Rifamycin Derivatives Research Articles

Effect of Co‐Crystallization on Physicochemical and Pharmacokinetic Properties of Rifaximin

AbstractRifaximin, a semi‐synthetic derivative of rifamycin is a BCS class IV drug having poor physicochemical properties. These poor physicochemical properties pose a major challenge in dosage form production and limited bioavailability restricts the systemic use of rifaximin. This study focuses on the improvement of physicochemical properties and in‐vivo bioavailability of rifaximin by utilizing co‐crystallization approach. Co‐crystallization of rifaximin with l‐proline (amino acid) resulted in improvement of physicochemical properties like saturation solubility, dissolution rate, flow‐ability, and 1.5‐fold improvement in anti‐microbial activity as compared to pure rifaximin. Ex‐vivo permeation rate was improved approximately two‐fold and in an in‐vivo study utilizing Sprague Dawley rats, relative bioavailability was estimated to be 785.5967±55.8986. The data suggest exponential improvement of both, physicochemical properties and bioavailability in the co‐crystallized form of rifaximin. This study might be a first step for the use of rifaximin in systemic infections and may open a path for rifaximin as a drug of choice for various bacterial infections.

Rifaximin: A Comprehensive Review of Structure, Uses, Mechanisms of Action, and Assay Methods

Rifaximin, a derivative of rifamycin, has emerged as a promising therapeutic tool in gastroenterology. This review explores rifaximin's intricate molecular structure and pharmacokinetic properties, highlighting its minimal systemic absorption and targeted action within the gut. The multifaceted mechanisms of action, including direct antibacterial effects and modulation of gut microbiota, are discussed. The review then examines the efficacy of rifaximin in treating various gastrointestinal disorders like traveler's diarrhea, Irritable Bowel Syndrome with Diarrhea (IBS-D), and Small Intestinal Bacterial Overgrowth (SIBO). Dosage recommendations and the well-tolerated safety profile of rifaximin are presented. Finally, the importance of quality control measures using techniques like HPLC and spectroscopy is emphasized to ensure the drug's effectiveness and safety.

Inhibition of porcine reproductive and respiratory syndrome virus replication by rifampicin in vitro.

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause significant economic losses to the global swine industry, yet effective prevention and control measures remain elusive. The development of novel antivirals is thus urgently needed. Rifampicin (RFP), a semisynthetic derivative of rifamycin, has been previously reported to inhibit the replication of certain mammalian DNA viruses as well as RNA viruses. In this study, we unveil RFP as a potent inhibitor of PRRSV both in Marc-145 cells (half-maximal inhibitory concentration 61.26 μM) and porcine alveolar macrophages (half-maximal inhibitory concentration 53.09 μM). The inhibitory effect of RFP occurred during viral replication rather than binding, internalization and release. We also demonstrated that RFP inhibits PRRSV proteins production in the early stage of infection, without inhibiting host protein synthesis. Moreover, RFP effectively restricted porcine epidemic diarrhea virus (PEDV) and porcine enteric alphacoronavirus (PEAV) infection in Vero cells. In summary, these findings indicate the promising potential of RFP as a therapeutic agent for PRRSV, PEDV and PEAV infection in pig farms.

A SYSTEMATIC MAPPING REVIEW OF IN-VITRO AND IN-VIVO EVIDENCES EXPLORING THE ROLE OF STRAIN-SPECIFIC PROBIOTIC BIFIDOBACTERIUM LONGUM W11

