In vitro anti-trypanosomal activity of synthetic nitrofurantoin-triazole hybrids against Trypanosoma species causing human African trypanosomosis.

Human African trypanosomosis (HAT) which is also known as sleeping sickness is caused by Trypanosoma brucei gambiense that is endemic in western and central Africa and T. b. rhodesiense that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time-consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti-trypanosomal activity of nitrofurantoin-triazole hybrids against T. b. gambiense and T. b. rhodesiense parasites in vitro. This study screened 19 synthesized nitrofurantoin-triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin-Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n-alkyl hybrids influenced the increase in anti-trypanosomal activity against T. b. gambiense and T. b. rhodesiense. The short-chain n-alkyl hybrids showed decreased activity compared to the long-chain n-alkyl hybrids, with increased activity against both T. b. gambiense and T. b. rhodesiense. Incorporation of additional electron-donating substituents in some NFT hybrids showed increased anti-trypanosomal activity than to electron-withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti-trypanosomal activity against T. b. gambiense than T. b. rhodesiense. The NFT hybrid no. 16 was among the best performing hybrids against both T. b. gambiense (0.08 ± 0.04 µM) and T. b.rhodesiense (0.11 ± 0.06 µM), and its activity might be influenced by the introduction of fluorine in the para-position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10-100 times fold selective in their anti-trypanosomal activity. The synthesized NFT hybrids showed strong selectivity >10 to T. b. gambiense and T. b. rhodesiense, which indicates that they qualify from the initial selection criteria for potential hit drugs.

2-Aroyl quinazolinone: Synthesis and in vitro anti-parasitic activity.

Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC50 values of 4.7 µM (T. b. brucei) and 1.1 µM (T. b. rhodesiense), respectively.

Thiazolidin-4-one-based derivatives - Efficient tools for designing antiprotozoal agents. A review of the last decade.

Thiazolidin-4-one derivatives have a wide range of therapeutic implementations and clinical significance for medicinal chemistry. This heterocyclic ring has been reported to possess a variety of biological activities, including antiprotozoal activities that have inspired scientists to integrate this scaffold with different pharmacophoric fragments to design novel and effective antiprotozoal compounds. There are reviews describing thiazolidin-4-ones small molecules as good candidates with a single type of antiprotozoal activity, but none of these show collected news associated with the antiprotozoal activity of thiazolidin-4-ones and their SAR analysis from the last decade. In this review we are focusing on the antitoxoplasmic, anti-trypanosomal, antimalarial, antileishmanial, and antiamoebic activity of these derivatives, we attempt to summarize and analyze the recent developments with regard to the antiprotozoal potential of 4-TZD covering the structure-activity relationship and main molecular targets. The importance of various structural modifications at C2, N3, and C5 of the thiazolidine-4-one core has also been discussed in this review. We hope that all information concluded in this review can be useful for other researchers in constructing new effective antiprotozoal agents.

Anti-Trypanosomal Bufadienolides from the Oocytes of the Toad Rhinella alata (Anura, Bufonidae).

Amphibians are widely known as a prolific source of bioactive metabolites. In this work, we isolated and characterized compounds with antiparasitic activity from the oocytes of the toad Rhinella alata collected in Panama. Bio-guided isolation and structural elucidation were carried out using chromatographic and spectroscopic techniques, respectively. The organic extract was subjected to solid phase extraction followed by HPLC purification of the fraction with in vitro activity against Trypanosoma cruzi trypomastigotes. Seven steroids (1-7) of the bufadienolide family were isolated, and their structures were determined using NMR and MS analyses; of these 19-formyl-dyscinobufotalin, (3) is reported as a new natural product. Compounds 1 and 3-7 resulted in a good anti-trypanosomal activity profile. Among these, 16ß-hydroxyl-hellebrigenin (1) and bufalin (7) showed significant selectivity values of >5 and 2.69, respectively, while the positive control benznidazole showed a selectivity of 18.81. Furthermore, molecular docking analysis showed compounds 1, 3 and 7 interact through H-bonds with the amino acid residues GLN-19, ASP-158, HIS-159 and TRP-177 from cruzipain at the catalytic site. Given the lack of therapeutic options to treat American trypanosomiasis, this work can serve as the basis for further studies that aim for the development of bufadienolides or their derivatives as drugs against Chagas disease.

