Assessing the trophic status of a tropical microtidal estuary applying TRIX and Random Forest - A combined approach.

The present study assessed the trophic status of a medium-sized microtidal estuary, Rushikulya, India using a combination of mutimetric trophic indices (TRIX, TRBIX) and a machine learning approach (Random Forest). A total of 108 samples were considered to build a predictive model for chlorophyll a (Chl a) and 17 response water variables by observing two annual periods (2021-2023) at six sampling sites. Mean values of TRIX (5.04 ± 0.72) and TRBIX (0.17 ± 0.08) reflected that the estuary has a moderate degree of eutrophication with 'good' water quality and 'biomass saturated'. However, the threshold of TRIX represents a transition state from 'moderate' to 'high' eutrophic. Random Forest model reflected that no apparent association between Chl a and water turbidity above 30 NTU and eutrophication in the estuary fluctuated mainly due to PO43--P along with electrical conductivity. Linear statistical correlations showed high correlation between Chl a and conductivity and a negative correlation between Chl a and dissolved oxygen, unlike PO43--P.

Changes in soil microbial biomass and organic C pools improve the sustainability of perennial grass and legume system under organic nutrient management.

Introduction: The perennial grass-legume cropping system benefits soil because of its high biomass turnover, cover cropping nature, and different foraging behaviors. We investigated the response of soil organic carbon (SOC) pools and their stock to organic and inorganic nutrient management in the Guinea grass and legume (cowpea-Egyptian clover) cropping system. Methods: Depth-wise soil samples were collected after harvesting the Egyptian clover. Based on the ease of oxidation with chromic acid, different pools of SOC oxidizable using the Walkley-Black C method, very labile, labile, less labile, non-labile; and dissolved organic C (DOC), microbial biomass C (MBC), and total organic C (TOC) in soils were analyzed for computing several indices of SOC. Result and discussion: After 10 years of crop cycles, FYM and NPKF nutrient management recorded greater DOC, MBC, SOC stocks, and C sequestration than the NPK. Stocks of all SOC pools and carbon management index (CMI) decreased with soil depth. A significant improvement in CMI, stratification ratio, sensitivity indices, and sustainable yield index was observed under FYM and NPKF. This grass-legume intercropping system maintained a positive carbon balance sequestered at about 0.8Mg C ha-1 after 10 years without any external input. Approximately 44-51% of the applied carbon through manure was stabilized with SOC under this cropping system. The DOC, MBC, and SOC in passive pools were identified for predicting dry fodder yield. This study concludes that the application of organics in the perennial grass-legume inter cropping system can maintain long-term sustainability, enhance the C sequestration, and offset the carbon footprint of the farm enterprises.

Probing river health status: a study based on index of biotic integrity (IBI) in Tapti River of Deccan plateau, India.

Anthropogenic activities impacted the ecological health of rivers by altering the physical habitat and water flow as well as by pollution. Monitoring of biotic groups for gauging the river health is a prerequisite for assessing the extent of degradation and formulating management guidelines for river restoration. An assessment using fish-based index of biotic integrity (IBI) was carried out in the Central Indian river, Tapti, for probing its health status. For the multimetric index, twelve metrics were adopted under five categories: taxonomic richness, habitat composition, tolerance indicators, species resilience, and trophic composition. Among the studied sites, Betul in the upper stretch was selected as the reference site for River Tapti, which almost meets the upper expectation of the metrics explored. Continuous scoring method was applied to evaluate the biotic integrity in the selected sites of the river. The IBI score based on the pooled fish abundance data in River Tapti ranged from 33 to 60. Assessment of the ecological health revealed that three-fourth of the river stretch was moderately impaired (25-50% of impairment) and the most deteriorated site was Kamrej with 45% of impairment which might be due to its location in the urban area with high influx of domestic sewage and industrial effluents. The IBI scores were plotted and compared with an independent estimate of water quality. The CCA with environmental and IBI variables revealed higher correlation with each other and the functional groups such as carnivores, herbivores, and fishes with high population doubling time (PDT) were found in close association with nitrate-N, total alkalinity, and specific conductivity. The study urges the need for the adoption of proper management and mitigation measures to restore the health and wealth of aquatic ecosystem.

