Biological activity of synthesized 5-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-2-mercapto-1, 3, 4-oxadiazole derivatives demonstrated by in silico and BSA binding studies

We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.

Efficacy and safety of sofosbuvir based antiviral therapy for chronic hepatitis C infection in patients with advanced chronic kidney disease

Background: Screening studies for hepatitis C have proved that it is more prevalent in patients with renal diseases. Chronic hepatitis C infection in patients with kidney disease not only accelerates renal deterioration but also adversely effects morbidity and mortality. Availability of direct acting antiviral drugs has revolutionized treatment of hepatitis C even in difficult patients. In advanced kidney diseases, selection of treatment is difficult. Aim of this study was to evaluate the efficacy and safety of Sofosbuvir based DAAs in patients with advanced CKD.Methods: In this Quasi experimental study, CHC patients with or without cirrhosis having advance CKD (eGFR <30 ml/min per 1.73 m2) and/or on dialysis were enrolled. End points of the study were documentation of SVR 12 or discontinuation of therapy. Different regimens of oral DAAs with or without Ribavirin were used.Results: 86 patients with a median age of 53 years were enrolled. 37 patients were on maintenance dialysis and 49 were not on dialysis with eGFR <30 ml/min per 1.73 m2. Virological response was 92.68% at the end of treatment and SVR was achieved by 90.2% twelve weeks after therapy. Insomnia 14%, headache 11% and anemia 7% were main dverse effects. Mean eGFR and creatinine before and after treatment remained the same. Only 2 patients relapsed, both were on dialysis thrice weekly.Conclusions: All Sofosbuvir based regimens used for the treatment of CHC in patients with end stage renal disease are effective and well tolerated. Close follow up is advised to monitor side effects.

Fungal infections in patients with chronic liver disease: mortality and associated risk factors

Background: Patients with chronic liver disease are immunocompromised and prone to different opportunistic infections. Fungal infections in patients admitted with liver cirrhosis are not rare and they may increase mortality and morbidity of these patients. Aims of the study is to determine the mortality and its risk factors associated with fungal infections in patients with chronic liver disease.Methods: In this retrospective study, patients admitted with chronic liver disease during the last four years on this hospital were studied for diagnosed fungal infections. A matched control group of cirrhosis patients with a ratio of 1:2 admitted without fungal infections was also studied and mortality was compared between the two groups.Results: Seventy admitted patients of liver cirrhosis with microbial and histopathological evidence of fungal infection were found while 140 patients of the control group had no evidence of fungal infection. Hepatitis C virus infection was the major cause of cirrhosis (65%) and most of the patients were in child class C(63%). Urinary tract infection, esophageal candidiasis, and mucormycosis were major fungal infections. Mortality was much higher in the fungal infections group (34.3%) as compared to the non-infectious group (16%). On multivariate analysis, high WBCs count, hypo-albuminemia and high creatinine levels were the worst factors affecting mortality.Conclusions: Fungal infections are a significant cause of morbidity and mortality in patients with decompensated cirrhosis. Advanced cirrhosis, renal insufficiency, and leucocytosis are independent predictors of fatal outcome in these patients.

Chronic Diarrhea Caused By an Impacted Foreign Body in the Sigmoid Colon: A Rare Scenario

Chronic diarrhea is a very common disease which affects the quality of life of our patients. It is one of the major diseases for which patients are referred to gastrointestinal clinics. Irritable bowel syndrome, infectious diarrhea and abdominal tuberculosis due to unhygienic conditions in our part of the world and inflammatory bowel disease are the major causes of chronic diarrhea in young patients. We are reporting a young female patient who presented with chronic diarrhea, abdominal pain and bleeding per rectum mimicking ulcerative colitis for last many months but on colonoscopy examination an impacted foreign body was found in the sigmoid colon which was the culprit. Surgical retrieval of the foreign body resolved the symptoms.

Etiology and Impact of Hepatic Steatosis in Pakistan: Role of Hepatitis C Virus Genotype 3 Infection