The anti-Trypanosoma activities of medicinal plants: A systematic review of the literature.

BACKGROUND: The existing drug treatments for trypanosomiases are limited and suffer from shortcomings due to their toxicity and the emergence of resistant parasites. Developing anti-trypanosomal compounds based on natural products is a promising way of fighting trypanosomiases. OBJECTIVES: This study aims to identify through scientific review a large variety of medicinal plants (anti-trypanosomal) used worldwide and scientifically shown to display anti-trypanosomal effects. METHODS: To collect data, the anti-trypanosomal activities of Africa, Asia, the Middle East, South America, North America, Europe and Oceania medicinal plants have been checked by considering the published paper. RESULTS: Based on collected data, 77 natural molecules were reported in the literature. Of which 59 were from the African region, 11 from Asia, 3 from Europe and 4 from Latin America. These active components belong to alkaloids, triterpenoids, lactone, quinoids, flavonoids, iridoids, lignans, steroids, lipids, oxygenated heterocycles, benzenoids, proteins, coumarins, phenylpropanoids and peptides. We also specified the prosperous plants with unique anti-trypanosomal activities. CONCLUSIONS: However, there is a need for further studies on the ability of the isolated compounds to ameliorate the trypanosome-induced pathological alterations and also the elucidation of their modes of actions and activities against other trypanosome species.

Trypanosoma brucei: Metabolomics for analysis of cellular metabolism and drug discovery.

BACKGROUND: Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (also known as sleeping sickness), a disease causing serious neurological disorders and fatal if left untreated. Due to its lethal pathogenicity, a variety of treatments have been developed over the years, but which have some important limitations such as acute toxicity and parasite resistance. Metabolomics is an innovative tool used to better understand the parasite's cellular metabolism, and identify new potential targets, modes of action and resistance mechanisms. The metabolomic approach is mainly associated with robust analytical techniques, such as NMR and Mass Spectrometry. Applying these tools to the trypanosome parasite is, thus, useful for providing new insights into the sleeping sickness pathology and guidance towards innovative treatments. AIM OF REVIEW: The present review aims to comprehensively describe the T. brucei biology and identify targets for new or commercialized antitrypanosomal drugs. Recent metabolomic applications to provide a deeper knowledge about the mechanisms of action of drugs or potential drugs against T. brucei are highlighted. Additionally, the advantages of metabolomics, alone or combined with other methods, are discussed. KEY SCIENTIFIC CONCEPTS OF REVIEW: Compared to other parasites, only few studies employing metabolomics have to date been reported on Trypanosoma brucei. Published metabolic studies, treatments and modes of action are discussed. The main interest is to evaluate the metabolomics contribution to the understanding of T. brucei's metabolism.

Sponge-associated sp. RM66 metabolome induction with N-acetylglucosamine: Antibacterial, antifungal and anti-trypanosomal activities.

