and the drugs produced a synergistic effect in a dose-dependent order. When AQ plus DHA waer administered concurrently with 250 mg/kg and 500 mg/kg of extract, the percentage reduction in parasitaemia increased to 99.50 % and 99.59%, respectively. Conclusion: This shows that the aqueous extract of T. occidentalis possesses significant (p < 0.05) antiplasmodial activity which is comparable to AQ and DHA. It also enhances the efficacy of the standard drugs which indicates an advantage in the treatment of uncomplicated falciparum malaria.

Background: With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized novel piperidone fused dipeptide (DPPS) derivatives possessing dual action such as acetylcholinesterase (AChE) and beta-amyloid peptide (Aβ) aggregation inhibition. Designed peptide was synthesized by solid phase peptide synthesis using FMOC chemistry protocol and characterized by mass spectroscopy. Methods: The amino acid sequence in peptide was analyzed by LC-MS-MS. In silico docking analysis was carried out using GLIDE software. The docking score using GLIDE was found to be -7.88 against AChE and -9.74 against BACE1 enzyme. In vitro enzyme inhibition assay was carried out for AChE enzyme and BACE1 enzyme. Results: The IC50 values of AChE inhibition and BACE1 of DPPS were found to be 0.4796 μM/ml and 0.0154 μM/ml, respectively. The correlation of in silico and in vitro results showed that DPPS possessed a greater ability to inhibit BACE1 enzyme.

Background: In the prokaryotic unicellular bacteria, Streptomyces species are the most frequent producers of bioactive secondary metabolites. Our continuous quest for new antibiotics from Actinomycetes genera was put forward for isolation of a strain Streptomyces sp. 150 from the soil samples collected at the Daegu University premises in Korea. Objectives: The aims of this study were to isolate and identify bioactive compounds from the isolated microorganism and assess the efficacy of the compounds in controlling foodborne pathogens and phytopathogens. Methods: The isolated bacterium was characterized by the taxonomic analyses and a compound was isolated from the fermentation broth by applying different chromatographic techniques e.g., column chromatography, TLC and PTLC. The structure of the compound was established by UV, IR, 1H-NMR and 13CNMR spectral data analyses. The antibacterial and antifungal efficacy of the compound was assessed by disc diffusion assay, poisoned food technique, MIC determination and SEM analysis. Results: Different chromatographic techniques resulted in isolation and purification of a secondary metabolite from the fermentation broth of Streptomyces sp. 150. The analyses of the spectroscopic data identified the compound as cyclo(L-Pro-L-Tyr). The compound exhibited potential efficacy in controlling all the seven foodborne pathogenic bacteria with corresponding inhibition zone and minimum inhibitory concentration (MIC) ranging from 15.1 to 20.1 mm and 15.6 to 62.5 μg/mL respectively, and tested phytopathogenic fungi with mycelium growth inhibition varying from 57.1 to 68.5% and MIC from 125 to 250 μg/mL. Moreover, in scanning electron microscopy, the compound was found to bring morphological changes in Listeria monocytogenes ATCC 19166 at MIC dose. Conclusion: This study demonstrated the possibility to use the compound cyclo(L-Pro-L-Tyr) in food and agrochemical industries to control foodborne pathogens and phytopathogens.

Background: Leishmaniasis is a major health problem which is caused by the protozoan parasite of the genus Leishmania. Cutaneous leishmaniasis is one type of leishmaniasis and selflimited in most of the cases. However, when the lesions come with scars, they make a deep lifelong stigma. Despite being WHO's research priority, the optimum treatment for this disease has not been found yet. The current study aimed to synthesize and assess the activity of some new aminothiazole compounds against Leishmania major-induced cutaneous leishmaniasis in BALB/c mice. Methods: Eight new aminothiazole derivatives were synthesized and their chemical structures were characterized by spectral data 1H-NMR spectroscopy, Mass spectrophotometry and elemental analysis. L. major parasites were inoculated into the tail base of BALB/c mice and the induced lesions were treated every other day with three different doses of the synthesized compounds against meglumine antimoniate as the drug reference for two weeks. Size of the lesions was observed for three weeks and the collected data were analyzed by SPSS software. Also, these compounds are docked into the active site of 14- α-demethylase as the targets in the treatment of leishmaniasis. Results: Among the synthesized aminothiazole derivatives, compounds 1, 2, 3, 4, and 7 had good leishmanicidal effects. Docking binding energies showed that the synthesized compounds could act as inhibitors for 14- α-demethylase. Conclusion: Among the synthesized compounds, compound 3, (N-((4-chlorophenyl)(phenyl) methyl)thiazol-2-amine) was the most promising one which deserves future studies for the treatment of leishmaniasis.

Background: Rapid evolution of drug resistance and side effects of currently used drugs develop more efficacious and newer antimicrobial agents. Further, for the management of Type II Diabetes, α-gulcosidase and α-amylase inhibitors play a very important role by inhibiting the postprandial hyperglycemia. Objectives: The objective of this study was to synthesize N-aryl/N,N-dimethyl sulphonamides, investigate their antihyperglycemic and antimicrobial potential, develop QSAR model for identifying molecular descriptors and predict their binding modes and in silico ADMET properties. Methods: Synthesized derivatives were subjected to in vitro studies for their antidiabetic activity against α-glucosidase and α-amylase enzymes and antimicrobial activity. Molecular docking studies were carried out to find out molecular binding interactions of the ligand molecules with their respective targets. QSAR studies were carried out to identify structural determinants responsible for antimicrobial activity. Results: Antidiabetic study demonstrated the potent activity of two compounds 2 and 6 as α- glucosidase and α-amylase inhibitors, as well as compound 1 and 2, exhibited potent antimicrobial activity against all the tested microbes. All the compounds have more antifungal potential against Candida albicans. QSAR studies confirmed the role of molecular connectivity indices (valence first order and second order) in controlling the antimicrobial activity. Molecular docking studies supported the observed in vitro biological activities of the synthesized compounds. Conclusion: The compounds with 2,3-dimethyl substitution were found to be antidiabetic agents and molecules having bromo and 2,3-dimethyl substituents on phenyl ring have established themselves as potent antimicrobial agents. The role of valence first and 2nd order molecular connectivity indices as molecular properties were identified for antimicrobial activity and various electrostatic, hydrogen bonding and hydrophobic interactions were found to be prominent in the binding of molecules at the target site.