Gonad recrudescence and annual sex steroid patterns in female goldspot mullet, Liza parsia reared in brackishwater pond.

Goldspot mullet, Liza parsia is a commercially important fish of South East Asia, where its farming depends on wild seed resources due to unavailability of hatchery technology. It, therefore, is important to understand the annual reproductive cycle of female L. parsia in captivity. In this study, adult male and female L. parsia (body weight ranges: 45-90 g; total length ranges: 100-125 mm, age >1 year) were collected from the wild and reared in a brackishwater pond. Thereafter, fish were randomly sampled at monthly intervals to measure the hepatosomatic index (HSI), gonadosomatic index (GSI), levels of serum steroids (testosterone, T; 17ß-estradiol, E2 and 17α-hydroxyprogesterone, 17-OHP), and oocyte growth. Results exhibited that female L. parsia undergoes six different maturation stages, namely I (oocyte diameter, OD: <100 µm), II (OD: 100-350 µm), III (OD: 350-400 µm), IV (vitellogenic oocyte, OD: 400-450 µm), V (ripe oocyte, OD: 450-550 µm) and VI (atretic oocyte, OD: 60-150 µm), with synchronous oocyte development. The highest (P < 0.05) HSI (1.96 ± 0.24) and GSI (12.01 ± 0.73) were recorded in December and January, respectively. Concentration of E2 gradually increased from August and reached its peak (807.67 ± 25.98 pg mL-1, P < 0.05) in December. The level of 17-OHP (85.87 ± 0.91 pg mL-1) was at its peak during the normal spawning month (January) (P < 0.05). Overall, the results indicated that L. parsia attains maturity in brackishwater pond, which is consistent with previous observations, and altogether provide the basis to develop a breeding technology in captivity through hormonal and environmental manipulations.

Clinical profile and in-hospital outcomes of COVID-19 patients: Findings from secondary data analysis.

Background: Uttarakhand, a hilly state in north India, reported the first coronavirus disease (COVID) case on 15 March 2020. Since then, the case numbers rose multiple folds. As Uttarakhand has been on a 'war-footing' amidst the recent second wave and is gearing up to fight against the third wave, the present study aims to uncover baseline clinical profile and in-hospital outcomes of COVID patients in Dehradun district (Uttarakhand) during the first wave. Methods: A record-based descriptive analysis was carried out for 671 COVID patients admitted to a private dedicated COVID hospital in Dehradun district between August 2020 and February 2021. Data was collected from medical records on a standardized abstraction form. Data was entered and analyzed using Statistical Package for Social Sciences (SPSS) version 20. Results: The present study showed most admitted COVID patients were males, aged 40 years and above, moderately ill, had co-morbidities with about one-fourth lately succumbed to death. The proportions of deaths, moderate-to-severe and severe category of illness were invariably high for those with co-morbidities irrespective of the gender. Females, age <60 years, and absence of co-morbidities had overall high mean survival estimates from COVID. Conclusion: Females, younger age group, and absence of co-morbidities are more likely to survive from COVID than males, older age groups, and those with co-morbidities.

Liposome-polymer complex for drug delivery system and vaccine stabilization.

Liposomes have been used extensively as micro- and nanocarriers for hydrophobic or hydrophilic molecules. However, conventional liposomes are biodegradable and quickly eliminated, making it difficult to be used for delivery in specific routes, such as the oral and systemic routes. One way to overcome this problem is through complexation with polymers, which is referred to as a liposome complex. The use of polymers can increase the stability of liposome with regard to pH, chemicals, enzymes, and the immune system. In some cases, specific polymers can condition the properties of liposomes to be explicitly used in drug delivery, such as targeted delivery and controlled release. These properties are influenced by the type of polymer, crosslinker, interaction, and bond in the complexation process. Therefore, it is crucial to study and review these parameters for the development of more optimal forms and properties of the liposome complex. This article discusses the use of natural and synthetic polymers, ways of interaction between polymers and liposomes (on the surface, incorporation in lamellar chains, and within liposomes), types of bonds, evaluation standards, and their effects on the stability and pharmacokinetic profile of the liposome complex, drugs, and vaccines. This article concludes that both natural and synthetic polymers can be used in modifying the structure and physicochemical properties of liposomes to specify their use in targeted delivery, controlled release, and stabilizing drugs and vaccines.