The marine sponge Amphimedon sp., collected from Hurghada (Egypt) was investigated for its sponge-derived actinomycetes diversity. Nineteen actinomycetes were cultivated and phylogenetically identified using 16S rDNA gene sequencing were carried out. The strains belong to genera Kocuria, Dietzia, Micrococcus, Microbacterium and Streptomyces. Many silent biosynthetic genes clusters were investigated using genome sequencing of actinomycete strains and has revealed in particular the genus Streptomyces that has indicated their exceptional capacity for the secondary metabolites production that not observed under classical cultivation conditions. In this study, the effect of N-acetylglucosamine on the metabolome of Streptomyces sp. RM66 was investigated using three actinomycetes media (ISP2, M1 and MA). In total, twelve extracts were produced using solid and liquid fermentation approaches. Liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) data were analysed using metabolomics tools to compare natural product production across all crude extracts. Our study highlighted the elicitation effect of N-acetylglucosamine on the secondary metabolite profiles of Streptomyces sp. RM66. These results highlight the of N-acetylglucosamine application as an elicitor to induce the cryptic metabolites and for increasing the chemical diversity. All the twelve extracts were tested for their antibacterial activity was tested against Staphylococcus aureus NCTC 8325, antifungal activity against Candida albicans 5314 (ATCC 90028) and anti-trypanosomal activity against Trypanosoma brucei brucei. Extract St1 showed the most potent one with activities 2.3, 3.2 and 4.7 ug/ml as antibacterial, antifungal and anti-trypanosomal, respectively.

Anti-trypanosomal and anthelminthic properties of ethanol and aqueous extracts of Tetrapleura tetraptera Taub.

Trypanosomosis and helminthosis, considered as part of neglected tropical diseases, are parasitic infections of public health importance, especially in Africa. Medicinal plants have been used in most parts of Africa, to treat these parasitic infections. The study aims to determine the anti-trypanosomal and anthelminthic properties of Tetrapleura tetraptera (fruit and stembark). The aqueous extracts of T. tetraptera fruit (TTFaq) and stembark (TTSaq), as well as ethanol extracts of T. tetraptera fruit (TTFe) and stembark (TTSe), were screened for their in vitro anti-trypanosomal and anthelminthic activities against T. b. brucei and Pheretima posthuma worms, respectively. Preliminary phytochemical screening of all extracts and gas chromatography-mass spectrometry (GC-MS) analysis of most active extracts were conducted. TTFaq exhibited anti-trypanosomal activity with IC50 of 18.18 µg/mL. TTSe and TTFe had moderate anti-trypanosomal activity with IC50 of 34.76 and 34.84 µg/mL, respectively. TTSaq had relatively low activity against the parasite with IC50 of 55.03 µg/mL. The SI of T. tetraptera extracts was between the range of 0.14-2.09. TTFaq showed dose-dependent activity causing paralysis and death of the adult worms at all concentrations. At the least concentration of 0.625 mg/mL, TTFaq induced paralysis and death after 101.88 ± 0.8 and 242.64 ± 0.38 min of exposure, respectively compared with the negative control (p < 0.0001). TTFe, TTSe and TTSaq caused paralysis of worms after 318.32 ± 0.74, 422.5 ± 0.72, 422.20 ± 0.55 min of exposure at minimum concentrations of 2.5, 10 and 5 mg/mL, respectively (p < 0.0001). However, no death was observed in worms treated with TTFe, TTSe and TTSaq at all test concentrations. In the presence of sub-minimal inhibitory concentration of the extracts, TTFaq potentiated the anthelminthic activity of albendazole whiles TTFe, TTSaq and TTSe inhibited the activity of albendazole. Phytochemical screening revealed the presence of saponins, triterpenoids, reducing sugars, flavonoids (absent in TTFe), steroids (absent in TTFaq) and tannins (absent in TTSe and TTFe) in the extracts. GC-MS revealed the presence of 9-octadecenamide and betulic acid in TTFaq. Hence, there was evidence provided here that Tetrapleura tetraptera may be effective. This gives credence to their folkloric use. However, further study might be necessary to ascertain safety use in both humans and animals.

Eugenia uniflora and Syzygium samarangense extracts exhibit anti-trypanosomal activity: Evidence from in-silico molecular modelling, in vitro, and in vivo studies.

