Harnessing the structural complexity and bioactivity of natural products is a proven strategy for discovering novel therapeutics. Here, we report a natural product-inspired structural elaboration of 2-aryl pyridopyrimidinones with C3 installation of drug-privileged motifs. Molecularly diverse analogues were synthesized by an approach of construction of pyridopyrimidinone skeleton, a Pd-catalyzed heterocyclic ring imine-ether CO bond activation-arylation reaction followed by Ullmann-type or Buchwald-Hartwig coupling reactions of CN, CP, CO, and CS bond formations, which enabled an efficient access to flavonoid-inspired molecules with various substitution/functional motifs. These analogs exhibited potent anticancer activity against multiple carcinoma cell lines. The representative most potent compound 3 s showed significant cytotoxicity against highly aggressive triple-negative breast adenocarcinoma (MDA-MB-231, IC₅₀ = 1.16 ± 0.36 μM), minimal toxicity toward normal kidney epithelial cells (HEK 293) and remarkable selectivity (SI = 72). Wound closure and transwell assays indicated that compound 3s was found to suppress cell migration in a concentration-dependent fashion. Functional mechanistic studies with various biophysical experiments revealed the compound's pronounced effect in apoptosis induction and biological function interference, such as Bax upregulation, caspase-3/PARP cleavage, and AKT suppression, mitochondrial membrane potential disruption, accumulation of cytoplasmic and mitochondrial ROS, which led to sub-G0 accumulation and G2/M phase cell cycle arrest. Structure-activity and cheminformatics analyses provides identification of potential key pharmacophoric features and favorable natural product- and drug-likeness profiles.

Two novel azaartemisinin scaffolds N-ethanamine-11-azaartemisinin (EAZA) 10 and N-propanamine-11-azaartemisinin (PAZA) 11 were synthesized from artemisinin 1 on multigram scale in excellent yields without the need for further column chromatography purification and evaluated for their in vitro antimalarial potential. Relative to artemisinin (IC₅₀ = 6.978 nM), EAZA (IC₅₀ = 1.43 nM) and PAZA (IC₅₀ = 144.4 pM) exhibited approximately 3.5-fold and 30-fold greater antimalarial potency, respectively, while maintaining low cytotoxicity toward HepG2 cells, as indicated by their high cytotoxic concentration values. Thermogravimetric Analysis (TGA), isothermal titration calorimetry (ITC), and density functional theory (DFT) provided insights into their structure-property relationships. This study highlights the profound impact of minimal structural variations on the biological and thermal properties of azaartemisinins.

Non-typhoidal Salmonella (NTS) infections have gained global scientific attention due to the wide spectrum of illnesses they cause and associated treatment challenges. Antimicrobial therapy is critical for severe NTS infections, but the emergence of resistant strains raises concerns for public health authorities. This study focuses on the isolation of an extremely drug-resistant NTS serovar, Salmonella enterica serovar Weltevreden (S. Weltevreden), in India. The serovar was subjected to comprehensive biotyping, serotyping, antibiogram profiling, and ESBL production. The presence of blaCTX-M-15, blaTEM, blaSHV, and blaCMY-2 genes was also investigated in the isolate. The serovar was further tested for biofilm and colicin production. The findings revealed a high level of antimicrobial resistance exhibiting resistance to 16 out of the total 20 tested antimicrobial drugs viz. ampicillin, amikacin, ciprofloxacin, cotrimoxazole, cefepime, ceftriaxone, ceftazidime, cefotaxime, cefuroxime, gentamicin, kanamycin, meropenem, nalidixic acid, nitrofurantoin, norfloxacin, trimethoprim. The serovar was also found to be an ESBL producer, harboring the blaCTX-M-15 and blaCMY-2 genes. Biofilm and colicin production were also detected in the serovar. These findings point towards the extent of drug resistance present in the NTS serovar and the need for urgent attention from the public health authorities. Although, this study reports a single case of extensively drug-resistant NTS serovar, the possibility of more such serovars circulating in the community cannot be ruled out. Hence, there is an urgent need to implement effective antibiogram surveillance among NTS to detect such serovars and to formulate effective policies regarding antibiotic usage.