New record of two isopods Alitropus typus and Tachaea spongillicola from riverine freshwater fishes in the river Tapti.

The present paper deals with the infestation of freshwater fishes Labeo boggut, Oreochromis niloticus, Systomus sarana, and Xenentodon cancila by the parasitic isopods Alitropus typus and Tachaea spongillicola in Tapti, a westward freshwater flowing river of India. The isopods Alitropus typus H. Milne Edwards, 1840 and Tachaea spongillicola Stebbing, 1907 were identified with the taxonomic keys of Milne Edwards (1840) and Stebbing (1907), respectively. It is the first record of the infestation of parasitic isopods Alitropus typus, and Tachaea spongillicola in the freshwater fishes of river Tapti with new hosts' species Labeo boggut, Oreochromis niloticus, and Systomus sarana.

Variability in the zooplankton assemblages in relation to environmental variables in the tidal creeks of Sundarbans estuarine system, India.

The present study illustrates a holistic account of zooplankton community dynamics in relation to physicochemical variables in the tidal creeks of Indian Sundarbans estuarine system. Eleven water variables and zooplankton samples were collected in a monthly basis from the six sampling locations between July 2016 and June 2018. Out of the 11 water parameters, seven parameters (temperature, salinity, dissolved oxygen, turbidity, PO4 - P, NO3 - N, and NO2 - N) varied significantly (p ≤ 0.05) among seasons. A total of 63 zooplankton taxa were recorded with the predominance of Copepoda. Permutational multivariate analysis of variance (PERMANOVA) depicted the significant variations of zooplankton population both spatially (F = 2.313; p = 0.001) and temporally (F = 6.107; p = 0.001). Out of the 41 species of Copepoda recorded, 14 species (Paracalanus parvus, Parvocalanus dubia, Bestiolina similis, Acrocalanus gibber, A. gracilis, Acartia erythraea, A. spinicauda, Pseudodiaptomus serricaudatus, P. annandalei, P. aurivilli, Oithona brevicornis, O. similis, Longipedia weberi and Microsetella norvegica) were indicated as "characterizing species" in the creek environment, which highlighted the euryhaline nature as well as broad range of thermal tolerance of these species. Acrocalanus longicornis, Eucalanus crassus, Candacia bradyi, and Acartia sewelli were specifically found in pre-monsoon; Euterpina acutiformis, Clytemnestrata rostrata, Acartia plumosa, and Canthocalanus pauper were specific to post-monsoon season, whereas Mesocyclops leuckarti, Temora turbinata, and Temora discaudata were found only during monsoon. Thus, it explains the limited period of existence, highlighting the temporal shift in species abundance in the creeks. Overall, the calculated mean value of α-diversity (d' = 4.07; H' = 2.31) indicated a "good" zooplankton diversity in the creeks. The biota-environmental relationship following canonical correspondence analysis revealed that variables, viz., water temperature, turbidity, and NO3 - N, were the explanatory variables during monsoon; pH and DO in post-monsoon; PO4 - P, SiO4 - Si, and salinity in pre-monsoon that explained the variations of zooplankton community compositions in the creeks. The variables (PO4 - P, NO3 - N, and SiO4 - Si) that are correlated to the zooplankton community implied their indirect effect on the distribution of zooplankton by supporting the phytoplankton succession and production in the mangrove-dominated creeks.

Development and Characterization of Natural Product Derived Macromolecules Based Interpenetrating Polymer Network for Therapeutic Drug Targeting.

