Recent synthetic methodologies for imidazo[1,5-a]pyridines and related heterocycles.

Imidazo[1,5-a]pyridine is a significant structural component of a large number of agrochemicals and pharmaceuticals. The synthesis of imidazo[1,5-a]pyridine has been a subject of intense research for numerous decades. A large number of transformations are now available to conveniently access imidazo[1,5-a]pyridine from readily available starting materials. This review details the recent development in imidazo[1,5-a]pyridine construction involving cyclocondensation, cycloaddition, oxidative cyclization, and transannulation reactions.

Sulfamic acid catalyzed synthesis of new 3,5-[(sub)phenyl]-1H-pyrazole bearing N1-isonicotinoyl: And their pharmacological activity evaluation.

A sustainable synthesis of new 3,5-[(sub)phenyl]-1H-pyrazole bearing N1-isonicotinoyl derivatives from substituted chalcones and isoniazid by using sulfamic acid and their pharmacological activity evaluation is reported. An anti-oxidant study is performed by using DPPH assay. In vitro anti-mycobacterial activity of compounds bearing R/R' = 4-CH3/4-F and 3-OCH3/4-Cl showed complete inhibition (99%) at the MIC of 31 and 34 µM respectively. Antibacterial screening of compounds bearing R/R' = 4-CH3/4-F; 4-OCH3/4-Br; and 4-OCH3/4-Cl has shown noticeable inhibition (27 mm) against Staphylococcus aureus. The anti-cancer bioassay demonstrated that the five compounds were active on human breast cancer cell line MCF-7; however on HeLa cervical cancer cells only two compounds are active in comparison to standard drug Doxorubicin. Higher inhibitory effects observed in this study appear to be dependent on the chloro, bromo, fluoro and methoxy functionality present on the aromatic nucleus. The structures of all the compounds are established using NMR (1H and 13C), FT-IR, Mass and elemental analysis.

Allyl-isothiocyanate ameliorates the pre-neoplastic changes induced by the fern Dryopteris nigropalaceae on experimental feeding in Guinea pigs.

Enzootic bovine haematuria, caused by long-term ingestion of ferns, is a chronic disease of hill cattle characterized by neoplastic lesions in the urinary bladder. Objectives of this study were to investigate the toxicity potential of long-term feeding of the fern Dryopteris nigropalaceae and effect of allyl isothiocyanate (AITC) to ameliorate fern toxicity and the associated pathological changes. The LC-MS analysis of the fern showed presence of ptaquiloside (4.5 ±â€¯1.0 µg/g) and pterosin B (39 ±â€¯9.1 µg/g). Groups of animals were fed dried fern powder at the dose of 20% w/w in normal feed and treated with and without AITC at graded doses. Long term feeding of fern induced inflammatory and pre-neoplastic lesions in urinary bladder. The important lesions included cystitis, squamous metaplasia and high-grade dysplasia. Urothelium showed positive immunoreactions for nuclear expression of H-ras and p53. However, no mutation suggestive of neoplastic change was observed on partial mRNA sequences analyses of exon 2 of H-ras and 5 or 7&8 of p53 genes. Strikingly, AITC showed dose-dependent amelioration of pre-neoplastic changes in fern-fed animals. In conclusion, AITC is shown to limit pre-neoplastic changes caused by D. nigropalaceae feeding in guinea pigs.

Sub-chronic toxicopathological study of lantadenes of Lantana camara weed in Guinea pigs.

