Morpholinodiazenyl chalcone blocks influenza A virus capsid uncoating by perturbing the clathrin-mediated vesicular trafficking pathway.

Influenza A virus (IAV) is a highly contagious respiratory pathogen that significantly threatens global health by causing seasonal epidemics and occasional, unpredictable pandemics. To identify new compounds with therapeutic potential against IAV, we designed and synthesized a series of 4'-morpholinodiazenyl chalcones using the molecular hybridization method, performed a high-content screen against IAV, and found that (E)-1-{4-[(E)-morpholinodiazenyl]phenyl}-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (MC-22) completely neutralized IAV infection. While MC-22 allowed IAV to successfully internalize into the cell and fuse at the acidic late endosomes, it prevented viral capsid uncoating and genome release. Since IAV majorly utilizes clathrin-mediated endocytosis (CME) for cellular entry, we examined whether MC-22 had any effect on CME, using nonviral cargoes that enter cells via clathrin-dependent or -independent pathways. Although MC-22 showed no effect on the uptake of choleratoxin B, a cargo that enters cells majorly via the clathrin-independent pathway, it significantly attenuated the clathrin-dependent internalization of both epidermal growth factor and transferrin. Cell biological analyses revealed a marked increase in the size of early endosomes upon MC-22 treatment, indicating an endosomal trafficking/maturation defect. This study reports the identification of MC-22 as a novel CME-targeting, highly potent IAV entry inhibitor, which is expected to neutralize a broad spectrum of viruses that enter the host cells via CME.

First-in-class pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones against leishmaniasis and tuberculosis: Rationale, in vitro, ex vivo studies and mechanistic insights.

Pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones were synthesized, for the first time, from indole chalcones and 6-aminouracil, and their ability to inhibit leishmaniasis and tuberculosis (Tb) infections was evaluated. The in vitro antileishmanial activity against promastigotes of Leishmania donovani revealed exceptional activities of compounds 3, 12 and 13, with IC50 values ranging from 10.23 ± 1.50 to 15.58 ± 1.67 µg/ml, which is better than the IC50 value of the standard drug pentostam of 500 µg/ml. The selectivity of the compounds towards Leishmania parasites was evaluated via ex vivo studies in Swiss albino mice. The efficiency of these compounds against Tb infection was then evaluated using the in vitro anti-Tb microplate Alamar Blue assay. Five compounds, 3, 7, 8, 9 and 12, showed MIC100 values against the Mycobacterium tuberculosis H37 Rv strain at 25 µg/ml, and compound 20 yielded an MIC100 value of 50 µg/ml. Molecular modelling of these compounds highlighted interactions with binding sites of dihydrofolate reductase, pteridine reductase and thymidylate kinase, thus establishing the rationale of their pharmacological activity against both pathogens, which is consistent with the in vitro results. From the above results, it is clear that compounds 3 and 12 are promising lead candidates for Leishmania and Mycobacterium infections and may be promising for coinfections.

Stimuli-Responsive Cycloaurated "OFF-ON" Switchable Anion Transporters.

Anion transporters have shown potential application as anti-cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are "switched on" in situ in the presence of the reducing agent GSH by decomplexation of gold. GSH is found in higher concentrations in tumors than in healthy tissue and hence this approach offers a strategy to target these systems to tumors.

Enhancing antifungal properties of chitosan by attaching isatin-piperazine-sulfonyl-acetamide pendant groups via novel imidamide linkage.

World health organization listed fungi as priority pathogens in 2022 to counter their adverse effects on human well-being. The use of antimicrobial biopolymers is a sustainable alternative to toxic antifungal agents. In this study, we explore chitosan as an antifungal agent by grafting a novel compound N-(4-((4-((isatinyl)methyl)piperazin-1-yl)sulfonyl)phenyl) acetamide (IS). The acetimidamide linkage of IS to chitosan herein was confirmed by 13C NMR and is a new branch in chitosan pendant group chemistry. The modified chitosan films (ISCH) were studied using thermal, tensile, and spectroscopic methods. The ISCH derivatives strongly inhibit fungal pathogens of agricultural and human importance, namely Fusarium solani, Colletotrichum gloeosporioides, Myrothecium verrucaria, Penicillium oxalicum, and Candida albicans. ISCH80 showed an IC50 value of 0.85 µg/ml against M. verrucaria and ISCH100 with IC50 of 1.55 µg/ml is comparable to the commercial antifungal IC50 values of Triadiamenol (3.6 µg/ml) and Trifloxystrobin (3 µg/ml). Interestingly, the ISCH series remained non-toxic up to 2000 µg/ml against L929 mouse fibroblast cells. The ISCH series showed long-standing antifungal action, superior to our lowest observed antifungal IC50 values of plain chitosan and IS at 12.09 µg/ml and 3.14 µg/ml, respectively. ISCH films are thus suitable for fungal inhibition in an agricultural setting or food preservation.