The gut microbiome has a significant role in overall well-being. Various probiotics are currently used for the improvement of the gut microbiome; the current scoping review aimed to critically examine the effectiveness of Bifidobacterium longum W11 in healthy and disease states. A thorough search of the literature was done in three scientific databases (PubMed, ScienceDirect, and Google Scholar) to identify and retrieve in-vitro, pre-clinical, and clinical evidence that evaluated the effect of B. longum W11 probiotic. Two independent reviewers identified and screened articles, published from 2000 to 2023 from the databases. Data from eligible studies were extracted, compiled, critically evaluated for scientific strength, and presented in this scoping review. Initially, 663 articles were identified and after a complete screening and evaluation process, twenty-one articles (eight in-vitro and animal studies; thirteen clinical studies) were included. Pre-clinical data suggest that B. longum W11 can withstand the severe gastrointestinal environment and colonize the intestinal epithelial cells to a significant degree. Due to the presence of a specific EPS cluster gene, B. longum W11 is capable of producing unique exopolysaccharides that might be responsible for the adhesion and functional capabilities of B. longum W11. Additionally, the specific mutation in the rpoB gene confers the B. longum W11 resistance to all rifamycin derivatives (including rifaximin). Clinical studies involving individuals with constipation and irritable bowel syndrome have shown that B. longum W11 supplementation significantly improves the overall quality of life and reduces the severity of symptoms. Furthermore, B. longum W11 was found to be effective in minimal hepatic encephalopathy and active celiac disease conditions. Due to the antibiotic resistance, the simultaneous use of rifaximin and B. longum W11 in patients with uncomplicated diverticular disease condition resulted in greater improvement in various symptoms compared to rifaximin supplementation alone. These data suggest that B. longum W11 is a potential probiotic that can be administered along with antibiotics in various gastrointestinal disease conditions. This evidence suggests that B. longum W11 is a promising probiotic with potential applications in various functional and inflammatory GI-related complications. Further clinical studies and stringent systematic reviews are needed to strengthen the outcomes of the current study.

Therapeutic efficacy of rifalazil (KRM-1648) in a M. ulcerans-induced Buruli ulcer mouse model.

Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced M. ulcerans infection model. Six-week-old female BALB/c mice were infected with 3.25 x 104 colony-forming units (CFU) of M. ulcerans subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5–8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 104 decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model.

C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus.

Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.

A Comparative Insight on the Newly Emerging Rifamycins: Rifametane, Rifalazil, TNP-2092 and TNP-2198

Rifamycins are considered a milestone for tuberculosis (TB) treatment because of their proficient sterilizing ability. Currently, available TB treatments are complicated and need a long duration, which ultimately leads to failure of patient compliance. Some new rifamycin derivatives, i.e., rifametane, TNP-2092 (rifamycin-quinolizinonehybrid), and TNP-2198 (rifamycin-nitromidazole hybrid) are under clinical trials, which are attempting to overcome the problems associated with TB treatment. The undertaken review is intended to compare the pharmacokinetics, pharmacodynamics and safety profiles of these rifamycins, including rifalazil, another derivative terminated in phase II trials, and already approved rifamycins. The emerging resistance of microbes is an imperative consideration associated with antibiotics. Resistance development potential of microbial strains against rifamycins and an overview of chemistry, as well as structure-activity relationship (SAR) of rifamycins, are briefly described. Moreover, issues associated with rifamycins are discussed as well. We expect that newly emerging rifamycins shall appear as potential tools for TB treatment in the near future.