The parasite Trypanosoma brucei is the main cause of the sleeping sickness threatening millions of populations in many African countries. The parasitic infection is currently managed by some synthetic medications, most of them suffer limited activity spectrum and/or serious adverse effects. Some studies have pointed out the promising therapeutic potential of the plant extracts rich in polyphenols to curb down parasitic infections caused by T. brucei and other trypanosomes. In this work, the main components dominating Eugenia uniflora and Syzygium samarangense plant extracts were virtually screened, through docking, as inhibitors of seven T. brucei enzymes validated as potential drug targets. The in vitro and in vivo anti-T. brucei activities of the extracts in two treatment doses were evaluated. Moreover, the extract effects on the packed cell volume level, liver, and kidney functions were assessed. Five compounds showed strong docking and minimal binding energy to five target enzymes simultaneously and three other compounds were able to bind strongly to at least four of the target enzymes. These compounds represent lead hits to develop novel trypanocidal agents of natural origin. Both extracts showed moderate in vitro anti-trypanosomal activity. Infected animal groups treated over 5 days with the studied extracts showed an appreciable in vivo anti-trypanosomal activity and ameliorated in a dose dependent manner the anaemia, liver, and kidney damages induced by the infection. In conclusion, Eugenia uniflora and Syzygium samarangense could serve as appealing sources to treat trypanosomes infections.

Synthesis and anti-trypanosomal activity of 3'-fluororibonucleosides derived from 7-deazapurine nucleosides.

Trypanosoma brucei parasites cause Human African Trypanosomiasis and the current drugs for its treatment are often inefficient and toxic. This urges the need to development of new antitrypanosomal agents. We report the synthesis and biological profiling of 3'-deoxy-3'-fluororibonucleosides derived from 7-deazaadenine nucleosides bearing diverse substituents at position 7. They were synthesized through glycosylation of 6-chloro-7-bromo- or -7-iodo-7-deazapurine with protected 3'-fluororibose followed by cross-coupling reactions at position 7 and/or deprotection. Most of the title nucleosides displayed micromolar or submicromolar activity against Trypanosoma brucei brucei. The most active were the 7-bromo- and 7-iododerivatives which exerted double-digit nanomolar activity against T. b. brucei and T. b. gambiense and no cytotoxicity and thus represent promising candidates for further development.

Singly and doubly modified analogues of C20-epi-salinomycin: A new group of antiparasitic agents against Trypanosoma brucei.

Polyether ionophores, with >120 molecules belonging to this group, represent a class of naturally-occurring compounds that exhibit a broad range of pharmacological properties, including promising activity towards a variety of parasites. In this context, salinomycin (SAL) seems to be interesting, as this ionophore has been found to be active against parasites that are responsible for a number of human and animal diseases. On the other hand, less explored is the investigation into the anti-parasitic activity of SAL derivatives. Recently, we identified C1 amides and esters of SAL and its analogue, C20-oxosalinomycin, as promising structures for trypanocidal drug candidates. In search for novel compounds effective against African trypanosomes, the synthetic access to a completely new series of C20-epi-salinomycin (compound 2) analogues is described in this paper. This series includes products obtained via derivatisation of either the C1 carboxyl or the C20 hydroxyl of 2, but also C1/C20 double modified derivatives. The anti-trypanosomal activity as well as the cytotoxic activity of these analogues were evaluated with bloodstream forms of T. brucei and human myeloid HL-60 cells, respectively. It was found that the C20 single modified derivatives 8, 12, and 18 (C20 decanoate, C20 ethyl carbonate, and C20 allophanate of 2, respectively) were the most active compounds in selectively targeting bloodstream-form trypanosomes, with 50% growth inhibition (GI50) values of 0.027-0.043 µM and selectivity indices of 165-353. These results indicate that modification at the C20 position of C20-epi-salinomycin 2 can provide semi-synthetic products with enhanced trypanocidal activity that could be of great value for the development of new drugs to treat African trypanosomiasis.

Molecular Docking, QSAR and Microscopic Studies of Anti-trypanosomal Compounds from the Pathogen Box.