Chitosan with pendant (E)-5-((4-acetylphenyl)diazenyl)-6-aminouracil groups as synergetic antimicrobial agents.

Conventional antimicrobial agents are losing the war against drug resistance day-by-day. Chitosan biopolymer is one of the alternative materials that lends itself well to this application by fine-tuning its bioactivity using different pendant groups. Herein, we report the synthesis of novel chitosan with pendant (E)-5-((4-acetylphenyl)diazenyl)-6-aminouracil (APAU) groups by forming Schiff base linkages between chitosan and the pendant groups. These chitosan biopolymers with pendant APAU groups form films superior in thermal stability compared to the neat chitosan. Interestingly, APAU alone was inactive against K. pneumoniae, E. coli, S. aureus, T. rubrum and C. albicans. However, novel chitosan samples were active against S. aureus with an MIC of 390 µg mL-1, half that of plain chitosan at 780 µg mL-1. APAU modified chitosan samples, CA80 and CA100 showed an MIC (against K. pneumoniae and E. coli) of 23.4 µg mL-1, superior to plain chitosan's MIC of 187.5 µg mL-1 and is close to commercial Fluconazole's MIC of 11.7 µg mL-1. The activity of chitosan changes with APAU content and at higher concentrations shows a strong synergetic antimicrobial effect.

Uracil derivatives as HIV-1 capsid protein inhibitors: design, in silico, in vitro and cytotoxicity studies.

A series of novel uracil derivatives such as bispyrimidine dione and tetrapyrimidine dione derivatives were designed based on the existing four-point pharmacophore model as effective HIV capsid protein inhibitors. The compounds were initially docked with an HIV capsid protein monomer to rationalize the ideas of design and to find the potential binding modes. The successful design and computational studies led to the synthesis of bispyrimidine dione and tetrapyrimidine dione derivatives from uracil and aromatic aldehydes in the presence of HCl using novel methodology. The in vitro evaluation in HIV p24 assay revealed five potential uracil derivatives with IC50 values ranging from 191.5 µg ml-1 to 62.5 µg ml-1. The meta-chloro substituted uracil compound 9a showed promising activity with an IC50 value of 62.5 µg ml-1 which is well correlated with the computational studies. As expected, all the active compounds were noncytotoxic in BA/F3 and Mo7e cell lines highlighting the thoughtful design. The structure activity relationship indicates the position priority and lower log P values as the possible cause of inhibitory potential of the uracil compounds.

Acetylene containing 2-(2-hydrazinyl)thiazole derivatives: design, synthesis, and in vitro and in silico evaluation of antimycobacterial activity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis resistance to commercially available drugs is increasing day by day. To address this issue, various strategies were planned and are being implemented. However, there is a need for new drugs and rapid diagnostic methods. For this endeavour, in this paper, we present the synthesis of acetylene containing 2-(2-hydrazinyl) thiazole derivatives and in vitro evaluation against the H37Rv strain of Mycobacterium tuberculosis. Among the developed 26 acetylene containing 2-(2-hydrazinyl) thiazole derivatives, eight compounds inhibited the growth of Mycobacterium tuberculosis with MIC values ranging from 100 µg ml-1 to 50 µg ml-1. The parent acetylene containing thiosemicarbazones showed promising antimycobacterial activity by inhibiting up to 75% of the Mycobacterium at 50 µg ml-1. In addition, in silico studies were employed to understand the binding mode of all the novel acetylene-containing derivatives against the KasA protein of the Mycobacterium. Interestingly, the KasA protein interactions with the compounds were similar to the interactions of KasA protein with thiolactomycin and rifampicin. Cytotoxicity study results indicate that the compounds tested are non-toxic to human embryonic kidney cells.

Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections.

Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.

Therapeutic potential of uracil and its derivatives in countering pathogenic and physiological disorders.

