Synthesis and structure-activity relationship of disubstituted benzamides as a novel class of antimalarial agents

Malaria is a devastating world health problem. Using a compound library screening approach, we identified a novel series of disubstituted benzamide compounds with significant activity against malaria strains 3D7 and K1. These compounds represent a new antimalarial molecular scaffold exemplified by compound 1, which demonstrated EC(50) values of 60 and 430 nM against strains 3D7 and K1, respectively. Herein we report our findings on the efficient synthesis, structure-activity relationships, and biological activity of this new class of antimalarial agents.     

2,4-diarylthiazole antiprion compounds as a novel structural class of antimalarial leads

A significant intersection between antimalarial and antiprion activity is well established for certain compound classes, specifically for polycyclic antimalarial agents bearing basic nitrogen-containing sidechains (e.g., chloroquine, quinacrine, mefloquine). Screening a recently reported set of antiprion compounds with such sidechains showed these 2,4-diarylthiazole based structures also possess significant antimalarial activity. Of particular note, all but one of the compounds displayed activity against a chloroquine-resistant Plasmodium falciparum strain, identifying them as interesting leads for further development in this context. In addition, three new members of the series showed superior antiprion activity compared to the earlier-reported compounds.     

Bis-alkylamine quindolone derivatives as new antimalarial leads

Quindolone derivatives, designed to target the malaria parasite digestive vacuole and heme detoxification pathway, have been synthesized by reaction with 2-chloro-N,N-diethylethanamine. This reaction gave N,O-, N,N- and O-alkylated products containing one or two basic side-chains. The compounds were evaluated for antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum W2 strain and for cytotoxicity in HepG2 A16 hepatic cells. By incorporating alkylamine side chains and chlorine atoms in the quindolone nucleus we transformed the inactive tetracyclic parent quindolones into moderate or highly active and selective antimalarial compounds. The most active and selective compound, 5c, showed an IC₅₀ = 51 nM for P. falciparum and a selectivity ratio of 98.     

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.     

Sulfamoyl benzamides as novel CB2 cannabinoid receptor ligands

Sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Starting from a screening hit 8 that had modest affinity for the cannabinoid CB₂ receptor, a parallel synthesis approach and initial SAR are described, leading to compound 27 with 120-fold functional selectivity for the CB₂ receptor. This compound produced robust antiallodynic activity in rodent models of postoperative pain and neuropathic pain without traditional cannabinergic side effects.     

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.     

Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents

A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC(50); 0.62microM) and E. coli (IC(50); 0.26microM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.     

Substituted dithiazole piperazine benzamides as novel amyloid beta peptide reducing agents

Alzheimer’s disease is a persistent neurodegenerative disorder of elderly characterized clinically by irreversible loss of memory due to accumulation of amyloid beta peptides within the amyloid plaques. We report the parallel synthesis and screening results of diverse substituted di-thiazole piperazine benzamides. A new compound TPI-1917-49 was identified as a promising amyloid reducing agent by lowering the levels of Aβ at least in two cell types and in vivo.     

Design,synthesis and bioevalution of novel benzamides derivatives as HDAC inhibitors

A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure–activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development.     

Novel thiolactone-isatin hybrids as potential antimalarial and antitubercular agents

The synthesis of a novel series of thiolactone-isatin hybrids led to the discovery of tetracyclic by-products which displayed superior antiplasmodial activity. The tetracycles thus formed the basis of a more focused SAR study. Identified from this series is a compound with an IC₅₀ of 6.92 μM against the chloroquine-resistant (W2) strain of Plasmodium falciparum. Useful antimalarial SARs delineated include the need for substitution at C-5 of the isatin scaffold and the enhancement of activity by increasing the linker length. In contrast to their antimalarial activity, the tetracycles were devoid of antitubercular activity whereas the advanced intermediates displayed growth inhibitory activity against the H₃₇Rv strain of Mycobacterium tuberculosis as revealed by BACTEC, MABA and LORA assays.     

Natural products as leads to potential mosquitocides

Mosquitoes are the crucial vectors for a number of mosquito-borne infectious diseases i.e. dengue, yellow fever, chikungunya, malaria, Rift Valley fever, elephantiasis, Japanese Encephalitis, and Murray Valley encephalitis etc. Besides, they also transmit numerous arboviruses (arthropod-borne viruses) for example West Nile virus, Saint Louis encephalitis virus, Eastern equine encephalomyelitis virus, Everglades virus, Highlands J virus, and La Crosse Encephalitis virus. The emergence of widespread insecticide resistance and the potential environmental issues associated with some synthetic insecticides (such as DDT) has indicated that additional approaches to control the proliferation of mosquito population would be an urgent priority research. The present review highlights some natural product mosquitocides that are target-specific, biodegradable, environmentally safe, and botanicals in origin.     