14-Deoxy-11,12-didehydroandrographolide (14-DDA, 3), a secondary metabolite found in Andrographis pan-iculata nees, has been synthetically modified into a new series of C-8 spiro-isoxazoline derivatives. Androgra-pholide and its derivatives were well reported for the anticancer activity so herein we have synthesised C-8 spiro-isoxazoline derivatives (4a-l) and screened for in vitro studies against four human cancer cell lines: breast (MCF-7), lung (A549), pancreatic (MiaPaCa-2), and prostate (PC-3). Most of the synthesized compounds exhibited better anti-cancer activities than the parent natural products andrographolide (1) and 14-deoxy-11,12-didehy-droandrographolide (3) for different human cancer lines. Among all compounds, compound 4k displayed most potent cytotoxicity (IC50 =3 mu M) in breast cancer cells (MCF-7). Further, mechanistic studies revealed that compound 4k affected the nuclear morphology of MCF-7 cells, increased the production of cellular and mito-chondrial ROS, decreased the mitochondrial membrane potential (MMP), and inhibited the colony formation. The compound 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. The expression of Cdk-4 was also downregulated by 4k. The overall findings of this study indicate that the compound 4k exhibited significant anticancer activity with reduced toxicity in-vitro and might thus be a promising anti-cancer lead candidate.

Salmonella and E. coli, both are gram negative, facultative anaerobe, non-spore forming bacilli which belongs to family Enterobacteriaceae. Salmonella species are leading cause of human gastroenteritis and typhoid fever. Pathogenic E.coli cause various diseases like diarrhea, UTI, sepsis and meningitis. Both of these bacteria consist wide range of virulence factors that help bacteria to invade the host, cause disease and evade host defenses. Moreover, virulence has also been directly related to multidrug resistance among bacteria. Salmonella and E. coli consist of wide range of virulence factors which has also been directly related to multidrug resistance. Although antimicrobial resistance and bacterial virulence have developed on different timescales, they share common characteristic that include the direct involvement of efflux pumps, porins, cell wall alterations and to activate or repress the expression of genes etc. Escherichia coli and Salmonella isolates from different sources (Human, Animal, Poultry, Food, Water, Farm environment) were taken for the study. Various virulence factors present in Salmonella and E. coli were detected by cell hydrophobicity, colicin, hemolysin production, siderophore production, aerobactin, gelatinase production. Antibiotic resistance among these isolates were also studied. The current study indicates that Salmonella and E. coli isolates from different sources possess variety of virulence factors that enables them to enhance their pathogenicity.

A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 μM) and PC-3 (IC50: 5.9 μM) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 μM. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.

Objectives: Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection, accounting for more than 80% of cases worldwide. This study presents data on prevalent serotypes, resistance profiles, and colonization-aiding virulence characteristics of UPEC from different geographical regions in India.Methods: UPEC were serotyped through microtiter plate agglutination. Standard techniques were used to detect various virulence characteristics, i.e., biofilm formation (tissue culture plate method), siderophore production (screened on Chrome Azurol S agar and categorized with Csaky's and Arnow's methods), colicin release (agar overlay technique), gelatin hydrolysis (on gelatinase agar), and cell surface hydrophobicity (salt aggregation method). Antibiotic resistance profiles (against 20 anti-microbial agents) and extended-spectrum beta-lactamase (ESBL) were evaluated according to Clinical and Labo-ratory Standards Institute guidelines. Results: UPEC strains exhibited very high drug resis-tance rates to most of the commonly used antimicrobial agents; the highest resistance rates were observed for ampicillin (63.4%), nalidixic acid (63.4%), and cefotax-ime (62.1%). High rates of multi-drug resistance (63.36%), ESBL-production (34.1%), and carbapenem-resistance (25.0%) were detected in UPEC strains from all geographical regions of India. Hydrophobicity (61.2%), biofilm production (62.5%), and siderophore production (67.7%) were the most common virulence characteristics of UPEC isolates. Co-expression of viru-lence characteristics was common (69.8%) in UPEC strains.Conclusion: UPEC strains with very high antimicrobial -resistance are in circulation in India, and have diverse serotypes and virulence characteristics.

