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Journal of Medicinal Chemistry Feb 2019We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified...
We have designed and synthesized a series of new imidazole-based compounds structurally related to an antiprotozoal agent with nanomolar activity which we identified recently. The new analogues possess micromolar activities against Trypanosoma brucei rhodesiense and Leishmania donovani and nanomolar potency against Plasmodium falciparum. Most of the analogues displayed IC within the low nanomolar range against Trypanosoma cruzi, with very high selectivity toward the parasite. Discussion of structure-activity relationships and in vitro biological data for the new compounds are provided against a number of different protozoa. The mechanism of action for the most potent derivatives (5i, 6a-c, and 8b) was assessed by a target-based assay using recombinant T. cruzi CYP51. Bioavailability and efficacy of selected hits were assessed in a T. cruzi mouse model, where 6a and 6b reduced parasitemia in animals >99% following intraperitoneal administration of 25 mg/kg/day dose for 4 consecutive days.
Topics: Animals; Antiprotozoal Agents; Cytochrome P-450 Enzyme Inhibitors; Drug Design; Drug Evaluation, Preclinical; Humans; Imidazoles; Parasitic Sensitivity Tests; Trypanosoma
PubMed: 30615444
DOI: 10.1021/acs.jmedchem.8b01464 -
Expert Review of Anti-infective Therapy Apr 2006The well-known problems of classic treatment of the leishmaniases with pentavalent antimony (reduced efficacy), difficulties of administration and increasing frequency... (Review)
Review
The well-known problems of classic treatment of the leishmaniases with pentavalent antimony (reduced efficacy), difficulties of administration and increasing frequency and severity of adverse events have stimulated the search for new drugs to treat these diseases. Other injectable, oral and topical drugs have not been consistently effective, especially in the modern World. Beginning in 1998, Indian researchers conducted several trials with hexadecylphosphocholine (miltefosine) in patients with visceral leishmaniasis, and in 1999, clinical studies were initiated in Colombia for cutaneous disease. More than 2500 patients have been treated, including patients with diffuse cutaneous leishmaniasis, mucosal disease and patients coinfected with HIV. Cure rates between 91 and 100% were reached with a dose of 2.5 mg/kg/day for 28 days, with no difference between treatment-naive and relapsing patients. Mild gastrointestinal events were present in 35-60% of patients and 10-20% had mild transaminase and creatinine elevations. Miltefosine has potent leishmanicidal activity as a consequence of its interference in parasite metabolic pathways and the induction of apoptosis. Miltefosine is the first effective and safe oral agent with the potential to treat all major clinical presentations of leishmaniasis.
Topics: Administration, Oral; Animals; Antiprotozoal Agents; Humans; Leishmaniasis; Phosphorylcholine
PubMed: 16597200
DOI: 10.1586/14787210.4.2.177 -
European Journal of Medicinal Chemistry Jan 2021Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine... (Review)
Review
Marine natural products are known for their diverse chemical structures and extensive bioactivities. Renieramycins, the member of tetrahydroisoquinoline family of marine natural products, arouse interests because of their strong antitumor activities and similar structures to the first marine antitumor agent ecteinascidin-743, approved by the European Union. According to the literatures, researches on the pharmacological activities of renieramycins mainly focus on their antitumor activities. In addition, by structural modification, derivatives of renieramycins show stronger antiproliferative activity and less accidental necrosis activity on cells. Nevertheless, the difficulties in extraction and separation hinder their further development. Hence, the synthetic chemistry work of renieramycins plays a key role in their further development. In this review, currently reported researches on the synthetic chemistry, pharmacological activities and structural modification of renieramycins are summarized, which will benefit future drug development and innovation.
Topics: Alkaloids; Anti-Infective Agents; Antibiotics, Antineoplastic; Antiprotozoal Agents; Biological Products; Molecular Structure; Neoplasms; Tetrahydroisoquinolines
PubMed: 33333398
DOI: 10.1016/j.ejmech.2020.113092 -
International Journal For Parasitology.... Aug 2021New drugs against visceral leishmaniasis with mechanisms of action differing from existing treatments and with adequate cost, stability, and properties are urgently...