Interpenetrating polymer network (IPN)-based bead formulations were exploited by cross-linking different hydrophilic polymers in different combinations and at different ratios. Polyvinyl alcohol, xanthan gum, guar gum, gellan gum, and sodium alginate (Na-alginate) were used in this work as hydrophilic polymers to enhance the solubility of diclofenac sodium and also to target the delivery at preferred locations. IPN beads based on polysaccharides were prepared by the ionic gelation method. Differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, and Fourier transform infrared spectroscopy data showed that the IPN microbeads solubilized and encapsulated the drug within the network. We found over 83% encapsulation efficiency of the drug delivery system for the drug, and this efficiency increased with the concentration of the polymer. Ex vivo experiments using the goat intestine revealed that the IPN microbeads were able to adhere to the intestinal epithelium, a mucoadhesive behavior that could be beneficial to the drug pharmacokinetics, while in vitro experiments in phosphate buffer showed that the IPN enabled significant drug release. We believe that these IPN microbeads are an excellent drug delivery system to solubilize drug molecules and ensure adhesion to the intestinal wall, thereby localizing the drug release to enhance bioavailability of poorly soluble drugs.

Etiologic Role of Kinases in the Progression of Human Cancers and Its Targeting Strategies.

Cancer is one of the dominant causes of death worldwide while lifelong prognosis is still inauspicious. The maturation of the cancer is seen as a process of transformation of a healthy cell into a tumor-sensitive cell, which is held entirely at the cellular, molecular, and genetic levels of the organism. Tyrosine kinases can play a major, etiologic role in the inception of malignancy and devote to the uncontrolled proliferation of cancerous cells and the progression of a tumor as well as the development of metastatic disease. Angiogenesis and oncogene activation are the major event in cell proliferation. The growth of a tumor and metastasis are fully depending on angiogenesis and lymphangiogenesis triggered by chemical signals from tumor cells in a phase of rapid growth. Tyrosine kinase inhibitors are compounds that inhibit tyrosine kinases and effective in targeting angiogenesis and blocking the signaling pathways of oncogenes. Small molecule tyrosine kinase inhibitors like afatinib, erlotinib, crizotinib, gefitinib, and cetuximab are shown to a selective cut off tactic toward the constitutive activation of an oncogene in tumor cells, and thus contemplated as promising therapeutic approaches for the diagnosis of cancer and malignancies.

Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning.

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

A Review on Designing Poly (Lactic-co-glycolic Acid) Nanoparticles as Drug Delivery Systems.

Poly (lactic-co-glycolic acid) (PLGA) is a versatile synthetic polymer comprehensively used in the pharmaceutical sector because of its biocompatibility and biodegradability. These benefits lead to its application in the area of nanoparticles (NPs) for drug delivery for over thirty years. This article offers a general study of the different poly (lactic-co-glycolic acid) nanoparticles (PNPs), preparation methods such as emulsification-solvent evaporation, coacervation, emulsification solvent diffusion, dialysis, emulsification reverse salting out, spray drying nanoprecipitation, and supercritical fluid technology, from the methodological point of view. The physicochemical behavior of PNPs, including morphology, drug loading, particle size and its distribution, surface charge, drug release, stability as well as cytotoxicity study and cellular uptake, are briefly discussed. This survey additionally coordinates to bring a layout of the significant uses of PNPs in different drug delivery system over the three decades. At last, surface modifications of PNPs and PLGA nanocomplexes (NCs) are additionally examined.

Transformational learning for health professionals through a Theatre of the Oppressed workshop.