Abstract 10302: A Case for Ending Rifampicin Use in Endocarditis

Background: Rifampicin has been employed in various endocarditis antibiotic regimens, particularly in prosthetic, staphylococcus aureus (SA) and culture-negative cases. However, this practice is not without controversy. Purpose: To perform a meta-analysis aimed at ascertaining the efficacy and safety of adjunctive rifampicin use in endocarditis. Methods: We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library and Google Scholar, from inception to June 1st, 2021, for studies comparing rifampicin-containing antibiotic regimens with those comprising no rifamycin derivatives, in the setting of endocarditis. The primary endpoint was all-cause death, while relapse, bail-out valvular surgery, microbiological failure (lasting positivity of blood cultures) and hepatotoxicity (fivefold or higher increase in transaminase levels) were secondary outcomes. SA infections were investigated separately, with respect to the primary endpoint. Mantel-Haenszel odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random-effects model. Results: 2 randomized, 1 non-randomized prospective and 6 retrospective studies, featuring 886 patients (of whom 322 allocated to rifampicin), were included. While 8 studies addressed staphylococcal endocarditis (with 3 of them dealing exclusively with SA infections), prosthetic and culture-negative cases were only focused on 1 study each. There were 96 deaths (from 7 studies), 32 relapses (from 6 studies), 35 bail-out valvular surgeries (from 4 studies), 14 microbiological failures (from 2 studies) and 32 hepatotoxicity cases (from 5 studies). Rifampicin use was associated with a tendency towards higher all-cause mortality (OR 1.63, 95% CI 0.85-3.12, P 0.14, i 2 12%), which held true for SA infections (OR 1.63, 95% CI 0.67-3.92, P 0.28, i 2 20%), and bail-out valve surgery (OR 2.03, 95% CI 0.65-6.34, P 0.22, i 2 5%). Relapse and microbiological failures rates were similar between groups (OR 1.25, 95% CI 0.59-2.65, P 0.56, i 2 0% and OR 1.3, 95% CI 0.24-6.90, P 0.76, i 2 41%, respectively). Hepatotoxicity odds were greater in the rifampicin arm (OR 3.24, 95% CI 1.35-7.77, P 0.008, i 2 0%). Conclusion: Currently available evidence does not support rifampicin use in endocarditis.

Extended-spectrum beta-lactamase-producing strains among diarrhoeagenic Escherichia coli-prospective traveller study with literature review.

BackgroundAntibiotics are no longer the primary approach for treating all travellers’ diarrhoea (TD): most cases resolve without antibiotics and using them predisposes to colonization by multidrug-resistant bacteria. Data are accumulating on increasing resistance among TD pathogens, yet research into the most common agents, diarrhoeagenic Escherichia coli (DEC), remains limited.MethodsA total of 413 travellers to the (sub)tropics were analyzed for travel-acquired diarrhoeal pathogens and ESBL-PE. To identify ESBL-producing DEC, ESBL-producing E. coli (ESBL-EC) isolates were subjected to multiplex qPCR for various DEC pathotypes: enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and enterohaemorrhagic (EHEC) E. coli.For a literature review, we screened studies among travellers and locals in low- and middle-income countries (LMICs) on the frequency of ESBL-producing DEC, and among travellers, also DEC with resistance to ciprofloxacin, azithromycin, and rifamycin derivatives.ResultsOur rate of ESBL-EC among all DEC findings was 2.7% (13/475); among EAEC 5.7% (10/175), EPEC 1.1% (2/180), ETEC 1.3% (1/80) and EHEC (0/35) or EIEC 0% (0/5). The literature search yielded three studies reporting ESBL-EC frequency and thirteen exploring resistance to TD antibiotics among travel-acquired DEC. For EAEC and ETEC, the ESBL-EC rates were 10–13% and 14–15%, resistance to fluoroquinolones 0–42% and 0–40%, azithromycin 0–29% and 0–61%, and rifaximin 0% and 0–20%. The highest rates were from the most recent collections. Proportions of ESBL-producing DEC also appear to be increasing among locals in LMICs and even carbapenemase-producing DEC were reported.ConclusionESBL producers are no longer rare among DEC, and the overall resistance to various antibiotics is increasing. The data predict decreasing efficacy of antibiotic treatment, threatening its benefits, for disadvantages still prevail when efficacy is lost.

In Vitro Activity of Rifamycin Derivatives against Nontuberculous Mycobacteria, including Macrolide-/Amikacin-Resistant Clinical Isolates.

We evaluated the in vitro activity of rifamycin derivatives, including rifampin, rifapentine, rifaximin, and rifabutin, against clinical nontuberculous mycobacteria (NTM) isolates. Of the rifamycin derivatives, rifabutin showed the lowest MICs against all NTM species, including Mycobacterium avium complex, M. abscessus, and M. kansasii Rifabutin also had effective in vitro activity against macrolide- and aminoglycoside-resistant NTM isolates. Rifabutin could be worth considering as a therapeutic option for NTM disease, particularly drug-resistant disease.

