An update on derivatisation and repurposing of clinical nitrofuran drugs.

5-nitrofurans (NFs) have been in clinical use for over 60 years. These affordable drugs are used for the treatment of a broad spectrum of diseases ranging from urinary tract infections to cancer. The anti-pathogenic effect of clinical NFs occurs following a step-wise process involving activation by azoreduction, followed by nitroreduction catalysed by azoreductases and nitroreductases (NTRs), respectively. Azoreduction yields stable metabolites that have the ability to covalently bind to cellular proteins. Nitroreduction, on the other hand, occurs by type I or II reduction of the nitro group in the presence of parasitic NADPH-cytochrome P450 reductases. Type I NTRs catalyse, under anaerobic conditions, the reduction of NFs to produce anti-pathogenic hydroxylamine. Under aerobic conditions, nitroreduction catalysed by type II NTRs produces reactive oxygen and nitrogen species (ROS/RNS), causing oxidative stress to pathogens and ultimate death. This multi-activity nature of NFs thus allows the repurposing of these drugs from agricultural chemicals and basic antibiotics to efficient therapies against human life-threatening diseases. Cases of NF resistance in pathogens are also limited likely due to this multi-activity, as well as effectivity under both aerobic and anaerobic conditions. However, multi-activity of these drugs can also infer toxicity. Molecular derivatisation is an effective strategy to improve efficacy, lower toxicity, diversify activity and address pathogen resistance associated with the use of these drugs.

Physicochemical, pharmacokinetic, efficacy and toxicity profiling of a potential nitrofuranyl methyl piperazine derivative IIIM-MCD-211 for oral tuberculosis therapy via in-silico-in-vitro-in-vivo approach.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 µM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.

Assessment of isorhamnetin 3-O-neohesperidoside from Acacia salicina: protective effects toward oxidation damage and genotoxicity induced by aflatoxin B1 and nifuroxazide.

Antioxidant activity of isorhamnetin 3-O-neohesperidoside, isolated from the leaves of Acacia salicina, was determined by the ability of this compound to inhibit xanthine oxidase activity and to scavenge the free radical 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS(.-)) diammonium salt. Antigenotoxic activity was assessed using the SOS chromotest assay. This compound has the ability to scavenge the ABTS(.+) radical by a hydrogen donating mechanism. We also envisaged the study of the antioxidant effect of this compound by the enzymatic xanthine/xanthine oxidase (X/XOD) assay. Results indicated that isorhamnetin 3-O-neohesperidoside was a potent inhibitor of xanthine oxidase and superoxide anion scavengers. Moreover, this compound induced an inhibitory activity against nifuroxazide and aflatoxine B1 (AFB1) induced genotoxicity. Taken together, these observations provide evidence that isorhamnetin 3-O-neohesperidoside isolated from the leaves of A. salicina is able to protect cells against the consequences of oxidative stress.

Antioxidant activity and inhibition of aflatoxin B1-, nifuroxazide-, and sodium azide-induced mutagenicity by extracts from Rhamnus alaternus L.

The effect of extracts obtained from Rhamnus alaternus L. leaves on genotoxicity and SOS response induced by aflatoxin B(1) (10 microg/assay) as well as nifuroxazide (20 microg/assay) was investigated in a bacterial assay system, i.e., the SOS chromotest with Escherichia coli PQ37. The evaluation of the mutagenic and antimutagenic actions of the same extracts against the sodium azide (1.5 microg/plate)-induced mutagenicity was assayed using the Salmonella typhimurium assay system. The R. alaternus tested extracts exhibited no genotoxicity either with or without the external S9 activation mixture. However, all the extracts, particularly aqueous extract (A) and its chloroformic fraction (A(2)) significantly decreased the genotoxicity induced by aflatoxin B(1) and nifuroxazide. Moreover, the different extracts showed no mutagenicity when tested with Salmonella typhimurium strains TA1535 and TA1538 either with or without the S9 mix. Aqueous extract as well as its A(2) fraction exhibited the highest level of protection towards the direct mutagen, sodium azide-induced response in TA1535 strain with mutagenicity inhibition percentages of 83.6% and 91.4%, respectively, at a dose of 250 microg/plate. The results obtained by the Ames test assay confirm those of SOS chromotest. These same active extracts exhibited high xanthine oxidase (XOD) inhibiting with respective IC(50) values of 208 and 137 microg/ml, and superoxide anion-scavenging effects (IC(50) values of 132 and 117 microg/ml) when tested in the XOD enzymatic assay system. Our findings emphasize the potential of R. alaternus to prevent mutations and also its antioxidant effect.

Antigenotoxic activities of crude extracts from Acacia salicina leaves.

