Delivery of mRNA Vaccine with 1, 2-Diesters-Derived Lipids Elicits Fast Liver Clearance for Safe and Effective Cancer Immunotherapy.

Messenger RNA (mRNA) vaccine is explored as a promising strategy for cancer immunotherapy, but the side effects, especially the liver-related damage caused by LNP, raise concerns about its safety. In this study, a novel library of 248 ionizable lipids comprising 1,2-diesters is designed via a two-step process involving the epoxide ring-opening reaction with carboxyl group-containing alkyl chains followed by an esterification reaction with the tertiary amines. Owing to the special chemical structure of 1,2-diesters, the top-performing lipids and formulations exhibit a faster clearance rate in the liver, contributing to increased stability and higher safety compared with DLin-MC3-DMA. Moreover, the LNP shows superior intramuscular mRNA delivery and elicits robust antigen-specific immune activation. The vaccinations delivered by the LNP system suppress tumor growth and prolong survival in both model human papillomavirus E7 and ovalbumin antigen-expressing tumor models. Finally, the structure of lipids which enhances the protein expression in the spleen and draining lymph nodes compared with ALC-0315 lipid in Comirnaty is further optimized. In conclusion, the 1, 2-diester-derived lipids exhibit rapid liver clearance and effective anticancer efficiency to different types of antigens-expressing tumor models, which may be a safe and universal platform for mRNA vaccines.

Mpox virus mRNA-lipid nanoparticle vaccine candidates evoke antibody responses and drive protection against the Vaccinia virus challenge in mice.

In response to the human Mpox (hMPX) epidemic that began in 2022, there is an urgent need for a monkeypox vaccine. Here, we have developed a series of mRNA-lipid nanoparticle (mRNA-LNP)-based vaccine candidates that encode a collection of four highly conserved Mpox virus (MPXV) surface proteins involved in virus attachment, entry, and transmission, namely A29L, A35R, B6R, and M1R, which are homologs to Vaccinia virus (VACV) A27, A33, B5, and L1, respectively. Despite possible differences in immunogenicity among the four antigenic mRNA-LNPs, administering these antigenic mRNA-LNPs individually (5 µg each) or an average mixture of these mRNA-LNPs at a low dose (0.5 µg each) twice elicited MPXV-specific IgG antibodies and potent VACV-specific neutralizing antibodies. Furthermore, two doses of 5 µg of A27, B5, and L1 mRNA-LNPs or a 2 µg average mixture of the four antigenic mRNA-LNPs protected mice against weight loss and death after the VACV challenge. Overall, our data suggest that these antigenic mRNA-LNP vaccine candidates are both safe and efficacious against MPXV, as well as diseases caused by other orthopoxviruses.

Evolutionary dissection of monkeypox virus: Positive Darwinian selection drives the adaptation of virus-host interaction proteins.

The emerging and ongoing outbreak of human monkeypox (hMPX) in 2022 is a serious global threat. An understanding of the evolution of the monkeypox virus (MPXV) at the single-gene level may provide clues for exploring the unique aspects of the current outbreak: rapidly expanding and sustained human-to-human transmission. For the current investigation, alleles of 156 MPXV coding genes (which account for >95% of the genomic sequence) have been gathered from roughly 1,500 isolates, including those responsible for the previous outbreaks. Using a range of molecular evolution approaches, we demonstrated that intra-species homologous recombination has a negligible effect on MPXV evolution. Despite the fact that the majority of the MPXV genes (64.10%) were subjected to negative selection at the whole gene level, 10 MPXV coding genes (MPXVgp004, 010, 012, 014, 044, 098, 138, 178, 188, and 191) were found to have a total of 15 codons or amino acid sites that are known to evolve under positive Darwinian selection. Except for MPXVgp138, almost all of these genes encode proteins that interact with the host. Of these, five ankyrin proteins (MPXVgp004, 010, 012, 178, and 188) and one Bcl-2-like protein (MPXVgp014) are involved in poxviruses' host range determination. We discovered that the majority (80%) of positive amino acid substitutions emerged several decades ago, indicating that these sites have been under constant selection pressure and that more adaptable alleles have been circulating in the natural reservoir. This finding was also supported by the minimum spanning networks of the gene alleles. The three positive amino acid substitutions (T/A426V in MPXVgp010, A423D in MPXVgp012, and S105L in MPXVgp191) appeared in 2019 or 2022, indicating that they would be crucial for the virus' eventual adaptation to humans. Protein modeling suggests that positive amino acid substitutions may affect protein functions in a variety of ways. Further study should focus on revealing the biological effects of positive amino acid substitutions in the genes for viral adaptation to humans, virulence, transmission, and so on. Our study advances knowledge of MPXV's adaptive mechanism and provides insights for exploring factors that are responsible for the unique aspects of the current outbreak.

