New imidazolidinedione derivatives as antimalarial agents

A series of new N-alky- and N-alkoxy-imidazolidinediones was prepared and assessed for prophylactic and radical curative activities in mouse and Rhesus monkey models. New compounds are generally metabolically stable, weakly active in vitro against Plasmodium falciparum clones (D6 and W2) and in mice infected with Plasmodium berghei sporozoites. Representative compounds 8e and 9c showed good causal prophylactic activity in Rhesus monkeys dosed 30 mg/kg/day for 3 consecutive days by IM, delayed patency for 19-21 days and 54-86 days, respectively, as compared to the untreated control. By oral, 9c showed only marginal activity in causal prophylactic and radical curative tests at 50 mg/kg/day×3 and 30 mg/kg/day×7 plus chloroquine 10 mg/kg for 7 days, respectively.     

Quinones as antimycobacterial agents

Mycobacterium tuberculosis is a serious worldwide health threat, killing almost 3 million people per year. Other mycobacterial species, especially Mycobacterium avium, are emerging pathogens in the immunocompromised population, most notably AIDS patients. These nontuberculous mycobacteria (NTM) are ubiquitous in the environment, and naturally resistant to many disinfection procedures. Treatment options are limited, and no new antibiotics have been developed against mycobacteria since the 1970s. There is a desperate need for new biocides and antibiotics to prevent and treat mycobacterial infections. A small aromatic compound library has been screened for effectiveness in growth inhibition or killing of mycobacteria. Four species, representing the M. tuberculosis complex, the slow-growing NTM, and the rapid-growing NTM were used. Active compounds had minimal inhibitory concentrations as low as 12.5 microg/mL, with the active component being a quinone. The primarily bactericidal activity observed represents a unique mechanism of action. A fluorescent assay involving M. smegmatis expressing gfp was analyzed as a rapid assay for predicting inhibitory activity, but failed to predict activity well. Our compounds may have significant utility as soluble biocides against mycobacteria and other hardy nosocomial pathogens.     

New pyrrole derivatives as antimycobacterial agents analogs of BM212

During the course of our investigations in the field of azole antimicrobial agents, we have identified BM212 a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivatives 2-6 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.     

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a–f, 7a–f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20–28.25?µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250?µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.     

Ethambutol analogues as potential antimycobacterial agents.

A range of new ethambutol analogues was synthesised and their inhibitory potencies were probed with Mycobacterium smegmatis. Interestingly, apparently even minor deviation from the structure of the parent compound resulted in reduced antimycobacterial activity.     

New synthetic antifungal agents

Summary New antifungal agents of the aromatic disulphide and sulphenamide type have been investigated by chemosynthesis.A large number of substances has been screened using several tests against various representative micro-organisms.In vitro tests of isomeric disulphides, symmetrically substituted with various groupings, revealed substances with high in vitro activity against human pathogenic fungi, amongst N, N'-monosubstituted bis-amides of 2,2'-diphenyldisulphide-dicarboxylic acid. Some of these substances show activity equal to or greater than that of the best-known natural and synthetic antifungal agents.The postulation of interdependence between the activity of these substances and the possibility in such molecules of tautomeric phenomena with prototropic equilibrium and also the proved importance of the sulphenamide function for antimycotic activity, led to investigation of N-substituted benzisothiazol-3-ones. Also these compounds proved highly active against pathogenic fungi.The level and range of activity of the bis-n.butylamide of 2,2' diphenyl-disulphide-dicarboxylic acid and N-cyclohexyl-benzisothiazol-3-one suggested the therapeutic study of these substances.For this reason, a pilot clinical investigation was carried out, which clearly showed that the two compounds, incorporated in suitable bases, are generally well tolerated by human skin either normal or with epidermomycotic lesions.The two compounds under test, when applied directly to epidermomycotic areas of various types (groin epidermophytia, erythrasma, pityriasis versicolor, monilial intertrigo and perlèche, athlete's foot, etc.) showed high antifungal activity, equal to or greater than that of well-known antifungal drugs in current therapeutic use.Read in the meeting of the First Congress of the International Society for Tropical Dermatology, Naples, June 8–13, 1964.     

Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids

This work describes the synthesis of a series of fatty acid hydrazide derivatives of isoniazid (INH). The compounds were tested against Mycobacterium tuberculosis H37Rv (ATCC 27294) as well as INH-resistant (ATCC 35822 and 1896 HF) and rifampicin-resistant (ATCC 35338) M. tuberculosis strains. The fatty acid derivatives of INH showed high antimycobacterial potency against the studied strains, which is desirable for a pharmaceutical compound, suggesting that the increased lipophilicity of isoniazid plays an important role in its antimycobacterial activity.     