For centuries, plants have been used in traditional medicines and there has been recent interest in the chemopreventive properties of compounds derived from plants. In the present study, we investigated the effects of extracts of Acacia salicina leaves on the genotoxicity of benzo[a]pyrene (B(a)P) and nifuroxazide in the SOS Chromotest. Aqueous, total oligomers flavonoids (TOF)-enriched, petroleum ether, chloroform, ethyl acetate, and methanol extracts were prepared from powdered Acacia leaves, and characterized qualitatively for the presence of tannins, flavonoids, and sterols. All the extracts significantly decreased the genotoxicity induced by 1 microg B(a)P (+S9) and 10 microg nifuroxazide (-S9). The TOF-enriched and methanol extracts decreased the SOS response induced by B(a)P to a greater extent, whereas the TOF-enriched and the ethyl acetate extracts exhibited increased activity against the SOS response produced by nifuroxazide. In addition, the aqueous, ethyl acetate, and methanol extracts showed increased activity in scavenging the 1,1-diphenyl- 2-picrylhydrazyl (DPPH) free radical, while 100-300 microg/ml of all the test extracts were active in inhibiting O2-production in a xanthine/xanthine oxidase system. In contrast, only the petroleum ether extract was effective at inhibiting nitroblue tetrazolium reduction by the superoxide radical in a nonenzymatic O2- -generating system. The present study indicates that extracts of A. salicina leaves are a significant source of compounds with antigenotoxic and antioxidant activity (most likely phenolic compounds and sterols), and thus may be useful for chemoprevention.

[Antibacterial activity and toxicity of a new nitrofuran]. / Antibakterial'naia aktivnost' i toksichenost' novogo nitrofurana.

A new nitrofuran, N-(5-nitrofurfurilidene)-5-nitrofuran-2-(N'-acetyl)carboxamidra zone designated as PAP-49 was synthesized. With the method of two-fold serial dilutions in the Hottinger's broth it was demonstrated that by its antimicrobial activity against cocci and enterobacteria PAP-49 was not inferior and in some cases it was even superior to such antibiotics and chemical drugs as benzylpenicillin, streptomycin, tetracycline, chloramphenicol, erythromycin, gentamicin, nitoxolin and furazolidone. The further study of the antibacterial properties of the new nitrofuran with the use of 101 strains of 16 bacterial species showed that its MICs for gram positive and gram negative bacteria were 0.03-3.13 and 0.78-125.0 micrograms/ml respectively. Combination of PAP-49 in the subbacteriostatic concentrations with other antimicrobial agents provided a 2-8-fold increase in the antimicrobial effect. The highest synergism was observed when nitrofuran was used in combination with aminoglycosides, benzylpenicillin or levomycetin. The primary screening revealed that PAP-49 belongs to the group of low toxic substances. Its LD50 after the oral administration to albino mice was 4631.9 mg/kg. The compound did not practically cumulate in the animal organism.

[Medico-biological evaluation of sodium salt of nitrofurylacrylic acid as a food additive]. / Mediko-biologicheskaia otsenka natrievoi soli 5-nitrofurilakrilovoi kisloty kak pishchevoi dobavki.

Nitrofurylacrylic acid sodium salt is a substance of moderate toxicity. Its LD50 for male rats after oral administration comprises 1220 mg/kg, for female rats--1400 mg/kg. The minimal toxic dose, in case of long-term administration comprises 14 mg/kg. At the level of doses from 0.04 to 4.0 mg/kg no mutagenic effect was detected. Oral and subcutaneous administration of minimal tolerance doses of the agent induced formation of malignant neoplasms developing, predominantly, from the epithelial tissue, with localization depending on the route of the agent administration. A conclusion has been made on impossibility of using this substance as a food additive.

Microbiological and pharmacological evaluation, in mice and rats, of a new nitrofuran: 2-amino-4-methyl-6-(2-ethinyl-5-nitrofuryl)-pyrimidine (nifurpyrimidine).

2-Amino-4-methyl-6-(2-ethinyl-5-nitrofuryl)-pyrimidine (nifurpyrimidine) is a new furan derivative. Its spectrum of activity is wide and includes both gram-positive and gram-negative microorganisms and fungi; moreover, it inhibits the growth of multiple-drug resistant salmonellae. The minimal inhibitory concentrations ranged from 0.25 to 10 microgram/ml. Resistance was developed in vitro in a step-wise manner and was partially reversed after 7-10 passages in drug-free media. The pharmacological study of the drug was carried out in rats and mice and gave the following results: (1) no acute toxicity was demonstrable following oral administration; (2) no intestinal absorption occurred and virtually the whole dose of nifurpyrimidine administered by oral route was recovered in the intestinal content; (3) the presence of urine, plasma or feces did not modify the antibacterial activity of the compound.

Malignant transformation of cryopreserved early passage syrian golden hamster cells by 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide.

2-(2-Furyl)-3-(5-nitro-2-furyl)-acrylamide (AF-2) induced the malignant transformation of secondary cultures of Syrian golden hamster embryo cells prepared from cryopreserved primary cells. Transformed cells grew in semi-solid agar medium and formed sarcomas when inoculated subcutaneously into non-immunosuppressed suckling hamsters.