New drugs against visceral leishmaniasis with mechanisms of action differing from existing treatments and with adequate cost, stability, and properties are urgently needed. No antitubulin drug is currently in the clinic against Leishmania infantum, the causative agent of visceral leishmaniasis in the Mediterranean area. We have designed and synthesized a focused library of 350 compounds against the Leishmania tubulin based on the structure-activity relationship (SAR) and sequence differences between host and parasite. The compounds synthesized are accessible, stable, and appropriately soluble in water. We assayed the library against Leishmania promastigotes, axenic, and intracellular amastigotes and found 0, 8, and 16 active compounds, respectively, with a high success rate against intracellular amastigotes of over 10%, not including the cytotoxic compounds. Five compounds have a similar or better potency than the clinically used miltefosine. 14 compounds showed a host-dependent mechanism of action that might be advantageous as it may render them less susceptible to the development of drug resistance. The active compounds cluster in five chemical classes that provide structure-activity relationships for further hit improvement and facilitate series development. Molecular docking is consistent with the proposed mechanism of action, supported by the observed structure-activity relationships, and suggests a potential extension to other Leishmania species due to sequence similarities. A new family of diarylsulfonamides designed against the parasite tubulins is active against Leishmania infantum and represents a new class of potential drugs with favorable cost, stability, and aqueous solubility for the treatment of visceral leishmaniasis (VL). These results could be extended to other clinically relevant species of Leishmania spp.
Topics: Antiprotozoal Agents; Drug Resistance; Humans; Leishmania infantum; Leishmaniasis, Visceral; Molecular Docking Simulation
PubMed: 34015753
DOI: 10.1016/j.ijpddr.2021.02.006 -
Journal of Pharmaceutical Sciences Dec 19841H-NMR and MS were employed to identify 13 rat urinary metabolites of 14C-labeled cis-3a,4,5,6,7,7a- hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole...
1H-NMR and MS were employed to identify 13 rat urinary metabolites of 14C-labeled cis-3a,4,5,6,7,7a- hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,2-benzisoxazole (MK-0436). The major free (unconjugated) metabolite was cis-3a,4,5,6,7, 7a-hexahydro-3-carboxamido-1,2-benzisoxazole; it was also the second most abundant metabolite released during hydrolysis of the conjugated fraction. All other identified metabolites were hydroxylated analogues substituted at C(4)-C(7a) of the cyclohexane ring. the 4-equatorial,5-axial,7a-triol was the second most abundant metabolite excreted in an unconjugated form. Four monohydroxy (5-axial, 6-axial, 6-equatorial, 7-equatorial) metabolites of the drug were identified; they were found in the conjugated fraction only and were released by hydrolysis. The 5-axial hydroxy compound is the major conjugated metabolite and is overall the most abundant of all the metabolites. Six dihydroxy metabolites were identified: one was found exclusively in the free state, three as conjugates only (including the 7-axial,7a-diol, which is the major dihydroxy species), and two both free and conjugated. A second triol was found both free and conjugated.
Topics: Animals; Antiprotozoal Agents; Biotransformation; Hydrolysis; Mass Spectrometry; Nitroimidazoles; Rats; Rats, Inbred Strains
PubMed: 6527245
DOI: 10.1002/jps.2600731218 -
Current Opinion in Infectious Diseases Oct 2003The leishmaniases consist of cutaneous, mucosal, and visceral syndromes. The classic treatment is with pentavalent antimonials. The disadvantages of the antimonials are... (Review)
Review
PURPOSE OF REVIEW
The leishmaniases consist of cutaneous, mucosal, and visceral syndromes. The classic treatment is with pentavalent antimonials. The disadvantages of the antimonials are their requirement for intramuscular or intravenous injection each day for 20-28 days, their toxicity, and the recent development of resistance in regions such as India. Amphotericin B is a potent secondary agent, but is also compromised by its parenteral nature and toxicity. Clinical investigation of treatment agents from January 2000 to January 2003 is reviewed to determine if there are new agents that can be used.