Imidazo[1,2-a]pyridine has attracted much interest in drug development because of its potent medicinal properties, therefore the discovery of novel methods for its synthesis and functionalization continues to be an exciting area of research. Although transition metal catalysis has fuelled the most significant developments, extremely beneficial metal-free approaches have also been identified. Even though pertinent reviews focused on imidazo[1,2-a]pyridine synthesis, properties ( physicochemical and medicinal), and functionalization at the C3 position have been published, none of these reviews has focused on the outcomes obtained in the field of global ring functionalization. We wish here to describe a brief synthesis and an overview of all the functionalization reactions at each carbon atom, viz, C2, C3, C5, C6, C7 and C8 of this scaffold, divided into sections based on site-selectivity and the type of functionalization methods used.

The present work describes the s-trichlorotriazine (TCT)-mediated formation of highly functionalized ester-based drugs, namely nafamostat mesylate and camostat mesylate. The TCT-mediated activation of acids followed by the attack of a hydroxyl group (-OH group) resulted in the formation of ester. The high aqueous solubility of cyanuric acid eases the work-up process and avoids repetitive washing process (better E-factor). The present method also avoids using pyridine as a base, and instead of that, N-methylmorpholine (NMM) was used for the coupling. Moreover, we have also demonstrated the synthesis of key intermediates namely, 4-guanidinobenzoic acid and 6-hydroxy-2-naphthimidamide from economical and readily available raw materials. The TCT-mediated coupling provides many advantages in scalability, cost-effectiveness and environmental friendly handling.

The interrelationship between human development, financial development and economic growth exhibited a very interesting yet peculiar fact that human development is the prime determinant of the development process bestowing significantly to economic growth as well as the development of the financial sector in the Indian economy. To explore short-run as well as long-run interactions between financial development, human development and economic growth of the Indian economy, the autoregressive distributed lag (ARDL) bound test has been employed. It is vital to state that financial development is detected as negatively impacting the growth of the Indian economy; alternatively, growth could have been additionally enhanced through auxiliary human development instead of emphasising financial development at large. Therefore, the need of the hour is to formulate concrete plans and policies to spearhead the development of human resources through the promotion of education and health facilities as an integral part of our policy frame which may axiomatically reinforce the potency of the financial system as well as economic growth in India.

A library of 49 analogs of imidazo[1,2-a]pyridine with 2-halo, aryl, styryl and phenylethynyl-substitution at C-2 position and N-/O-/S-methyl linkage at C-3 position, have been synthesized and evaluated for their antiproliferative activity against breast (MCF-7, MDA-MB-231), pancreatic (MiaPaca-2), lung (A549), prostate (PC-3) and colon (HCT-116) cancer cell lines and normal cells (HEK-293). Among the screened compounds, 5b exhibited best anticancer potential in all tested cancer cells with IC50 ranging from 3.5 to 61.1 mu M and no toxicity in normal cells. Further, mechanistic study of 5b revealed concentration dependent increased generation of ROS, reduced mitochondrial membrane potential (MMP), surface and nuclear morphological alterations and inhibition of colony formation in HCT-116 cells. Western blot results had shown that the cell death in HCT-116 colon cancer cells was achieved through the induction of apoptosis via upregulation of the PTEN gene and downregulation of AKT pathway. Similarly, 5b treatment induced caspase-3 cleavage which is a hallmark of apoptosis. Molecular docking and binding energy (Delta G) studies of hit 5b with respect to three important cancer targets (EGFR, mTOR and PI3Ka) revealed strong binding of inhibitor with PI3Ka (docking score -6.932 and Delta G -56.297).