Introduction: Hepatic steatosis has emerged as an important histological finding in patients with deranged liver function. It may be an important factor for the progression of hepatitis C virus-associated liver disease, particularly in genotype 3 infections. Aims: To determine the etiology and impact of hepatic steatosis in our patients presenting with chronic hepatitis. Methods: All liver biopsies performed at our hospital during 2010-2014 were analyzed by a single pathologist using histological activity index (HAI) scores and Brunt’s classification for steatosis. Patients were evaluated for factors reported to be associated with steatosis, including the prevalence of HCV. Results: Biopsies of 439 patients (284 male, mean ages 38.5 ± 11.2 years) were studied. Hepatic steatosis was present in 324 (73.8%) biopsies. It was mild in 190/439 (43.3%), moderate in 88/439 (20%) and severe in 46/439 (10.5%) cases. On univariate analysis, steatosis was associated with HCV infection (p=0.023), BMI >25 (p=0.008) and raised ALT (p=0.003), but not with diabetes, hypertriglyceridemia, HBV infection or alcohol intake. On multiple logistic regression HCV and BMI >25 were independent risk factors for steatosis. There was a linear ascending association of hepatic steatosis with grade and stage of liver disease (p ≤ 0.001). Among 369 HCV patients, 280 (76%) had steatosis. It was mild in 159/369 (43%), moderate in 82/369 (22.2%) and severe in 39/369 (10.6%) cases. There were only 32 non-alcoholic, non-viral hepatitis patients and 8/32 (25%) had moderate or severe steatosis. Conclusions: Significant hepatic steatosis is present in 30.5% of our patients with chronic hepatitis. HCV genotype 3 infection is the predominant factor for hepatic steatosis in Pakistan. Steatosis has a linear ascending correlation with hepatic inflammation and fibrosis.

Synthesis, spectral analysis and pharmacological study of N'- substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazides

ABSTRACT A series of molecules bearing multiple functional groups were synthesized to study their antibiotic effect against Gram-positive and Gram-negative bacteria and lipoxygenase activity as well. 2,4-Dimethylcarbolic acid (1) was refluxed with ethyl 2-bromoacetate to synthesize ethyl 2-(2,4-dimethylphenoxy)acetate (2). Compound 2 was converted to the corresponding hydrazide 3, again on refluxing with hydrazine. The compound 5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-thiol (4) was synthesized by the reaction of 3 and CS2 in the presence of KOH. Compound 4 was further converted to the corresponding ester 5 and then 2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide (6). The final molecules N'-substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide, 8a-m, bearing ether, 1,3,4-oxadiazole, thioether, hydrazone and azomethine functional groups were synthesized by stirring the aryl carboxaldehydes 7a-m with 6 in methanol at room temperature. The depicted structures of all synthesized molecules were corroborated by IR, 1H-NMR and EIMS spectral data analysis. 8m and 8i showed substantial antibacterial activity and lipoxygenase inhibitory activity, respectively.

Synthesis of some novel enzyme inhibitors and antibacterial agents derived from 5-(1-(4-tosyl)piperidin-4-yl)-1, 3, 4-oxadiazol-2-thiol

ABSTRACT Keeping in mind the pharmacological importance of the 1,3,4-oxadiazole moiety, a series of new S-substituted derivatives, 5a-h, of 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3) were synthesized. The reaction of p-toluenesulfonyl chloride (a) and ethyl isonipecotate (b) produced ethyl 1-(4-tosyl)piperidin-4-carboxylate (1) which was further transformed into 1-(4-tosyl)piperidin-4-carbohydrazide (2) by hydrazine hydrate in methanol. Compound 2 was refluxed with CS2 in the presence of KOH to synthesize 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3). The desired compounds, 5a-h, were synthesized by stirring 3 with aralkyl halides, 4a-h, in DMF using NaH as an activator. The structures of synthesized compounds were elucidated by 1H-NMR, IR and EI-MS spectral studies. These compounds were further evaluated for enzyme inhibitory activity against lipoxygenase and alpha-glucosidase, along with antibacterial activity against Gram-negative and Gram-positive bacteria.

RESUMO Tendo em vista a importância farmacológica da porção 1,3,4-oxadiazol, sintetizou-se uma série de novos derivados S-substituídos, 5a-h, de 5-(1-(4-tosi)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). A reação do cloreto de p-toluenossulfonila (a), com isonipecotato de (b) etila forneceu 1-(4-tosil)piperidin-4-carboxilato de metila (1), que foi, em seguida, transformado em 1-(4-tosil)piperidin-4-carbo-hidrazida (2) por reação com hidrato de hidrazina em metanol. O composto 2 foi submetido a refluxo com CS2 na presença de KOH para se obter 5-(1-(4-tosil)piperidin-4-il)-1,3,4-oxadiazol-2-tiol (3). Os compostos desejados, 5a-h, foram obtidos por agitação de 3 com haletos de aralquila, 4a-h, em DMF, na presença de NaH. As estruturas dos compostos sintetizados foram elucidadas através de análise dos espectros de 1H-MNR, IR e EI-MS. Estes compostos foram, ainda, avaliados quanto à inibição das enzimas lipoxigenase e alfa-glucosidase, juntamente com a atividade antibacteriana contra bactérias Gram positivas e Gram negativas.