BACKGROUND: Trypanosoma brucei (T. brucei) is the cause of the deadly human African trypanosomiasis (HAT) with a case fatality ratio of 10%. OBJECTIVE: Targeting the essential Trypanosomal glucose metabolism pathway through the inhibition of phosphoglycerate kinase (PGK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a valid strategy for anti-T. brucei drug development. METHODS: Here, quantitative structure activity relationship, molecular docking and microscopic studies were used to describe the mode of inhibition of selected compounds from the pathogen box PGK and GAPDH. RESULTS: We identified 4 hit compounds from the pathogen box with optimal binding and chemical interactions. Notably, it was identified that interacting charge surface and atomic mass were key aspects of both PGK and GAPDH inhibition. Also, novel anti-trypanosomal compounds were identified from the pathogen box and their half maximal inhibitory concentrations were described. CONCLUSION: Our study presents new anti-trypanosomal compounds with optimal pharmacological profiles and an optimization strategy for improving target specificity in the rational design of novel anti-trypanosomal compounds.

Repurposing Auranofin and Evaluation of a New Gold(I) Compound for the Search of Treatment of Human and Cattle Parasitic Diseases: From Protozoa to Helminth Infections.

Neglected parasitic diseases remain a major public health issue worldwide, especially in tropical and subtropical areas. Human parasite diversity is very large, ranging from protozoa to worms. In most cases, more effective and new drugs are urgently needed. Previous studies indicated that the gold(I) drug auranofin (Ridaura®) is effective against several parasites. Among new gold(I) complexes, the phosphole-containing gold(I) complex {1-phenyl-2,5-di(2-pyridyl)phosphole}AuCl (abbreviated as GoPI) is an irreversible inhibitor of both purified human glutathione and thioredoxin reductases. GoPI-sugar is a novel 1-thio-ß-d-glucopyranose 2,3,4,6-tetraacetato-S-derivative that is a chimera of the structures of GoPI and auranofin, designed to improve stability and bioavailability of GoPI. These metal-ligand complexes are of particular interest because of their combined abilities to irreversibly target the essential dithiol/selenol catalytic pair of selenium-dependent thioredoxin reductase activity, and to kill cells from breast and brain tumors. In this work, screening of various parasites-protozoans, trematodes, and nematodes-was undertaken to determine the in vitro killing activity of GoPI-sugar compared to auranofin. GoPI-sugar was found to efficiently kill intramacrophagic Leishmania donovani amastigotes and adult filarial and trematode worms.

Synthesis and anti-parasitic activity of achiral N-benzylated phosphoramidic acid derivatives.

Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity - in one case with an IC50 value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.

2-Amino-1,3,4-thiadiazoles as prospective agents in trypanosomiasis and other parasitoses.

Parasitic diseases are a serious public health problem affecting hundreds of millions of people worldwide. African trypanosomiasis, American trypanosomiasis, leishmaniasis, malaria and toxoplasmosis are the main parasitic infections caused by protozoan parasites with over one million deaths each year. Due to old medications and drug resistance worldwide, there is an urgent need for new antiparasitic drugs. 1,3,4-Thiadiazoles have been widely studied for medical applications. The chemical, physical and pharmacokinetic properties recommend 1,3,4-thiadiazole ring as a target in drug development. Many scientific papers report the antiparasitic potential of 2-amino-1,3,4-thiadiazoles. This review presents synthetic 2-amino-1,3,4-thiadiazoles exhibiting antitrypanosomal, antimalarial and antitoxoplasmal activities. Although there are insufficient results to state the quality of 2-amino-1,3,4-thiadiazoles as a new class of antiparasitic agents, many reported derivatives can be considered as lead compounds for drug synthesis and a promise for the future treatment of parasitosis and provide a valid strategy for the development of potent antiparasitic drugs.

Synthesis and biological evaluation of bis-N2,N2'-(4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccinodihydrazides.