BACKGROUND: In the field conditions, animals regularly consume small quantities of lantana leaves either while grazing or due to mixing with regular fodder. The hypothesis of this study was that consumption of lantana toxins over a long period of time leads to progression of sub-clinical disease. Toxicopathological effects of sub-chronic (90 days) administration of lantadenes of L. camara were investigated in guinea pigs. For this, a total of 40 animals were divided into 5 groups whereby groups I, II, III and IV were orally administered lantadenes, daily at the dose of 24, 18, 12, and 6 mg/kg bw, respectively while group V was control. The animals were evaluated by weekly body weight changes, haematology, serum liver and kidney markers, tissue oxidative markers and histopathology. RESULTS: The results of significant decrease in weekly body weights, haematology, liver and kidney marker enzymes (alanine aminotransaminase, aspartate aminotransaminase, acid phosphatase and creatinine), oxidation stress markers (lipid peroxidation, reduced glutathione, superoxide dismutase and catalase) in liver and kidneys, histopathology, and confirmation of fibrous collagenous tissue proliferation by Masson's Trichome stain showed that lantadenes led to a dose-dependent toxicity in decreasing order with the highest dose (24 mg/kg bw) producing maximum lesions and the lowest dose (6 mg/kg bw) producing minimum alterations. CONCLUSIONS: The study revealed that lantadenes which are considered to be classical hepatotoxicants in acute toxicity produced pronounced nephrotoxicity during sub-chronic exposure. Further studies are needed to quantify the levels of lantadenes in blood or serum of animals exposed to lantana in field conditions which would help to assess the extent of damage to the vital organs.

Survey of ferns and clinico-pathological studies on the field cases of Enzootic bovine haematuria in Himachal Pradesh, a north-western Himalayan state of India.

Enzootic bovine haematuria (EBH) in cattle occurs in upland areas of the world. In India, the disease is present in isolated pockets in the Himalayas and in the Nilgiri Hills. The variation in the disease incidence has been attributed to different environmental conditions and animal rearing practices followed in the different regions. The aim of the study was to conduct field surveys in parts of EBH endemic regions of Himachal Pradesh, a north-western Himalayan state of India. Out of the total 103 plant samples collected, a total of 95 samples were identified as ferns. The major ferns identified included, Onychium japonicum (Thunb.) Kunze, Polystichum piceopaleaceum Tagawa, Dryopteris juxtaposita Christ, Pseudocyclosorus canus (Baker) Holttum and J.W. Grimes, Onychium contiguum C. Hope, Dryopteris nigropaleacea (Fraser-Jenk.), Pteridium aquilinum (L.) Kuhn, Diplazium esculentum (Retz.) Sw., Allantodia maxima (D. Don) Ching, Woodwardia unigemmata (Makino) Nakai, Pteris cretica L., Pteris vittata L., Asplenium trichomanes L., Thelypteris phegopteris (L.) Sloss. ex Rydb, Adiantum venustum D. Don and Paraceterach vestita (Hook.) R.M. Tryon. The concentration of ptaquiloside (PTA) and pterosin B (PtB) in some of the ferns collected from Kullu and Chamba regions ranged from 0 to 358.6 ± 70.5 µg/g and 0 to 652.4 ± 50.0 µg/g, respectively. In addition, field cases of the disease in cattle were also studied in the EBH endemic districts. A total of sixteen cattle urine samples and one urinary bladder of EBH affected cattle were collected. On physical, chemical (benzidine test) and microscopic examination of urine sediment, all the sixteen field samples were found to be positive for erythrocytes and the cases were diagnosed as macrohaematuria. The clinico-pathological studies on the field cases and the presence of PTA and PtB in the ferns indicated that EBH is a prevalent disease and there is an association between chronic fern ingestion and EBH in cattle. On the basis of gross pathology, histopathology and immunohistochemistry (p53 and H-ras nuclear expression in the urothelial cells) of the urinary bladder tissue, the field case was diagnosed as transitional cell adenocarcinoma with chronic lymphocytic cystitis.

Cryptic etiopathological conditions of equine nervous system with special emphasis on viral diseases.

The importance of horse (Equus caballus) to equine practitioners and researchers cannot be ignored. An unevenly distributed population of equids harbors numerous diseases, which can affect horses of any age and breed. Among these, the affections of nervous system are potent reason for death and euthanasia in equids. Many episodes associated with the emergence of equine encephalitic conditions have also pose a threat to human population as well, which signifies their pathogenic zoonotic potential. Intensification of most of the arboviruses is associated with sophisticated interaction between vectors and hosts, which supports their transmission. The alphaviruses, bunyaviruses, and flaviviruses are the major implicated groups of viruses involved with equines/humans epizootic/epidemic. In recent years, many outbreaks of deadly zoonotic diseases such as Nipah virus, Hendra virus, and Japanese encephalitis in many parts of the globe addresses their alarming significance. The equine encephalitic viruses differ in their global distribution, transmission and main vector species involved, as discussed in this article. The current review summarizes the status, pathogenesis, pathology, and impact of equine neuro-invasive conditions of viral origin. A greater understanding of these aspects might be able to provide development of advances in neuro-protective strategies in equine population.