Benzimidazole analogues as efficient arsenals in war against methicillin-resistance staphylococcus aureus (MRSA) and its SAR studies.

Small molecule based inhibitors development is a growing field in medicinal chemistry. In recent years, different heterocyclic derivatives have been designed to counter the infections caused by multi-drug resistant bacteria. Indeed, small molecule inhibitors can be employed as an efficient antibacterial agents with different mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming lethal to mankind due to easy transmission mode, rapid resistance development to existing antibiotics and affect difficult-to-treat skin and filmsy diseases. Benzimidazoles are a class of heterocyclic compounds which have capability to fight against MRSA. High biocompatibility of benzimidazoles, synergistic behaviour with antibiotics and their tunable physico-chemical properties attracted the researchers to develop new benzimidazole based antibacterial agents. The present review focus on recent developments of benzimidazole-hybrid molecules as anti MRSA agents and the results of in-vitro and in-vivo studies with possible mechanism of action and discussing structure-activity relationship (SAR) in different directions. Benzimdazoles act as DNA binding agents, enzyme inhibitors, anti-biofilm agents and showed synergistic effect with available antibiotics to achieve antibacterial activity against MRSA. This cumulative figures would help to design new benzimidazole-based MRSA growth inhibitors.

Structure-activity relationships (SAR) of triazine derivatives: Promising antimicrobial agents.

The emergence of drug resistance has created unmet medical need for the development of new classes of antibiotics. Innovation of new antibacterial agents with new mode of action remains a high priority universally. Triazines are six-membered, nitrogen-containing heterocyclic scaffold with a wide range of pharmaceutical properties such as antibacterial, antifungal, anticancer, antioxidants, antitubercular, antimalarial, anti-HIV, anticonvulsant, anti-inflammatory, antiulcer, and analgesic activities. The present review focuses on the recent developments in the area of medicinal chemistry to discover various chemical structures as potential antimicrobial agents and their structure-activity relationships (SAR) studies are also discussed for further rational design of this kind of derivatives.

Rh-Catalyzed Highly Enantioselective Synthesis of Aliphatic Sulfonyl Fluorides.

Rh-catalyzed, highly enantioselective (up to 99.8% ee) synthesis of aliphatic sulfonyl fluorides was accomplished. This protocol provides a portal to a class of novel 2-aryl substituted chiral sulfonyl fluorides, which are otherwise extremely difficult to access. This asymmetric synthesis has the feature of mild conditions, excellent functional group compatibility, and wide substrate scope (51 examples) generating a wide array of structurally unique chiral ß-arylated sulfonyl fluorides for sulfur(VI) fluoride exchange (SuFEx) click reaction and drug discovery.

Making Carbonyls of Amides Nucleophilic and Hydroxyls of Alcohols Electrophilic Mediated by SO2F2 for Synthesis of Esters from Amides.

We discovered that with the promotion of sulfuryl fluoride, the carbonyl groups of amides performed as nucleophiles while the hydroxyl groups of alcohols were activated to functionalize as electrophiles. This study displayed that the amide C-N bonds could be easily cleaved with delicate nucleophiles to form the ester C-O bonds at room temperature without using transition metals. The broad substrate scope and excellent functional group compatibility were proved with 44 examples in up to 99% yields.

Regioselective installation of fluorosulfate (-OSO2F) functionality into aromatic C(sp2)-H bonds for the construction of para-amino-arylfluorosulfates.

The construction of para-amino-arylfluorosulfates was achieved through installation of fluorosulfate (-OSO2F) functionality into aromatic C(sp2)-H bonds by the reaction of N-arylhydroxylamine with sulfuryl fluoride (SO2F2). This method provides a mild process for the preparation of broadly applicable fluorosulfate moieties without the requirement of phenols or transition metals.

Discovery of novel arylethenesulfonyl fluorides as potential candidates against methicillin-resistant of Staphylococcus aureus (MRSA) for overcoming multidrug resistance of bacterial infections.

The multidrug-resistant Staphylococcus aureus (MRSA) is one of the most prevalent human pathogens involved in many minor to major disease burdens throughout the world. Inhibition of biofilm formation is an attractive strategy to treat diseases associated with MRSA infection. In the present investigation, a series of functional group diverse (hetero)aryl fluorosulfonyl analogs were designed, synthesized and tested as antibacterial agents against Staphylococcal spp., and as anti-biofilm candidates. Compounds 8, 15, and 67 were found to possess potent in vitro antibacterial activity among this class of sulfonyl fluorides (MIC = 0.818 ±â€¯0.42, 0.840 ±â€¯0.37 and 0.811 ±â€¯0.37 µg/mL respectively). The analogs 8, 15, 36, and 67 exhibited outstanding anti-biofilm properties compared to other available synthetic antibiotics. The efficacy of synthetic analogs displayed membrane-damaging effect and they are also validated by cellular content release assay. The insight physiological changes were explored by studying the intracellular redox activities through changing cyclic voltammetric (CV) method. The compounds 8, 15, 22, 32, 36, 51, and 67 were found to participate in the interfering in the electron transport chain (ETC) of MRSA. The analogs 8, 15, and 67 possess great potentiality for discovery and development of anti-staphylococcal drugs to treat the MRSA infections.