Microtubule inhibitors as potential antimalarial agents

The Steering Committee on Drugs for Malaria (CHEMAL) of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) has identified tubulin as a potential drug target, but one that is not yet ;validated'. Several inhibitors of tubulins, the principal proteins of microtubules, are potent inhibitors of the development and multiplication of malarial parasites in culture and in vivo. However, most of these compounds are also inhibitors of mammalian cell proliferation. Here, Angus Bell reviews the structure and properties of microtubules, their roles in Plasmodium cells, and the effects of various microtubule inhibitors on the parasite. He argues that microtubule inhibitors are not equally toxic to all proliferating cells but, by virtue of differential tubulin binding, show selective toxicity that might allow their use as antimalarial drugs.     

Unsaturated fatty acids as cytoprotective agents in the pancreatic β-cell

It is widely accepted that, in type 2 diabetes, elevated levels of free fatty acids and glucose contribute to a state of glucolipotoxicity in which β-cell function declines and, ultimately, cell viability is compromised. This suggests that β-cells do not readily tolerate chronic elevations in fatty acid levels. In vitro studies suggest, however, that β-cells respond differentially to long chain fatty acids, such that saturated species are lipotoxic whereas long chain mono-unsaturated fatty acids can provide cytoprotection. This difference does not appear to be mediated by a mutual metabolic antagonism between saturated and unsaturated species (although differential alterations in neutral lipid disposition may occur in response to these fatty acids) and the mechanisms remain unclear. This review summaries the current understanding of the actions of mono-unsaturated fatty acids in β-cells and highlights areas of controversy as well as key unresolved issues which require to be addressed.     

Discovery of benzothiazole amides as potent antimycobacterial agents

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12?μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1–2?μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.     

Oxygenated chalcones and bischalcones as potential antimalarial agents

Oxygenated chalcones (3a,b) and bischalcones (4a-j) have been synthesized and evaluated for antimalarial activity against chloroquine sensitive and resistant strains of Plasmodium berghei in mice. Some of the screened compounds, 3a, 4c, 4e, 4f and 4i, have shown significant activity at 100 mg/kg dose against sensitive strain.     

6-Oxo and 6-thio purine analogs as antimycobacterial agents

6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N⁹-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb.     

Novel amodiaquine congeners as potent antimalarial agents

To develop new classes of antimalarial agents, the possibility of replacing the phenolic ring of amodiaquine, tebuquine, and isoquine with other aromatic nuclei was investigated. Within a first set of pyrrole analogues, several compounds displayed high activity against both D10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. The isoquine structure was also modified by replacing the diethylamino group with more metabolically stable bicyclic moieties and by replacing the aromatic hydroxyl function with a chlorine atom. Among these compounds, two quinolizidinylmethylamino derivatives (6f and 7f) displayed high activity against both CQ-S and CQ-R strains.     

Discovery of novel methanone derivatives acting as antimycobacterial agents

A series of pyrazoline derivatives were synthesized and in vitro activity against Mycobacterium tuberculosis H37Rv was carried out. Among the synthesized compounds, compounds (4d) and (4f) 4-aminophenyl-3-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone and 4-aminophenyl-6,7-dimethoxy-3-phenyl-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone were found to be the most active agent against M. tuberculosis H37Rv with a minimum inhibitory concentration of 10?μg/mL.     

Discovery of novel phenoxyacetic acid derivatives as antimycobacterial agents

A series of 2-{4-[1-amino (thioxo) methyl-5-(substituted phenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid and 2-{4-[1-carbamoyl-5-(substituted phenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid were synthesized and the in vitro activity of the synthesized compounds against Mycobacterium tuberculosis H37Rv (MTB) and INH-resistant M. tuberculosis (INHR-MTB) was studied. Among the synthesized compounds, compound (3f) 2{-[4-(1-carbamoyl-5-(chlorophenyl)-4,5-dihydro-1H-3-pyrazolyl]-2-methoxyphenoxy}acetic acid was found to be the most active against M. tuberculosis H37Rv (MTB) and INH-resistant M. tuberculosis (INHR-MTB) with minimum inhibitory concentration of 0.06 microg/ml.     

Hydroxy fatty acids for the delivery of dideoxynucleosides as anti-HIV agents

A series of α- and β-carboxylated phospholipid prodrugs of dideoxy nucleosides have been synthesized and evaluated against HIV. An increase in biological effect with a factor of 500 has only been observed for the adenine nucleoside, which suggests that this prodrug approach is base specific.     

Synthesis and evaluation of galactofuranosyl N,N-dialkyl sulfenamides and sulfonamides as antimycobacterial agents

The recent emergence of clinically oppressive superbugs, some with resistance to nearly all frontline drug therapies, has challenged our ability to combat such infectious organisms as Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Our medicinal chemistry program targeting this pathogen has identified several potent galactofuranose-based in vitro inhibitors of mycobacterial growth. The most potent compound, the Galf N,N-didecyl sulfenamide 8d, displayed anti-mycobacterial activity (MIC) of 1 microg/mL in a cell based assay against a representative strain of Mycobacterium smegmatis.