Hepatoprotective effect of Ginkgo biloba leaf extract on lantadenes-induced hepatotoxicity in guinea pigs.

The hepatoprotective effect of freeze-dried methanolic leaf extract of Ginkgo biloba was evaluated against lantadenes-induced hepatic damage in guinea pigs. The reversed-phase HPLC analysis of lantadenes confirmed the presence of 72.82% of lantadene A. UPLC-ESI-MS analysis showed the presence of ginkgolide B, C, bilobalide and traces of ginkgolide A and J in G. biloba extract. The concentration of ginkgolide B in the sample was found as 0.29%. The elevated levels of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase due to lantadenes were significantly restored towards normal values by G. biloba extract in a dose-dependent manner. The effects of lantadenes and G. biloba extract on lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were assayed in liver homogenates to evaluate the antioxidant activity. G. biloba extract in a dose-dependent manner produced significant decrease in lantadenes-induced increased levels of LPO. The lantadene-induced decreased levels of SOD, GSH and catalase were elevated by G. biloba extract. The findings of biochemical and antioxidant enzyme levels were supported by gross and histopathological observations. Moreover, liver sections of G. biloba group also showed a marked decrease in apoptosis in comparison to lantadenes group. This study suggested that G. biloba could be used as a promising hepatoprotectant against lantadenes-induced hepatic damage. Future studies are needed to elucidate the precise mechanism of hepatoprotection for practical application.

Experimentally induced citrinin and endosulfan toxicity in pregnant Wistar rats: histopathological alterations in liver and kidneys of fetuses.

In the present investigation, citrinin (CIT) (10 mg kg(-1) feed) and endosulfan (1 mg kg(-1) body weight) were administered orally alone and in combination to pregnant Wistar rats from gestational day 6 to 20 and their fetuses were collected to evaluate the histopathological alterations in hepatic and renal tissues. In CIT-fed group fetal liver, the changes were less marked, showing only sinusoidal dilation and mild vacuolar degeneration, whereas the consistent changes in the fetal kidney included tubular degeneration, medullary tubular necrosis, cystic dilatation of tubules, distortion of glomerulur capillary tuft and interstitial fibroblastic proliferation which separated clusters of tubules. In the endosulfan group, the liver was predominantly affected, showing vacuolar degeneration, karyomegaly and severe sinusoidal dilation, whereas the renal changes were mainly confined to tubular degeneration and varying degree of interstitial fibrosis. In the combination group, the hepatic and renal histopathological alterations in the fetus, though of similar nature to those of the individual groups, were more severe.

Citrinin and endosulfan induced maternal toxicity in pregnant Wistar rats: pathomorphological study.

Dietary exposures to environmental food pollutants such as mycotoxin(s) or pesticide(s) have gained immense significance due to their adverse effects on production and reproduction in animal and human populations. The present investigation was conducted to evaluate the maternal toxicity of citrinin (CIT) and endosulfan administered per os either alone or in combination in pregnant rats during gestational days 6-20. CIT (group I, 10 mg kg(-1) feed, through diet) and endosulfan (group II, 1 mg kg(-1) body weight, by oral intubation) when administered either alone or in combination (group III) in Wistar rats caused clinical signs of toxicity and pathomorphological changes in all the toxin treated groups, the severity being more pronounced in the combination treatment compared with that observed in the control (group IV). The rate of fetal resorptions was highest (22.22%) in the combination treatment followed by endosulfan (16.48%) and CIT (12.50%) treatment groups compared with the control group (3.86%). The histopathological changes such as engorged vasculature, vacuolar degeneration and karyomegaly in liver; congestion, tubular degeneration and cast formation in kidneys; vascular changes and hemosiderosis in uterus and lymphocytic depletion and apoptosis in the lymphoid organs were recorded in the animals of the toxin treated groups. The lesions were consistent and more severe in the combination treatment group compared with the individual treatment groups, suggesting an additive interaction of CIT and endosulfan in inducing maternal toxicity in Wistar rats.

