Anti-Infective Agents - Volume 10, Issue 2, 2012

The present article deals with the synthesis, antimicrobial and antimycobacterial activities of a novel series of N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)benzamides (6a-o). The structures of these compounds have been elucidated by spectra (IR, 1H NMR, 13C NMR, mass spectra). All the synthesized compounds are screened for in vitro antibacterial activity against Gram-positive (Staphylococcus aureus, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. These compounds are also tested for their inhibitory action against three strains of fungi (Candida albicans, Aspergillus niger, Aspergillus clavatus). Same synthesized compounds are also tested for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv.

Tuberculosis infections of the central nervous system are a serious and often fatal disease predominantly impacting young children. Having a success rate of approximately 10%, an in silico data mining search generated 23 analogs to isoniazid, which is a first-line tuberculostatic. All analogs retained the hydrazide functional group in addition to configurations including: quinoline, pyridine, indole, quinolin-4-ol, quinoline-2,4-diol, and pyridine-2-one. Studies have shown that brain penetration is optimal when polar surface area is less than 90 A2. Sixteen of generated analogs have polar surface area less than 70 A2 (drugs 1, 2, 3, 4, 5, 6, 8, 11, 13, 14, 15, 16, 18, 19, 22, and 23) and six analogs have values between 70 A2 to 90 A2 (drugs 7, 9, 10, 12, 17, 21). All agents showed zero violations of the Rule of 5 which indicates favorable druglikeness. The aqueous solubility, formula weight, molecular volume, polar surface area, and Log P properties are determined. Pattern recognition analysis such as hierarchical cluster analysis, discriminate analysis, and ANOSIM identified underlying relationships among these 24 drugs that is based upon important pharmaceutical properties. Global resurgence of tuberculosis and the rapid emergence of multidrug resistant tuberculosis underscore the importance of the development of new tuberculostatic drugs.

We investigated the in vitro and in vivo antimicrobial potential of a selective serotonin reuptake inhibitor sertraline hydrochloride, against clinical isolates of bacteria and Candida species. Minimum Inhibitory Concentration of sertraline against 161 human isolates of 12 Gram negative and 5 Gram positive genera, Candida albicans ATCC10231 and Candida tropicalis ATCC13803 was determined by spot inoculation, broth and agar dilution methods along with its postantibiotic effect following a short drug exposure. The toxicity and protective efficacy was tested in vivo with a mousevirulent strain of Salmonella typhimurium NCTC74.The MIC was 20-200μg/ml for bacteria, and 200μg/ml for Candida. The growth inhibitory study with Bacillus subtilis UC564 and Shigella dysenteriae NCTC599/52 revealed that the drug is bacteriostatic at its MIC and cidal at higher concentrations. Study on its post-antibiotic effect following a short drug exposure revealed that Sertraline has a time- and dose-dependent effect. Treatment for 4h at concentrations below and equipotent to the minimal static concentration resulted in a lag of regrowth at 8-24h for Candida isolates. The in vivo study with Salmonella typhimurium in Swiss mice showed that the median lethal dose was 1.9 x 107 cfu and 50 LD50 was 0.95x109. Interestingly, the drug at a non-toxic single dose provides significant protection (P<0.001) to the mice challenged with S. typhimurium. Sertraline remarkably reduced the number of viable bacteria in organ homogenates and blood of the treated animals and demonstrate both in vitro and in vivo antibacterial potential at lower dose than its predesignated pharmacological activity.