Theatre of the Oppressed (TO) is a powerful participatory tool for communities to examine their struggles against oppression. The healthcare community has problems inherent to complex, unequal power equations, and TO may be a useful means to understand and respond to their struggle. A 3-day workshop on TO was facilitated by the authors in the Himalayan Institute of Medical Sciences (HIMS) in Dehradun, India, in August 2017. The workshop culminated in the 'Forum Theatre', which included five short plays, each depicting a struggle due to real-life oppression faced by one or the other participant. The audience (about 200 invited members of the HIMS community) chose one play depending on the struggle with which they identified most. That play was 'forumed': spectators were invited to replace the struggling person and demonstrate how they would handle the oppression. Over the next week, participants reflected on the workshop through a structured online questionnaire. The feedback (n=16/27 participants; response rate 59.3%) was subjected to descriptive statistics and to qualitative analysis. The highest average Likert score (out of a maximum of 5) was given to the following items: TO engages senses and emotions (4.6±0.50), can help inculcate ethical behaviour (4.4±0.81), identifies conflict (4.4±0.51), and resolves issues of attitude, behaviour, communication, diversity and empathy (4.4±0.73). The Forum Theatre was reported to be a means to "express emotions and opinions and to simultaneously gather the same from others"; "make people push their own limits"; "bring out social problems in public"; "examine the root causes behind lived experience"; "provide context for understanding and for exploring alternatives"; and "convert thoughts to action." In conclusion, TO is an engaging activity that identifies conflict; participants' initial reactions suggest that it may initiate change in the ABCDE attributes (attitude, behaviour, communication, diversity, ethics and empathy) of medical professionals.

Epidemiology of ROP update - Africa is the new frontier.

Several epidemics of blindness due to retinopathy of prematurity (ROP) have been described, with the most recent (the third) occurring in middle income countries in Latin America and Eastern Europe initially, and more recently in the more advanced economies in Asia. In these settings, which are characterized by variation in the quality of neonatal care and inadequate coverage of ROP screening and treatment, larger, more mature infants are affected as well as extremely preterm infants. In 2010 the annual incidence of blindness and visual impairment from ROP globally was estimated to be 32,300, with the lowest incidence in sub-Saharan countries. However, ROP is likely to become an increasingly important cause of blindness in children in sub-Saharan Africa as neonatal care expands unless policies and programmes for control are included at the outset.

Synthesis and characterization of interpenetrating polymeric networks based bio-composite alginate film: A well-designed drug delivery platform.

This study aimed to develop and characterize the calcium alginate films loaded with diclofenac sodium and other hydrophilic polymers with different degrees of cross-linking obtained by external gelation process. To the formed films different physicochemical evaluation were performed which showed an initial character of the films. The films produced by this external gelation process were found thicker (0.031-0.038 mm) and stronger (51.9-52.9 MPa) but less elastic (2.3%) than those non-cross-linked films (0.029 mm; 39.7 MPa; 4.4%). The lower water vapor permeability (WVP) values of the films were obtained where maximum level of crosslinking occurs. Composite films can be cross-linked in presence of external crosslinking agent to improve the quality of the produced matrices for various uses. The characterization of the film was performed using Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared Spectroscopy (FT-IR) analysis. The Scanning Electron Microscopy (SEM) study showed the morphology of treated composite films. The kinetic release studies showed a sustained release of the drug from the formulated films as it can be prolonged in composite film. The prepared biodegradable Ca-Alginate bio-composite film may be of clinical importance for its therapeutic benefit.

Extraembryonic heparin-binding epidermal growth factor-like growth factor deficiency compromises placentation in mice.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HBEGF) is expressed in the embryo and uterus at the implantation site, stimulating trophoblast invasive activity essential for placentation. The effect of extraembryonic HBEGF deficiency on placental development was investigated by breeding mice heterozygous for the Hbegf null mutation. On gestation day 13.5, the average placental weights of the wild-type (Hbegf+/+) and heterozygous (Hbegf+/-) mice were approximately 76 and 77 mg, respectively, as opposed to reduced average placental weights of approximately 61 mg in homozygous null (Hbgef-/-) females. In contrast, fetal weights were not significantly affected by genotype. HBEGF immunostaining in placental sections was Hbegf gene dosage-dependent, while expression of other EGF family members was comparable in Hbegf+/+ and Hbegf-/- placentas. Histological analysis revealed no apparent differences in trophoblast giant cells, but the spongiotrophoblast region was reduced compared to labyrinth (P < 0.05) in Hbegf null placentas. While no differences in cell apoptosis were noted, proliferation as assessed by nuclear Ki67 staining was elevated in the labyrinth and decreased in the spongiotrophoblast region of Hbegf-/- placentas. Labyrinth morphology appeared disrupted in Hbegf -/- placentas stained with laminin, a marker for capillary basement membrane, and the capillary density was reduced. Immunohistochemical staining revealed reduced vascular endothelial growth factor (VEGF) levels in both spongiotrophoblast and labyrinth (P < 0.01) regions of Hbegf-/- placentas. In vitro, HBEGF supplementation increases the expression of VEGF in a human trophoblast cell line. These findings suggest that trophoblast HBEGF promotes placental capillary formation by inducing VEGF in the developing placenta of mice.