Ochratoxin A and citrinin nephrotoxicity in New Zealand White rabbits: an ultrastructural assessment.

In the present investigation, ochratoxin A (OTA) (0.75 mg/kg feed) and citrinin (CIT) (15 mg/kg feed) were fed alone and in combination to young growing New Zealand White rabbits for 60 days to evaluate renal ultrastructural alterations. The severity and intensity of renal ultrastructural changes varied with the type of the treatment, and predominant and consistent lesions were recorded in the proximal convoluted tubule (PCT) lining cells. The significant changes in mitochondria, the most affected cell organelle in all the treatment groups, included mitochondrial disintegration and distortion, pleomorphism, cluster formation and misshapen appearance such as signet ring, dumbbell, cup and U shapes. Intra-cisternal sequestrations of involuting mitochondria, and thickening of basal layer of PCT epithelial cells with partial detachment, were the characteristic features observed in OTA and combination treatments. CIT treatment revealed crenated nucleus, loss of nucleolus, depletion of cytoplasmic organelles, mitochondrial pleomorphism, nuclear fragmentation, uniform folding of cell membrane and cytoplasmic vacuolations in the PCTs. Focal thickening of the glomerular basement membrane and degeneration of endothelial cells were the prominent alterations in the glomeruli in OTA and combination treatments. Distal convoluted tubules were unaffected in CIT treatment, however, mild to moderate lesions were observed in OTA and combination treated rabbits. It may be concluded that on simultaneous exposure, CIT potentiated the toxic effects of OTA on renal ultrastructure.

Citrinin and endosulfan induced teratogenic effects in Wistar rats.

Dietary exposures to food pollutants such as mycotoxin(s) or pesticide(s) are most significant due to their adverse effects on the production and reproduction in animals and the human population. The present investigation was conducted to evaluate the teratogenic potential of citrinin (CIT) and endosulfan either alone or in combination in pregnant rats during gestational days 6-20. Endosulfan (1 mg kg(-1) body weight, by oral intubation) and CIT (10 mg kg(-1) feed, through diet) when administered either alone or in combination in pregnant rats caused significant teratogenic effects in the developing fetuses. There was no maternal mortality, however, reduced maternal weight gain and number of live fetuses and increased fetal resorptions were recorded in all the treated groups. The fetal body weights and crown to rump lengths were significantly decreased and the per cent gross, visceral and skeletal anomalies were significantly increased in the fetuses of dams of all the treated groups. The internal hydrocephalus, cerebellar hypoplasia, microphthalmia, contracted and notched kidneys, multilobulated liver, dilated renal pelvis, incomplete ossification of skull bones, rib anomalies and sacral and caudal vertebrae agenesis were the important fetal malformations. The occurrence of fetal gross, skeletal and visceral malformations was more severe in the combination group, suggesting an additive interaction of CIT and endosulfan in inducing developmental toxicity in Wistar rats.

Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats.

Ochratoxin A (OTA), a potent in vivo teratogen, has been tested in various laboratory animal species. Present investigation was conducted to determine critical dose and critical time for the developmental toxicity of OTA in pregnant Wistar rats after single oral dose administration. OTA at different graded dose levels (2-4 mg/kg body weight) and at different gestation days (6-15), caused variable developmental defects in developing fetuses. OTA at 2.75 mg/kg body weight, dissolved in 0.1 M sodium bicarbonate (vehicle) and administered by oral intubation as a single dose on one of the gestational days 6-15, caused significant maternal toxicity in the dams and various gross, visceral and skeletal anomalies in the fetuses. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal defects were developmental defects in skull bones, sternebrae, vertebrae and ribs. The gestational days 6 and 7 were found to be the most critical for the induction of teratogenicity in rats. Single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose in pregnant Wistar rats.