A new series of novel 1-(4-oxo-3-(3-methoxyphenyl)-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides were synthesized by the reaction of 2-hydrazino-3-(3-methoxyphenyl) quinazolin-4(3H)-one with various methyl esters of dithiocarbamic acid. When tested for their in vitro antitubercular activity using H37Rv strain on Middle brook 7H11 agar slants with OADC growth supplement, all the test compounds inhibited the growth of Mycobacterium tuberculosis at microgram concentration. Among the test compounds, three compounds 1-(4-oxo-3-(3-methoxy phenyl)-3H-quinazolin-2-yl)-4-(thiazol- 2-yl) thiosemicarbazide (A1), 1-(4-oxo-3-(3-methoxyphenyl)-3H-quinazolin-2-yl)-4-(4-chlorophenyl) thiosemi-carbazide (A6) and 1-(4-oxo-3-(3-methoxyphenyl)-3H-quinazolin-2-yl)-4-(4-nitrophenyl) thiosemicarbazide (A7) were inhibited at the 6 μg/mL concentration. The title compounds are also screened for the antimicrobial activity against some other gram positive and gram negative bacteria by agar dilution method, compounds A6 and A7 were emerged as the most active compounds of the series. Compound A6 showed most potent activity against E. coli, K. pneumoniae and B. subtilis.

Leishmaniasis is a global disease, which has become a major health challenge for Pakistan and other developing countries. Infections caused by the parasitic protozoa constitute a major hindrance in socioeconomic development in many developing countries. In this study, we developed a topical application (gel), containing active ingredients derived from garlic, on which in vitro, in vivo, and clinical studies were conducted. Anti-leishmanial activity observed in vitro was followed by in vivo study with the application of this active ingredient, prepared in gel form, and applied once daily on experimental mouse model. Their lesions cured completely within 4-6 weeks. This was followed by clinical trials in humans. A total of 70 patients, 58 (82.85%) males, and 12 (17.14%) females, were selected with positive Leishmania parasites by smear examination. Out of 70 patients, 57 patients (81.42%) responded to the treatment, while 13 patients (18.57%) did not. Ten patients (17.54%) showed complete clinical recovery after 06 weeks of therapy, while 40 (70.17%) showed complete clinical recovery after 08 weeks of therapy. The results of this clinical study establish the efficacy, and cost effectiveness of garlic-based topical gel, and pave the way for further research in its therapeutic applications.

In the present investigation, a series of 3-substituted-N-aryl-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2- c]pyrazole-2-carboxamide analogs were synthesized based on the structure of known antitubercular drug thiacetazone and were evaluated for antitubercular activity by two fold serial dilution technique. A computational study was carried out for prediction of pharmacokinetic properties and none of the compounds violated Lipinski “Rule of Five”. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. All the newly synthesized compounds showed low to good activity inhibitory activities against Mycobacterium tuberculosis H37Rv (MTB) and isoniazid resistant M. tuberculosis (INHR-MTB). 3-(4-fluoromethyl)-N-(2-chlorophenyl)-6,7-dimethoxy-3a,4- dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c) was found to be the most promising compound active against M. tuberculosis H37Rv and isoniazid resistant M. tuberculosis (INHR-MTB) with minimum inhibitory concentration 0.83 and 3.35 μM respectively.

As the human race is still threatened by prospective avian flu endemics, new motivations and systematic approaches should be placed high on agenda in order to alleviate the potential losses of both human life and local economics. A balance and comprehensive measures between economy and the ecosystem of the endemic regions must also be considered. One of the top priorities in these explorations should be effective therapy for infected patients, including better uses and applications of vaccines and antiviral agents. In order to be better prepared for prospective avian flu epidemics, experimental and theoretical inquiry of therapeutic and technical feasibilities against avian viruses in humans deserve to be priority concerned, and extensive experimental and clinical exploitations of fatal pathogenesis of virus infection in human cells at genetic and cytological levels, are urgently needed. In this review, we address and discuss these important questions and review some important solutions for avian flu in future, including antiviral agents, virus vaccinations, Chinese medicine and genetic treatment of the disease.