Uracil is one of the most notable pharmacophores in medicinal chemistry as the pyrimidine nucleobase forms an integral part of many commercial drugs. Though the name uracil is usually associated with cancer drugs, there are many uracil-based compounds which can treat different diseases when they are employed. So far, there has been no in-depth review concerning uracil drugs in the market, or in the different stages of clinical trials, including those approved or discontinued. The current work focuses on the importance of uracil and its derivatives in treating different diseases. The use of uracil compounds in treating viral infections, cancer, diabetic, thyroid and autosomal recessive disorders are discussed in the review. The mechanism of action of each uracil drug with emphasis on their structure and properties are discussed in detail. The targeted action of these drugs on sites or on the different stages of a disorder/pathogenic life cycle are also discussed. This review encompasses uracil drugs approved as well as those in development from the 1950's onwards. The utility of uracil in drug discovery and its association with a wide range of diseases is brought forth within this review to demonstrate its potential to a wider audience.

In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.

Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis.

Indole chalcones were designed and synthesized as a promising set of compounds against H37Rv strain of Mycobacterium tuberculosis. Within this library of compounds, (E)-1-(furan-3-yl)-3-(1H-indol-3-yl)prop-2-en-1-one (18), (E)-3-(1H-indol-3-yl)-1-(thiophen-2-yl)prop-2-en-1-one (20) and (E)-2-((1H-indol-2-yl)methylene)cyclopentan-1-one (24) displayed high anti-tubercular activity at 50 µg/ml with MIC values of 210, 197 and 236 µM respectively. The in-silico studies revealed that compound 18 exhibit binding modes similar to FAS-II inhibitors like INH or Thiolactomycin against KasA protein. Cytotoxicity assay results suggest that the compounds 18, 20 and 24 are non-cytotoxic to human megakaryocytes and murine B cells.

Clinico-Epidemiological Study and Treatment Outcome of Multinodular Goitre at A Tertiary Care Hospital.

BACKGROUND: Thyroid enlargement has been a common problem encountered in general surgical practice. Thyroid being an endocrine gland, its involvement has a diverse issue from a meagre cosmetic problem to a more concerned malignancy. AIM: This study was conducted to study the age and sex distribution along with the mode of presentation of Multinodular Goitre (MNG). The incidence of malignancy and the surgical complications in the study population were also studied. MATERIALS AND METHODS: In this descriptive study, patients diagnosed with MNG from January 2011 to July 2012 were chosen from the in-patient of our teaching hospital. One hundred such patients who qualified to undergo surgery were included in the study after a detailed history and clinical examination. Patients underwent Fine needle aspiration cytology (FNAC) for preoperative pathological diagnosis and the goitre was confirmed to be benign. Patients diagnosed with malignancy were excluded from the study. Following thyroidectomy, the thyroid specimens were subjected to histopathological examination. RESULTS: Among the 100 cases of MNG, 59% patients belonged to 3rd and 4th decade of life, 90% patients were females, 82% presented before 5yrs. The most common symptom at presentation was swelling (100%). Among the patients 80% were in euthyroid state, 19% were hyperthyroid and 1% hypothyroid. Most of the patients were treated with sub-total thyroidectomy (59%), followed by total (20%), near total (11%), and Hemithyroidectomy (10%). Following surgery complications like stridor and laryngeal oedema (3%), wound infection (2%), hypocalcemia (2%), haemorrhage (1%) and seroma (1%) were noted. On Histopathological examination (HPE) of the surgical specimen, 3% were reported to be malignant. CONCLUSION: As noted by this study, Multinodular Goitre is more common among females in the third and fourth decades. Patients can present with various complaints. MNG can present as hyperthyroid, hypothyroid but mostly in euthyroid state. The indication for surgery in patients with MNG includes cosmesis, hyperthyroidism, local compressive symptoms and most importantly malignancy. Subtotal thyroidectomy is the preferred surgery, but a trend towards total and near total thyroidectomy is noticeably replacing the old belief in subtotal thyroidectomy.

Eccrine porocarcinoma: a case report.

Eccrine porocarcinoma is an extremely rare malignancy of the eccrine sweat gland. It is believed to arise from the intra-epithelial portion of eccrine sweat glands. It can either arise de novo or it can develop in a long standing eccrine poroma. It often occurs in the elderly, with the mean age of occurrence being 67 years. The tumour favours extremities, particularly the legs and feet. The propensity to form multiple cutaneous metastases is an unusual feature of eccrine porocarcinoma. It is also associated with visceral metastasis, resulting in death. An early diagnosis and prompt treatment are thus essential, owing to the aggressive behaviour of the tumour. Keeping in view its rarity of occurrence, we are hereby presenting a case of eccrine porocarcinoma which occurred in a 55-year-old female.