Effect of rifaximin on gut-lung axis in mice infected with influenza A virus

Gut-lung axis injury is a common finding in patients with respiratory diseases as well as in animal model of influenza virus infection. Influenza virus damages the intestinal microecology while affecting the lungs. Rifaximin, a non-absorbable derivative of rifamycin, is an effective antibiotic that acts by inhibiting bacterial RNA synthesis. This study aimed to determine whether rifaximin-perturbation of the intestinal microbiome leads to protective effects against influenza infection, via the gut-lung axis. Our results showed that influenza virus infection caused inflammation of and damage to the lungs. The expression of tight junction proteins in the lung and colon of H1N1 infected mice decreased significantly, attesting that the barrier structure of the lung and colon was damaged. Due to this perturbation in the gut-lung axis, the intestinal microbiota became imbalanced as Escherichia coli bacteria replicated opportunistically, causing intestinal injury. When influenza infection was treated with rifamixin, qPCR results from the gut showed significant increases in Lactobacillus and Bifidobacterium populations, while Escherichia coli populations markedly decreased. Furthermore, pathology sections and western blotting results illustrated that rifaximin treatment strengthened the physical barriers of the lung-gut axis through increased expression of tight junction protein in the colon and lungs. These results indicated that rifaximin ameliorated lung and intestine injury induced by influenza virus infection. The mechanisms identified were the regulation of gut flora balance and intestinal and lung permeability, which might be related to the regulation of the gut-lung axis. Rifaximin might be useful as a co-treatment drug for the prevention of influenza virus infection.

A Semisynthetic Kanglemycin Shows In Vivo Efficacy against High-Burden Rifampicin Resistant Pathogens

Semisynthetic rifamycin derivatives such as rifampicin (Rif) are first line treatments for tuberculosis and other bacterial infections. Historically, synthetic modifications made to the C-3/C-4 region of the rifamycin naphthalene core, like those seen in Rif, have yielded the biggest improvements in pharmacological properties. However, modifications found in natural product rifamycin congeners occur at other positions in the structure. The kanglemycins (Kangs) are a family of rifamycin congeners with a unique collection of natural modifications including a dimethylsuccinic acid appended to their polyketide backbone. These modifications confer activity against the single most common clinically relevant Rif resistance (RifR) mutation in the antibiotic’s target, the bacterial RNA polymerase (RNAP). Here we evaluate the in vivo efficacy of Kang A, the parent compound in the Kang family, in a murine model of bacterial peritonitis/sepsis. We then set out to improve its potency by combining its natural tailoring modifications with semisynthetic derivatizations at either its acid moiety or in the C-3/C-4 region. A collection of C-3/C-4 benzoxazino Kang derivatives exhibit improved activity against wild-type bacteria, and acquire activity against the second most common clinically relevant RifR mutation. The semisynthetic analogue 3′-hydroxy-5′-[4-isobutyl-1-piperazinyl] benzoxazino Kang A (Kang KZ) protected mice against infection with either Rif sensitive MRSA or a highly virulent RifRStaphylococcus aureus strain in a neutropenic peritonitis/sepsis model and led to reduced bacterial burdens. The compounds generated in this study may represent promising candidates for treating RifR infections.

Spiropiperidyl rifabutins: expanded in vitro testing against ESKAPE pathogens and select bacterial biofilms.

The expanded microbiological evaluation of a series of rifastures, novel spiropiperidyl rifamycin derivatives, against clinically relevant ESKAPE bacteria has identified several analogs with promising in vitro bioactivities against antibiotic-resistant strains of Enterococcus faecium and Staphylococcus aureus. Thirteen of the rifastures displayed minimum inhibitory concentrations (MICs) below 1 µg/ml against the methicillin- and vancomycin-resistant forms of S. aureus and E. faecium (MRSA, VRSA, VRE). Aryl-substituted rifastures 1, 11, and 12 offered the greatest bioactivity, with MICs reaching ≤0.063 µg ml-1 for these human pathogens. Further analysis indicates that diphenyl rifasture 1 had greater antibiofilm activity against S. aureus and lower cytotoxicity in mammalian HEK cells than rifabutin.

Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis.

Rifamycin derivatives, such as rifampicin, have potent antibiotic activity and have long been used in the clinic as mainstay components for the treatment of tuberculosis, leprosy, and AIDS-associated mycobacterial infections. However, the extensive usage of these antibiotics has resulted in the rapid development of bacterial resistance. The resistance mechanisms mainly include mutations of the rifamycin target RNA polymerase of bacteria and enzymatic modifications of rifamycin antibiotics. One modification is the recently characterized rifamycin degradation catalyzed by Rox enzymes, which belong to the widely occurring flavin monooxygenases. Intriguingly, our recent sequence analysis revealed the rifamycin producers also encode Rox homologs that are not yet characterized. In this work, we expanded the study of the Rox-catalyzed rifamycin degradation. We first showed that the Rox proteins from rifamycin producers have the enzymatic rifamycin SV-degrading activity. Then we used the structurally diverse rifamycin compounds rifampicin and 16-demethylrifamycin W to probe the substrate scope and found that they each have a slightly different substrate scope. Finally, we demonstrated that Rox proteins can also catalyze the transformation of 16-demethylsalinisporamycin to 16-demethylsaliniketal A. Since 16-demethylsalinisporamycin and 16-demethylsaliniketal A are the counterpart analogs of salinisporamycin and saliniketal A, our biochemical findings not only uncover a previously uncharacterized self-resistance mechanism in the rifamycin producers, but also bridge the gap between the biosynthesis of the potential antitumor compound saliniketal A.

Prediction of Transcription Factors and Their Involvement in Regulating Rifamycin Production in Amycolatopsis mediterranei S699.

Amycolatopsis mediterranei S699 produces rifamycin B and successors of this strain are in use for the industrial production of rifamycin B. Semisynthetic derivatives of rifamycin B are used against Mycobacterium tuberculosis that causes tuberculosis. Although the rifamycin biosynthetic gene cluster was characterized two decades ago, the regulation of rifamycin B biosynthesis in Amycolatopsis mediterranei S699 is poorly understood. In this study, we analysed the genome and proteome of Amycolatopsis mediterranei S699 and identified 1102 transcription factors which comprise about 10% of the total genome. Using interactomics approaches we delineated 30 unique transcription factors directly involved in secondary metabolism that regulate rifamycin B biosynthesis. We also predict the role of RifN as hub in controlling the regulation of other genes involved in rifamycin biosynthesis. RifN is important for maintaining the integrity of the rifamycin-network. Thus, these transcription factor can be exploited to improve rifamycin B production in Amycolatopsis mediterranei S699.

Synthesis, characterization, and antitumor activity of a new iron-rifampicin complex: A novel prospective antitumor drug

Rifampicin is a semi-synthetic derivative of rifamycin. It has a broad antibacterial activity. Iron is the most plentiful transition metal in human body. It is a crucial nutrient needed for numerous essential cellular functions. The present study is a trial to develop a novel antitumor candidate depending on formation of a complex between iron and rifampicin. After successful preparation, the resultant complex was characterized. Then its antitumor activity was investigated in vitro and in vivo. Comparison with the antitumor activity of pure rifampicin and cisplatin was also done. Compared to pure rifampicin (dose 0.107 mg/kg), iron-rifampicin complex was more potent in holding back the progression of the tumor. This was manifested by tumor mass shrinking, life span extension, and improvements in hematological portrait, liver and kidney functions, as well as antioxidant status. The complex mode of action may depend on its redox activity and/or induction of a mitochondrial apoptotic pathway. Regarding comparison with cisplatin, iron-rifampicin complex was a bit better antitumor. The complex administration to healthy mice displayed a non-toxic effect. Upon these, iron-rifampicin complex could be a promising addition in the upcoming generation of chemotherapeutics after more validation.