Pharmaceutical significance of azepane based motifs for drug discovery: A critical review.

Azepane-based compounds showed a variety of pharmacological properties, and its derivatives possess a high degree of structural diversity, and it is useful for the discovery of new therapeutic agents. The development of new less toxic, low-cost and highly active azepane-containing analogs is a hot research topic in medicinal chemistry. Now, more than 20 azepane-based drugs have been approved by FDA, and widely used to treat various types of diseases. This review highlights the recent developments of azepane-based compounds in a wide range of therapeutic applications, such as anti-cancer, anti-tubercular, anti-Alzheimer's disease, and antimicrobial agents, as well as, histamine H3 receptor inhibitors, α-glucosidase inhibitors, anticonvulsant drugs and other miscellaneous applications. We here briefly describe the structure-activity relationship (SAR) and molecular docking studies of potential bioactive compounds for future discovery of suitable drug candidates. It can serve as an inspiration for new ideas for design and development of less toxic and more powerful azepane-based drugs against numerous devastating diseases.

SO2F2-Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes.

Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C≡C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).

Ethenesulfonyl fluoride derivatives as telomerase inhibitors: structure-based design, SAR, and anticancer evaluation in vitro.

Based on our previous docking model, in order to carry out more rational drug design, totally 82 vinyl sulfonyl fluorides, including some 2-(hetero)arylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides derivatives as potential human telomerase inhibitors were designed and synthesised. The in vitro anticancer activity assay showed that compound 57 (1E,3E)-4-(4-((E)-2-(fluorosulfonyl)vinyl)phenyl)buta-1,3-diene-1-sulfonyl fluoride exhibited high activity against A375 and MDA-MB-231 cell lines with IC50 1.58 and 3.22 µM, but it manifested obvious un-toxic effect against GES-1 and L-02 with IC50 with IC50 values less than 2.00 mM. By the modified TRAP assay, some compounds including 57 exhibited potent inhibitory activities against telomerase with IC50 values of 0.71-0.97 µM.

A portal to a class of novel sultone-functionalized pyridines via an annulative SuFEx process employing earth abundant nickel catalysts.

An efficient nickel catalyzed annulative process for the synthesis of a class of structurally unique heterocycles containing pharmaceutically important moieties of both pyridines and sultones was developed by using SuFEx chemistry. This mild and efficient method features a wide scope to serve as an irreplaceable asset for medicinal chemistry and drug discovery.

Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents.

A series of new benzo[d]thiazole-hydrazones analogues were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compounds 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the reference drug chloramphenicol and rifampicin. Compounds 5, 9, 10, 11, 12, 28 and 30 were found to be good antifungal activity compared to the standard drug ketoconazole. A preliminary study of the structure-activity relationship (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the phenyl ring. The electron donating (OH and OCH3) groups presented in the analogues, increase the antibacterial activity (except compound 12), interestingly, while the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 19 and 20). In addition, analogues containing thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliphatic analogues (24-26) shown no activities in both bacterial and fungal stains even in high concentrations (100µg/mL). Molecular docking studies were performed for all the synthesized compounds of which compounds 11, 19 and 20 showed the highest glide G-score.

Discovery of potential anticancer multi-targeted ligustrazine based cyclohexanone and oxime analogs overcoming the cancer multidrug resistance.

The drug research and development nowadays is focusing on multi-target drugs. In the treatment of cancer, therapies using drugs inhibiting one numerous targets signify a novel viewpoint. In comparison with traditional therapy, multi-targeted drugs directly aim cell subpopulations which are involved in progression of tumor. The current study comprises the synthesis of 34 novel ligustrazine-containing α, ß-unsaturated carbonyl-based compounds and oximes. The growth of 5 various cancer cell types was strongly inhibited by ligustrazine-containing oximes as revealed by biological evaluation. A strong SAR was provided by the antiproliferative activity. The mechanistic effects of most active antiproliferative compounds on tubulin polymerization, EGFR TK kinases, KAF and BRAFV600E were investigated, followed by in vitro investigation of reversal of efflux-based resistance developed by cancer cells. EGFR was strongly inhibited by two oximes 7e and 8o. Out of all linkers including positive control, 1-isopropyl-piperidin-4-one linker-bearing compounds showed best inhibition of FAK. The strongest inhibitory activity of BRAFV600E was showed by compound 5e with an IC50 of 0.7 µM. Analogs such as 5 and 7 (b,e,f) exhibited a dual role as anticancer as well as MDR reversal agents. For understanding the target protein integrations with new compounds, molecular docking studies were also carried out.