Enterobacteriaceae are major pediatric pathogens, but little is known regarding treatment options for multidrug-resistant strains. In this study, we investigated the susceptibility patterns of healthcare- and community-associated Enterobacteriaceae isolates expressing plasmid-borne, broad-spectrum beta-lactam resistance (PBLR). Using E-test methodology, we tested susceptibility to imipenem, meropenem, ertapenem, doripenem, piperacillin-tazobactam, minocycline, tigecycline, fosfomycin, and colistin in all 90 clinical isolates (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Salmonella enterica) which are derived from urine (n=62), blood (n=12), and other specimens (n=16). These strains are confirmed to carry PBLR determinants. Although malignancy, urogenital and neurological diseases, and multiple antibiotic exposure were present in most patients, twenty three isolates (26%) were characterized as communityassociated. Enterobacteriaceae isolates expressing PBLR retained in vitro susceptibility to colistin (100%), minocycline (72%), tigecycline (97%), and fosfomycin (92%). Five unlinked isolates (6%; two isolates of E. coli and three of K. pneumoniae) showed resistance to one or all carbapenem agents. All community-associated isolates were susceptible to carbapenems and exhibited greater susceptibility to other agents compared to healthcare-associated isolates. In our study population, carbapenems remained broadly active and colistin, fosfomycin, and tigecycline demonstrated therapeutic potential against PBLR-positive isolates. Our findings have implications for susceptibility testing and empirical antimicrobial strategies targeting serious pediatric infections.

The mechanisms by which patients infected with T. cruzi develop or not the disease are not completely understood. We investigated the importance of parasite persistence as a factor in generating cardiomyopathy. Fifty trypomastigote forms from the Tulahuen strain were used as inoculum for 160 Albino Swiss mice. Parasitemia, survival, histopathological and electrocardiographic studies were done on days 90, 180, 270 and 360 post infection (pi). Parasite presence in the tissues was determined by immunofluorescence. Maximum parasitemia was observed on day 21pi and became negative on day 42pi. By day 90pi, 50% of the infected mice presented electrocardiographic alterations and 67% by day 360pi; the non infected group of mice didn’t present elecrocardiographic alterations. Inflammatory infiltrates were observed throughout the infection, with a higher percentage in those mice with electrocardiographic alterations. The presence of the parasite was observed throughout the infection in skeletal muscle samples and on day 90pi in the myocardium. The highest mortality occurred on day 21pi, surviving 10% of the mice until the end of the experiments. These results demonstrate the presence of the parasite in the host tissues along the infection which could produce the injuries found in the myocardium and the electrocardiographic alterations.

A series of 4-thiazolidinone derivatives containing 1,4-benzodioxane ring system was synthesized starting from 2,3-dihydro-1,4-benzodioxane-2-carbohydrazide. The synthesized compounds were characterized and evaluated for antibacterial activity against Staphylococcus aureus, Escherichia coli and Bacillus subtilis and antifungal activity against Aspergillus niger, Aspergillus flavus and Candida albicans by two fold serial dilution technique. Some of the synthesized compounds displayed comparable or even better antibacterial and antifungal activities than reference drugs norfloxacin, chloramphenicol and fluconazole, against tested strains.

Gram-positive cocci are responsible for many severe infections in community and hospital settings, and these multidrug resistant organisms have increased markedly in the past decade. This trend is particularly evident for methicillin/ oxacillin-resistant Staphylococcus aureus (MRSA). MRSA is any strain of Staphylococcus aureus that has developed resistance to beta-lactam antibiotics, which include the penicillins (methicillin, dicloxacillin, nafcillin, oxacillin, etc.) and the cephalosporins. S. aureus strains have developed resistance to almost all antibiotics, thereby complicating disease management. Antibiotics are an essential part of modern medicine and that has helped dramatically in curing patients suffering from bacterial infections. However, emerging antimicrobial resistance in bacteria threatens to undermine the management of bacterial infections. A number of factors, which may promote antimicrobial resistance such as availability of antimicrobials without prescription, suboptimal hygiene, immunosuppression due to malnutrition or HIV, aggressive cancer chemotherapy and an increase in organ transplantation have resulted in hospitalized patients with immune compromise at high risk of nosocomial infections. The emergence of antibiotic-resistant mutants among bacteria is seemingly inevitable, that results in the decreased efficacy and withdrawal of the antibiotic from wide-spread usage. The purpose of this review is to discuss the increase in isolates of multidrug resistant S. aureus which has created an urgent need for the development of new anti-staphylococcal agents.