Rifamycin derivatives active against pathogenic rapidly-growing mycobacteria.

Infections due to rapidly growing mycobacteria (RGM), and in particular the RGM species Mycobacterium abscessus (Mab), are very difficult to treat and reports on novel therapeutic options are scarce. A hallmark of all pathogenic RGM species is their resistance to the four first-line drugs used to treat infections with Mycobacterium tuberculosis including rifampicin. This study demonstrates that modification of the rifampicin scaffold can restore rifampicin activity against the three most commonly isolated pathogenic RGM species including Mab. We also note that the structure-activity relationship for Mab is different as compared to the non-pathogenic RGM species Mycobacterium smegmatis.

Automated determination of Rifamycins making use of MPA–CdTe quantum dots

Rifamycins are a group of antibiotics particularly effective against mycobacteria and they are used for the treatment of important diseases and disorders such as tuberculosis, cancer, hepatic encephalopathy or intestinal infections. Taking into account the great clinical potential of these drugs it is important to develop a rapid, simple and reliable strategy for its quality control. This paper presents an automated quantum dots-based analytical method making use of a multicommutated flow system and the quenching effect that rifampicin and rifaximin, two important Rifamycin derivatives, have on the fluorescence of water-soluble mercaptopropionic acid-capped CdTe quantum dots.Under the optimized conditions, the relationship between the fluorescence intensity of the quantum dots and rifampicin or rifaximin concentrations were linear in the range of 5–80 and 3–40µgmL−1, with a detection limit of 1.5 and 1.0µgmL−1, respectively. Relative standard deviations (RSD) lower than 3% were observed in all cases. A sample throughput of 70 determinations per hour and good recoveries were also achieved. The proposed method was satisfactorily applied to the determination of rifamycins in pharmaceutical formulations and human urine.

Ternary Inclusion Complexes of Rifaximin with β-Cyclodextrin and Sodium Deoxycholate for Solubility Enhancement.

Rifaximin is a rifamycin derivative, having extremely poor aqueous solubility. The objective of present study was to improve dissolution and solubility of drug using β-cyclodextrin inclusion complexes and also to evaluate the effect of presence of sodium deoxycholate on solubilization efficiency of β-cyclodextrin. The stochiometry of inclusion complexes of binary (drug-cyclodextrin) and ternary system (drug-cyclodextrin-sodium deoxycholate) were determined by phase solubility studies at 25 °C. The stability constants (K1:2) calculated from phase solubility analysis were 126 M(-1) and 267 M(-1) for binary and ternary systems respectively. The inclusion complexes were prepared by solvent evaporation method with the inclusion efficiency of 43% and 56.9% for binary and ternary systems followed by their characterization using fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry and in-vitro antibacterial activity. The solubility of drug was improved by 4.3 and 11.9 folds in binary and ternary inclusion complexes, respectively. Therefore, it can be concluded that the ternary inclusion complexation having better solubilization efficiency as compared to binary complexation.

Regioselective long-range proton transfer in new rifamycin antibiotics: a process in which crown ethers act as stronger Brønsted bases than amines.

Water-mediated proton transfer in six new derivatives of 3-formylrifamycin SV that contain crown, aza-crown, and benzo-crown ether rings were investigated by FTIR and NMR spectroscopy. (1)H-(1)H COSY couplings provide evidence for the formation of zwitterionic structures of the aza-crown and crown ether derivatives of rifamycin, in which a proton from one of the phenolic groups is transferred to tertiary and secondary nitrogen atoms. The increased intensity of the continuous absorption in the mid-infrared region together with the NMR data indicate proton transfer from the phenol group of the rifamycin core to the cavity of the benzo-crown ether ring. This proton transfer is achieved by formation of hydronium (H3O(+)) or Zundel ions (H5O2(+)), which form intermolecular hydrogen bonds with the oxygen atoms of the crown ether. DFT calculations are in agreement with the spectroscopic data and allow visualization of the structures of all new rifamycin derivatives, characterized by different intramolecular protonation sites.