Palladium-Catalyzed Fluorosulfonylvinylation of Organic Iodides.

A palladium-catalyzed fluorosulfonylvinylation reaction of organic iodides is described. Catalytic Pd(OAc)2 with a stoichiometric amount of silver(I) trifluoroacetate enables the coupling process between either an (hetero)aryl or alkenyl iodide with ethenesulfonyl fluoride (ESF). The method is demonstrated in the successful syntheses of eighty-eight otherwise difficult to access compounds, in up to 99 % yields, including the unprecedented 2-heteroarylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides.

Cooperativity of axial and centre chirality in the biaryl disulfoxide/Rh(i)-catalysed asymmetric 1,4-addition of arylboronic aids to 2-cyclohexenone: a DFT study.

Atropisomeric biaryl disulfoxides contain two independent chiral elements. Previously, the (M,S,S)-diastereomer showed very high catalytic activity and selectivity in the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,ß-enones whereas the (M,R,R) counterpart - none. Herein, DFT computations on the key transmetallation (turnover-determining) and carborhodation (enantioselectivity-determining) steps of the catalytic cycle show that the (M,S,S)-ligand gives rise to lower reaction barriers for these elementary steps. However, the barriers for the (M,R,R)-ligand are not sufficiently high to explain the lack of reactivity. Hence, this phenomenon is most likely due to the failure of catalyst formation from the ligand and the dimeric Rh precatalyst complex. The hitherto unknown (M,S,R)-ligand shows predicted enantioselectivity similar to the (M,S,S)-ligand as a consequence of lower reaction barriers associated with those isomers whose key features resemble the (M,S,S)-ligand.

Synthesis of benzo[d]thiazole-hydrazone analogues: molecular docking and SAR studies of potential H+/K+ ATPase inhibitors and anti-inflammatory agents.

A series of new benzo[d]thiazole-hydrazones were synthesized and characterized by analytical and spectroscopic techniques. All the compounds were screened for their in vitro inhibition of H+/K+ ATPase and anti-inflammatory effects. The results revealed that compounds 6-8, 13-15, 18-20, 22, 23 and 27-30 displayed excellent inhibitory activity against H+/K+ ATPase, and their IC50 values were lower than those of the standard compound omeprazole. Compounds 2-5, 9-12, 28 and 30 exhibited better anti-inflammatory activity in comparison to the standard compound indomethacin. Studies of the structure-activity relationship (SAR) showed that electron-donating groups (OH and OCH3) favored inhibitory activity against H+/K+ ATPase, whereas electron-withdrawing groups (F, Cl, Br and NO2) favored anti-inflammatory activity, and derivatives with both electron-donating (OH and OCH3) and electron-withdrawing (Br) groups (16-18) displayed reasonable activity, whereas aliphatic analogues (24-26) exhibited less activity and heterocyclic analogues (27-30) displayed moderate activity in both biological studies. Molecular docking studies were performed for all the synthesized compounds, among which compounds 19 and 20 exhibited the highest docking scores for inhibitory activity against H+/K+ ATPase, whereas compounds 10 and 12 displayed the highest docking scores for anti-inflammatory activity.

Expeditious trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodoniums by [XCF3]- (X = S, Se) anions.

Trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodonium tosylates by [XCF3]- (X = S, Se) ions was accomplished in 5-10 minutes at room temperature under a N2 atmosphere and provided a variety of alkynyl trifluoromethyl sulfides and selenides in good yields. Compared to the known methods, this approach has several advantages such as short reaction times and metal- and additive-free conditions without needing excess [Me4N][XCF3] reagents. Moreover, the less efficient reactions of (phenylethynyl)benziodoxol(on)e with [Me4N][XCF3] under the standard conditions demonstrate that acyclic alkynyl(phenyl)iodoniums are more powerful alkynyl sources in the conversion. This protocol allows for a fast and convenient access to numerous alkynyl trifluoromethyl sulfides and selenides.

Biological evaluation of synthetic α,ß-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-ß aggregation.

A series of new α,ß-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aß1-42 aggregation. The effect of these compounds against amyloid ß-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aß1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037µM) inhibitory potential. Furthermore, compound 3o disassembled the Aß fibrils produced by self-induced Aß aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aß aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aß-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.