The present work was undertaken to study the ultrasonographic and clinico-biochemical parameters of hepatobiliary system in apparently healthy adult non gravid buffaloes. The present study revealed that, the hepatic parenchyma was homogenously coarse echogenic, interspersed with anechoic bands of hepatic vessels, with sharp margin and was hyperechoic relative to right renal cortex. It was imaged from just behind the last rib to the 6th intercostal space. The gallbladder was visualized between the 12th to 9th intercostal spaces, seen as a pear-shaped fluid-filled anechoic structure with hyperechoic wall, restricted to one to two intercostal spaces. The portal vein was seen as a stellate, branching, anechoic structure with hyperechoic wall and the hepatic vein as anechoic tubular structure with anechoic wall within the hepatic parenchyma. The caudal vena cava was observed as a triangular anechoic structure in transverse view and tubular in longitudinal view. It is concluded that the ultrasonography is a useful tool for the non-invasive examination of liver. Its sonographic appearance and parameters measured in healthy buffaloes can serve as reference values for the diagnosis of pathological changes in liver.

2-Arylquinazolines with a range of alkyl polyamines as side chain/ring functional motifs at the 4th-position were considered for antileishmanial study with the rationale that related heterocyclic scaffolds and polyamine functionalities are present in drugs, clinical trial agents, natural products and anti-parasitic/leishmanial agents. Synthesis involves construction of the 2-arylquinazolin-4-one ring and deoxyamination via deoxychlorination followed by SNAr-based amination or a methodology of SNAr-deoxyamination driven by BOP-mediated hydroxyl-activation. Various alkyl-polyamines important for activities were incorporated. A total of 26 compounds were prepared and screened against Leishmania donovani (Ld) promastigote cells using the MTT assay. Most of the investigated series of compounds showed characteristic leishmanicidal properties. Several compounds showed pronounced leishmanicidal activities (IC50: 5-6.5 μM) with higher efficiency than the antileishmanial drug miltefosine (IC50: 10.5 μM), and relatively less cytotoxicity to macrophage host cells (SI: 9.27-13.5) compared to miltefosine (SI: 3.42). Important pharmacophoric skeletons were identified.

Serotyping is the most widely used epidemiological marker to characterize pathogenic E. coli. Pathogenic E. coli is diverse as different serotypes are known to be prevalent in different area. Certain serotypes are known to be closely associated with pathotypes especially among diarrheagenic E. coli. Analysis of E. coli serotypes prevalence and its distribution pattern in different geographical area is important from better understanding its epidemiology and better control and management of E. coli diarrhea and non-intestinal infections. Present study was carried out to study prevalence of various “O”serogroups in clinical E. coli isolates in India and its distribution in different geographical locations of the country. A total of 783 clinical isolates suspected to be E. coli comprising of 437 Intestinal (human diarrheal) and 346 extra-intestinal isolates (human UTI) were biotyped using conventional Biotyping method to confirm isolates as E. coli. A total 534 confirmed E. coli isolates were sero-typed using specific anti E. coli “O” antiserum by micro titer plate agglutination assay. The 534 E. coli isolates were found to be clustered over 36 different groups. O8, O11, O22, O126, O88, O83, O35, O7, O149 and O141 being the most frequently detected “O” serogroups. Serogroup O157 was also detected in only seven isolates. Big six serotypes were not detected. This study indicates that diverse E. coli serotypes are in circulation in the country. With very low frequency of serogroup O157 frequently associated with EHEC/STEC.

A (4+1)‐annulation of arylidene heterocyclic‐N‐fused imidazolones with α‐carbonyl sulfoxonium ylides has been developed. The reaction enabled efficient access to a range of N‐heterocycle‐fused furans, such as secondary hydroxyl and the structural parts of drug/bioactive compounds. A unique triple‐role of α‐carbonyl sulfoxonium ylides and a characteristic stereo‐electronic functional behavior of the arylidene N‐fused imidazolones have been explored.