A series of N2,N2'-bis[4-hydroxycoumarin-3-yl)ethylidene]-2,3-dihydroxysuccino-hydrazides, containing 4-hydroxycoumarin, hydrazine and tartaric acid moieties, have been prepared and examined for possible biological activity. Several of these compounds exhibit promising HIV-1 integrase inhibition (IC50 = 3.5 µM), and anti-T. brucei (32% viability) and anti-mycobacterial (Visual MIC90 = 15.63 µM) activity.

A Unified Total Synthesis of the Actinoallolides, a Family of Potent Anti-Trypanosomal Macrolides.

Trypanosoma protozoan parasites are the causative agents of Chagas disease and sleeping sickness, two neglected tropical diseases where there is an urgent need for improved treatments and the evaluation of promising drug leads like the actinoallolides. Enabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks, an efficient first total synthesis of the potent anti-trypanosomal macrolide (+)-actinoallolide A has been achieved in 17 steps and 8 % overall yield. Our convergent route features an adventurous ring-closing metathesis to form the requisite trisubstituted (8E)-alkene in the 12-membered macrolactone, followed by the controlled installation of the labile transannular hemiacetal. Late-stage diversification then provides ready access to the congeneric (+)-actinoallolides B-E.

Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors.

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC50 of 0.70 µM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.

Anti-trypanosomal activity of crude root extract of Leptadenia hastata (Pers) decne in Wistar rats infected with Trypanosoma brucei brucei and associated hematological changes.

OBJECTIVE: An in vivo study was carried out to evaluate the possible anti-trypanosomal activity of Leptadenia hastata crude root extract with also its associated hematological changes particularly the packed cell volume (PCV) in experimental Trypanosoma brucei brucei infection using Wistar rats. MATERIALS AND METHODS: Thirty Wistar rats comprising of both males and females were categorized into six separate groups starting from A to F. Wistar placed in Group A and Group B were inoculated with T. brucei brucei and administered crude root extract of L. hastata at 100 and 200 mg/kg, respectively, as the treatment. Group C was infected with the parasite but untreated, while Group D was not infected with the parasite and was not treated. The remaining Groups E and F were inoculated with the parasite using diminazene diaceturate at 3.5 and 7.0 mg/kg, respectively. The extract was administered enterally when parasitemia was detected. Standard laboratory techniques were employed to determine parasitemia and PCV after collection of blood samples every 2 days via the tail vein. RESULTS: Infected Groups (A, B, C, E, and F) showed a pre-patent period 2 days post infection (P.I) with mean parasitic counts of 3.93 ± 2.38, 2.46 ± 2.20, 0.67 ± 0.77, 4.60 ± 4.45, and 1.53 ± 1.44, respectively, which continued unabated in groups treated with the extract.The pack cell volume did not decline significantly in the in Groups A and B. Acute toxicity study revealed the absence of any clinical or behavioral changes suggesting toxicity. CONCLUSION: There was no effect on parasitemia of Wistar rats infected with the parasite after administration of 100 and 200 mg, respectively, using the extract as the treatment. PCV of the groups infected remained fairly constant with the control groups throughout the study with the extract being non-toxic.

Cinnamamide: An insight into the pharmacological advances and structure-activity relationships.

The cinnamamide (cinnamic acid amide and cinnamide) is a privileged scaffold present widely in a number of natural products. The scaffold acts as a useful template for designing and arriving at newly drug-like molecules with potential pharmacological activity. An attempt has been made to review the extensive occurrence of cinnamamide scaffold in many lead compounds reported for treating various diseases, their binding interactions with the therapeutic targets as well as mechanism of action and their structure-activity relationships. The discoveries of cinnamamide systems and some examples of unusual cinnamamides having an aromatic, aliphatic, and heterocyclic or other rings condensed to the basic cinnamamide structure also have been extensively covered in this review.