RECENT FINDINGS
A large number of pilot studies on visceral and cutaneous leishmaniasis have been performed. There can be more confidence in the visceral studies because visceral disease is incurable if untreated, and because large numbers of patients have been treated in highly endemic regions such as India. There is less confidence in pilot studies of the cutaneous disease, because most are uncontrolled, and there is a variable, and often high, cure rate without treatment.
SUMMARY
Liposomal amphotericin B, which is injected infrequently and is easily tolerated, is virtually 100% effective for Indian visceral disease at a total dose of 15 mg/kg and is 90% effective at a dose of 5-10 mg/kg. The oral agent, miltefosine, is more than 95% effective for Indian visceral disease. Fluconazole treatment for 6 weeks speeds up the already-rapid cure rate of cutaneous disease due to Leishmania major.
Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Clinical Trials as Topic; Fluconazole; Humans; Leishmaniasis; Paromomycin; Pentamidine; Phosphorylcholine
PubMed: 14501991
DOI: 10.1097/00001432-200310000-00005 -
Parasitology International Feb 2020Natural resources are recognized as important sources of potential drugs for treating various infections, and microorganisms are a rich natural source of diverse...
Natural resources are recognized as important sources of potential drugs for treating various infections, and microorganisms are a rich natural source of diverse compounds. Among the world's microorganisms, actinomycetes, which are abundant in soil and marine, are the well-known producers of a wide range of bioactive secondary metabolites and antibiotics. In the present study, four actinomycetes (samples N25, N6, N18, and N12) were isolated from soil samples in Mongolia. Phylogenetic analysis of these isolates revealed that they share the highest similarity with Streptomyces canus (N25), S. cirratus (N6), S. bacillaris (N18) and S. peucetius (N12), based on 16S rRNA gene sequencing. Crude extracts were obtained from them using ethyl acetate, and the crude fractions were separated by thin layer chromatography. The fractions were then evaluated for their cytotoxicities and their anti-Toxoplasma and antimalarial activities in vitro. The S. canus (N25) crude extract was selected for further chemical characterization based on its antiprotozoal activities. Using liquid chromatography-high resolution mass spectrometry, phenazine-1-carboxylic acid (PCA) was detected and identified in the active fractions of the metabolites from strain N25. We next confirmed that commercially available PCA possesses antiprotozoal activity against T. gondii (IC: 55.5 μg/ml) and Plasmodium falciparum (IC: 6.4 μg/ml) in vitro. The results of this study reveal that soil actinomycetes are potential sources of antiprotozoal compounds, and that PCA merits further investigation as an anti-protozoal agent.
Topics: Antiprotozoal Agents; Mongolia; Phylogeny; RNA, Ribosomal, 16S; Soil Microbiology; Streptomyces
PubMed: 31437553
DOI: 10.1016/j.parint.2019.101961 -
Acta Parasitologica Mar 2021Treatment of parasitic infections with conventional drugs is associated with high toxicity, and undesirable side effects require cogent substitutions. Nanotechnology has...
BACKGROUND
Treatment of parasitic infections with conventional drugs is associated with high toxicity, and undesirable side effects require cogent substitutions. Nanotechnology has provided novel approaches to synthesize nano-drugs to improve efficient antipathetic treatment.
PURPOSE
Nano-chitosan as a nontoxic antimicrobial agent was examined against three most prevalent protozoa in humans, Plasmodium falciparum, Giardia lamblia and Trichomonas vaginalis.