Objective: Non-typhoidal Salmonellae (NTS) are a neglected group of enteric pathogens whose prevalence is increasing at alarming rates across India. The disease burden is being underestimated because of a lack of effective surveillance of NTS infections in the Indian population. This study depicts the acquisition of NTS infection, and its persistence and spread through a diverse range of hosts, including humans and animals, and food and environmental sources.Methods: During the study period from 2016 to 2018, a total of 999 suspected NTS isolates were received from across India and were phenotypically and serologically characterized for the presence of NTS.Results: Of the 999 isolates, 539 (53.95%) were confirmed as NTS, consisting of 17 different NTS sero-vars. The majority were isolated from human samples (n = 319, 59.18%), followed by food products (n = 99, 18.37%), animals (n = 83, 15.4%) and the environment (n = 38, 7.05%). Some predominant serovars obtained included S. Typhimurium (n = 167, 30.98%), S. Lin-denberg (n = 135, 25.05%), S. Enteritidis (n = 56, 10.39%), S. Weltevreden (n = 44, 8.16%), S. Choler-aesuis (n = 41, 7.61%) and S. Mathura (n = 33, 6.12%). Conclusion: This study depicts the NTS disease burden across India, on the basis of the isolation of NTS serovars across diverse geographic locations. The emergence of newer or less common NTS serovars implicated in human infection poses a potential challenge to the healthcare system in India. Therefore, national and regional level surveillance is needed to implement effective control strategies and safeguard community health in India.

In order to understand the TLR pathway defence mechanism of Penaeus monodon, the essential molecule involved in the transduction of Toll-pathway, Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) was investigated by the mechanism of RNA interference (RNAi) by silencing of the mRNA expression of IRAK-4 gene.In this study we have developed short hairpin RNA (shRNA) construct in pSUPER vector targeting IRAK-4 gene silencing of TLR pathway in P. monodon.The silencing efficiency of pSh-IRAK-4 construct was first confirmed in-vitro in primary haemocyte culture by transfection using pSh-IRAK-4 plasmid, followed by induction with Lipopolysaccharides (LPS).Loss of expression of IRAK-4 was studied by relative gene expression in pSH-IRAK-4 group compared to LPS induced group, the maximum suppression of IRAK-4 gene in cell culture was recorded as 96% at 12h and 93.5% at 24h post LPS induction in pSh-IRAK-4 group.After confirmation of silencing efficiency of construct, the expression of TLR genes of IRAK-4 mediated pathway, was studied post LPS induction both in vitro using real-time qRT-PCR with β-actin as the internal reference gene.For this IRAK-4 downstream genes TRAF6, Dorsal and 4 Antimicrobial peptides (AMPs) (ALF, PEN, AST, Crustin) molecules were studied.Significant downregulation of mRNA expression level in downstream molecules of TLR pathway below IRAK-4 gene viz., TRAF6, Dorsal, and 4 AMPs (ALF, PEN, AST, Crustin) compared to LPS group in response to LPS stimulation was observed in pSh-IRAK-4 group (P ≤ 0.05).Taking all these results together, it is confirmed that TLR pathway is governed by central mediator kinase molecule IRAK-4, when induced by LPS ligand, NF-kB activates the downstream cascades of AMPs of the Toll pathway in P. monodon.Our result confirms the designing of a novel pSh-IRAK-4 construct and its application in efficient silencing of IRAK-4 gene in P. monodon.Plasmid-based IRAK-4 knockdown approach would provide an insight to the role of IRAK-4 in shrimp immune system.

A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/ functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo [1,2-a]pyridinones and (Z)-2-Arylidenebenzo[d]imidazo[2,1-b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-toproperties of the investigated chemotypes.