Ethosomes as Novel Vesicular Carrier: An Overview of the Principle, Preparation and its Applications.

BACKGROUND: In the study of lipid vesicular carriers in permeation enhancement of drug molecules across skin after the success story of liposomes, ethosomes are a recent addition. There are a number of published reviews but still, there is a lack of reviews representing various aspects in a systematic way with a detailed description of current research works. This review serves to fill this deficiency along with special emphasize on its preparation methods and applications. METHODS: Information was collected from previously published literatures which were represented after analysis in terms of various aspects such as principles, composition, preparation, mechanism of penetration, modified forms, characterization, marketed preparations and its applications. RESULT: This review is represented in an informative and easily understandable way. Basic principles and background were covered in the introduction section. Composition section contains the basic components of formulations along with the impact of various parameters on the characterization of the ethosome. A detailed discussion of all the methods along with their own utility is elaborately provided. Various aspects of characterization studies of ethosomes are also discussed. Therapeutic and cosmetic applications of ethosomes are also outlined here. CONCLUSION: In spite of having a excellent permeation-enhancing and targeted drug release profile, ethosome suffers from limited commercialization. Various challenges regarding their commercialization and product development are also discussed in this review with an objective of acting as a directional route for the researchers.

Examination of VDR/RXR/DRIP205 Interaction, Intranuclear Localization, and DNA Binding in Ras-Transformed Keratinocytes and Its Implication for Designing Optimal Vitamin D Therapy in Cancer.

Retinoid X receptor (RXR) occupies a central position within the nuclear receptor superfamily, serving as an obligatory partner to numerous other nuclear receptors, including vitamin D receptor (VDR). In the current study, we examined whether phosphorylation of RXRα at serine 260 affects VDR/RXR and VDR interacting protein (DRIP) 205 coactivator recruitment, interactions, and binding of the VDR/human RXRα (hRXRα)/DRIP205 complex to chromatin. Serine 260 is a critical amino acid on the hRXRα that is located in close spatial proximity to regions of coactivator and corepressor interactions. Using fluorescence resonance energy transfer and immunofluorescence studies, we showed that the physical interaction between hRXRα and DRIP205 coactivator was impaired in human keratinocytes with the ras oncogene (HPK1Aras) or transfected with the wild-type hRXRα. Furthermore, the nuclear colocalization of VDR/DRIP205, hRXRα/DRIP205, and VDR/hRXRα/DRIP205 complex binding to chromatin is impaired in the HPK1Aras cells when compared with the normal human keratinocytes (HPK1A cells). However, transfection with the nonphosphorylatable hRXRα (S260A) mutant or treatment with the mitogen-activated protein kinase (MAPK) inhibitor UO126 rescued their nuclear localization, interaction, and binding of the complex to chromatin in the HPK1Aras cells. In summary, we have demonstrated, using highly specific intracellular tagging methods in live and fixed cells, important alterations of the vitamin D signaling system in cancer cells in which the ras-raf-MAPK system is activated, suggesting that specific inhibition of this commonly activated pathway could be targeted therapeutically to enhance vitamin D efficacy.

Discovery of Novel Allosteric HCV NS5B Inhibitors. 2. Lactam-Containing Thiophene Carboxylates.

Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors. This series, exemplified by 12f, provided 3-5-fold improvement in potency against HCV replication, as measured by replicon assays. The synthesis, structure-activity relationships, in vitro ADME characterization, and in vivo evaluation of this novel series are discussed.