METHODS
Chitosan extracted from Penicillium fungi was converted to nanoparticles to maximize its therapeutic properties. Safety of nano-chitosan was examined by determining its hemolytic property and toxicity on PC12 cells. The studied parasites were identified with RFLP-PCR and cultivation in relevant media. Characteristics of nano-chitosan as an useful and valuable curative compound was evaluated by FTIR, DLS and SEM. Dose dependent anti-parasitic effect of nano-chitosan was evaluated.
RESULTS
The highest anti-parasitic activity of the nano-chitosan was observed at 50 μg/mL by which growth rates of cultivated P. falciparum, T. vaginalis and G. lamblia were inhibited by 59.5%, 99.4%, and 31.3%, respectively. The study demonstrated that nano-chitosan with the least toxicity, low side effects, and substantial efficacy deserved to be considered as an anti-parasitic nano-compound.
CONCLUSION
Nano-chitosan significantly inhibited protozoan growth in vitro promising to explore its use to combat parasitic infections. Further investigations covering extended sample size, in vivo experiments and optimizing the concentration used may lead to efficient treatment of protozoan diseases.
Topics: Animals; Anti-Infective Agents; Antiprotozoal Agents; Chitosan; Giardia lamblia; Humans; Plasmodium falciparum; Rats; Trichomonas vaginalis
PubMed: 32666158
DOI: 10.1007/s11686-020-00255-6 -
PLoS Neglected Tropical Diseases Mar 2021Cutaneous leishmaniasis has been endemic since decades. Millions of cases are reported worldwide specially in developing and underdeveloped countries. There are 2 major... (Review)
Review
Cutaneous leishmaniasis has been endemic since decades. Millions of cases are reported worldwide specially in developing and underdeveloped countries. There are 2 major types of cutaneous leishmaniasis based on the causating species found in different regions of the world. These include New and Old World cutaneous leishmaniasis, which are self-healing, but if not treated, these may cause severe scars and many other complications like mucosal involvement. The conventional gold standard treatment for both types is mainly intralesional or parenteral administration of antimonial. Lately, a great deal of research has been done on development of topical treatment based on single agent or combination therapy. This review summarizes the current state of literature regarding therapeutic outcome of topical treatment against cutaneous leishmaniasis caused by different species in different regions.
Topics: Administration, Topical; Antiprotozoal Agents; Drug Combinations; Humans; Leishmania; Leishmaniasis, Cutaneous
PubMed: 33657097
DOI: 10.1371/journal.pntd.0009099 -
Molecules (Basel, Switzerland) Jan 2023The natural product aurachin D is a farnesylated quinolone alkaloid, which is known to possess activity against the causative agent of malaria, spp. In this study, we...
The natural product aurachin D is a farnesylated quinolone alkaloid, which is known to possess activity against the causative agent of malaria, spp. In this study, we show that aurachin D inhibits other parasitic protozoa as well. While aurachin D had only a modest effect on , two other trypanosomatids, and , were killed at low micromolar and nanomolar concentrations, respectively, in an in vitro assay. The determined IC values of aurachin D were even lower than those of the reference drugs benznidazole and miltefosine. Due to these promising results, we set out to explore the impact of structural modifications on the bioactivity of this natural product. In order to generate aurachin D derivatives with varying substituents at the C-2, C-6 and C-7 position of the quinolone ring system, we resorted to whole-cell biotransformation using a recombinant strain capable of aurachin-type prenylations. Quinolone precursor molecules featuring methyl, methoxy and halogen groups were fed to this strain, which converted the substrates into the desired analogs. None of the generated derivatives exhibited improved antiprotozoal properties in comparison to aurachin D. Obviously, the naturally occurring aurachin D features already a privileged structure, especially for the inhibition of the causative agent of visceral leishmaniasis.
Topics: Humans; Trypanosoma cruzi; Escherichia coli; Antiprotozoal Agents; Chagas Disease; Leishmania donovani; Biotransformation; Quinolones; Biological Products; Plasmodium falciparum; Parasitic Sensitivity Tests
PubMed: 36770729
DOI: 10.3390/molecules28031066