Synthesis and evaluation of febrifugine analogues as potential antimalarial agents

Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum. Strong liver toxicity has precluded febrifugine as a potential clinical drug. In this study novel febrifugine analogues were designed and synthesized. Lower toxicity was achieved by reducing or eliminating the tendency of forming chemically reactive and toxic intermediates and metabolites. Synthesized compounds were evaluated in vitro against chloroquine sensitive (D6) and chloroquine resistant (W2) P. falciparum strains for efficacy and in freshly isolated rat hepatocytes for potential cytotoxicity. The IC(50)'s of the best compounds were superior to their parent compound febrifugine. Noticeably, these compounds were also over 100 times less toxic than febrifugine. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.     

Design and synthesis of Pfmrk inhibitors as potential antimalarial agents

The synthesis and inhibitory activities of 10 potential inhibitors of Pfmrk, a Plasmodium falciparum cyclin-dependent protein kinase, are described. The most potent inhibitor is a 3-phenyl-quinolinone compound with an IC(50) value of 18 microM. It is the first compound reported to inhibit Pfmrk at the micro molar range.     

Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents

Plasmodium falciparum thioredoxin reductase (PfTrxR: NADPH+Trx(S)2+H+<-->NADP++Trx(SH)2) is a high Mr flavin-dependent TrxR that reduces thioredoxin (Trx) via a CysXXXXCys pair located penultimately to the C-terminal Gly. In this respect, PfTrxR differs significantly from its human counterpart which bears a Cys-Sec redox pair at the same position. PfTrxR is essentially involved in antioxidant defense and redox regulation of the parasite and has been previously validated by knock-out studies as a potential drug target for malaria chemotherapy. Moreover, human TrxR is present in most cancer cells at levels tenfold higher than in normal cells. Here we report the discovery of a series of potent inhibitors of PfTrxR. The three most promising inhibitors, 3(IC50(PfTrxR)=2 microM and IC50(hTrxR)=50 microM), 7(IC50(PfTrxR)=2 microM and IC50(hTrxR)=140 microM), and 11(IC50(PfTrxR)=0.5 microM and IC50(hTrxR)=4 microM) were selective for the parasite enzyme. Detailed mechanistic characterization of the effects of these compounds on the PfTrxR-catalyzed reaction showed clear uncompetitive inhibition with respect to both substrate and cofactor. For the most specific PfTrxR inhibitor 7, an alkylation mechanism study based on a thiol conjugation model was performed. Furthermore, all three compounds were active in the lower micromolar range on the chloroquine-resistant P. falciparum strain K1 in vitro.     

Design and synthesis of novel proline based factor XIa selective inhibitors as leads for potential new anticoagulants

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC₅₀ = 1 nM and FXIa IC₅₀ = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.     

High-throughput docking as a source of novel drug leads

Receptor-based virtual screening has become a viable source of novel leads in the pharmaceutical industry. The rapidly growing availability of structural information across protein families, the accessibility to increased computational power at affordable cost, as well as an improved understanding on how to effectively apply virtual screening technologies has contributed to their emergence. Nonetheless, continued improvement in the accuracy of scoring functions and a greater understanding of protein mobility is critical to advance the technology further.     

1-Azaaurones derived from the naturally occurring aurones as potential antimalarial drugs

We report the synthesis and in vitro antiplasmodial activity of 35 compounds, designed as analogues of the naturally occurring aurones. Several of these analogues showed submicromolar antimalarial activity against a chloroquine-resistant strain of Plasmodium falciparum (FcB1-Columbia strain) cultured on human erythrocytes. Substitution of the intracyclic oxygen in aurones by a nitrogen atom and systematic variation of the substituent at the B-ring revealed promising leads showing good activity on the CQ-resistant strain. In particular, 4,6-dimethoxy-4′-ethylazaaurone 22 showed antiplasmodial potency without noticeable toxicity. The easy synthesis of this family of compounds and the relevant antiplasmodial activity are in favor of promising candidates for further development.     

Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators

Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.     

Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists

Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT_1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and ‘inverted’ indazole provided more potent and selective 5-HT_1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT_1F receptor agonists, and the 5-HT_1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT_1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT_1F receptor recognition.     

Identification of aminopiperidine benzamides as MCHr1 antagonists

The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.