Malaria has been derived from an Italian word i.e., ‘mal’ ‘area’ which describes ‘bad air’ as the disease is said to be earlier connected to marshy areas [1]. Malaria is a serious pyretic disease which is the result of infection by Plasmodium parasite and spreads when a female Anopheles mosquito bite [2], [3], [4], [5], [6]. Between the five parasite species causing malaria (Plasmodium falciparum [7], Plasmodium vivax [8], Plasmodium ovale [9], Plasmodium malariae [10] and Plasmodium knowlesi [11]), Plasmodium falciparum is the most fatal malaria parasite which can also cause death to humans [12], [13], [14], [15]. Even after continuous global efforts of decimating malaria, the disease is still a threat worldwide with about 241 million cases and 6,27,000 deaths estimated in the year 2020. The African region now accounts for 95 % of total malaria cases and 96 % of malaria deaths; with youngsters under the age of five, accounting for an estimated 80 % of the region’s total malaria deaths. Half of all malaria deaths worldwide have been accounted by the four African countries: United Republic of Tanzania (4.1 %), the Democratic Republic of the Congo (13.2 %), Nigeria (31.9 %) and Mozambique (3.8 %) [16], [17], [18]. Increasing cases of malaria have been noticed in the Amazon region, the global climatic conditions are favouring the spread of Plasmodium falciparum in the northern region, malaria parasite with high level of pyrimethamine which came from southeast Asia to Africa are now spreading in high rates creating health crisis in the sub-Saharan region of Africa [19], [20], [21]. Some mosquitoes have specific breeding sites and are unable to fly farther than 100 yards therefore, study of malaria had to be done at a micro level [22]. In Indonesia, some people use goat gallbladder in its whole form to treat and prevent malaria [23]. Certain amino acid/peptides conjugated heterocycles and a privileged scaffold Benzisoxazole is also proven to be novel therapeutics for treatment of malaria as reported by Rakesh et al. recently [23]. The biogenic synthesis of hemozoin crystals, a critical step in the malaria parasite's heme detoxification process, is examined as a potential target for antimalarial medications [24]. Also, Metal-based substances may function as effective and reasonably priced medications for the treatment of malaria. The development of antiparasitic metal-based treatments can be encouraged by looking at ruthenium(II)chloroquine, gold(I)chloroquine and ferroquine, an antiparasitic drug that has started phase II clinical trials against malaria [25]. The models which identify to investigate the critical factors are (i) Generalised immunity (GI) model, in which overall regulation of immunity is done by immunity and (ii) Specific immunity (SI) wherein regulation of each clone in the infection is done independently [26].

Malaria control is getting more challenging owing to resistance [27]. Antimalarial medication resistance monitoring aims to identify instances of treatment failure brought on by resistant parasites before they spread across the community and raise morbidity and mortality rates [28]. The synthesis of chemical libraries and evaluation of those libraries against the majority of verified biochemical targets of the malarial parasite are two of the most significant contemporary approaches to the development of novel therapeutics [29]. Various strategies to combat malaria resurgence are discussed by Cohen et al. [30]. Different methods for developing antimalarial drugs to combat the issue of drug resistance are discussed in Fig. 1 [31].

Despite recent advances in the treatment of some infectious diseases, the morbidity and mortality caused by malaria continue to be significant burdens [32]. For the treatment of this deadly disease, study of the most effective nontoxic malarian drug becomes important mainly for the parasites which have advanced multidrug resistance in current periods and they are detrimental to human life, such as Plasmodium falciparum [33], [34], [35], [36], [37], [38], [39], [40], [41]. P. falciparum and P. vivax were transmitted from non-human primates (apes or monkeys) to humans through host switching. They have to adjust to humans as a novel habitat. The evolution of particular genetic features and adaptations was likely favoured because distinct elements of this new environment established a new selection landscape [42]. Earlier quinoline alpha acids which are extracted from the bark of cinchona plant [43], like quinine [44], [45], [46] and Chloroquine [47], [48] were into effect, the comprehensive synthesis of quinine was reported by Woodward, which had been the only effective therapy for malaria for a long time. Quinine has proven to be a desirable and challenging synthetic target [49] but they were no further used as the parasite showed resistance against them [50], [51], [52].

At the same time when the doctors from Peru and Bolivia were working on the cinchona bark, in China, experiments on the leaves of Artemisia Annua (sweet wormwood) were taking place. During the war between US and Vietnam, a situation arrived when an antimalarial drug was in much of need to treat the illness of people, it was this time when the Vietnamese reached China for help and project 523 was given a green signal by the Chinese scientists which led to the discovery of artemisinin and also some new derivatives of quinoline were discovered. Around 500 scientists, along with 60 different laboratories and institutes were involved in this discovery and approximately 2000 different types of traditional Chinese herbs were investigated [53], [54], [55], [56], [57], [58], [59], [60], [61].

Chemotherapy continues to be the cornerstone of the malaria control approach since efforts to create an effective malaria vaccine have not yet been successful. Despite the fact that the isolation of artemisinin-resistant strains is a cause for worry, ACT (Artemisinin-based combination therapy) is the antimalarial medicine that acts the fastest and is most effective against strains that are resistant to several drugs. Moreover, Plasmodium falciparum has not yet evolved resistance to any other class of antimalarial drugs [62], [63], [64], [65], [66]. Although hypersensitivity to artemisinin derivatives has been consistently documented as an undesirable medication event, its incidence is still unknown despite the well-known high tolerability of ACTs. A considerable proportion of cases may go unreported since the clinical signs of an artemisinin-induced hypersensitivity reaction can range in intensity from moderate to life-threatening [67]. About 40 countries have formally adopted artemisinin-based combination therapy as a cure against Plasmodium falciparum [68] infection since 2001. Artemisinin and its derivatives have come out to be the most powerful and operative antimalarial drug reducing the malarial parasite biomass to around 1/10000 times per cycle. Artemisinin resistance is still rare yet the parasites have developed resistance against almost all available medicines at present and so it is important to find a synthetic pathway to combat the disease whose annual mortality is ranging from 0.5 to 2.5 million deaths [69], [70], [71]. Drug development strategy for anti-malarial drugs (AMD) has been provided in Fig. 2 [72].

Some secondary metabolites of plants are divided in seven classes of antiplasmodium agents that can also be used as potential antimalarial drugs [73], [74], [75]. Natural products are a sizable collection of various secondary metabolites with a wide range of biological functions. The foundation of the modern healthcare system is found in plant-based medications. Natural products have also been introduced as preventive and therapeutic agents in the fight against coronavirus [76], [77]. Traditionally, the medicinal plant Cissampelos pareira L. has been used to treat malaria. The two main groups of alkaloids reported from this plant are benzylisoquinolines and bisbenzylisoquinolines from a phytochemical perspective [78]. A promising method for creating new generations of secure and highly effective therapeutic candidates to treat malarial disease is structural hybridization of pharmacologically active compounds that have been clinically and preclinically confirmed [79].

So many studies have been done on genus Artimisia [80] and multiple studies have been done on ART [81], thus after all research it has been pharmacodynamically and through the semi-synthetic analogs of artemisinin (ART) (1) shown that the ring system of 1,2,4-trioxane is primarily accountable for the biological activity of ART and its derivatives [82], [83]. Bis- and tris-1,2,4-trioxane ring peroxides, have turned out to be most promising novel lead structures, found to occur in natural anti-malaria terpenoid i.e., artemisinin and its derivatives, such as artemether [84] (1a), arteether (1b), artesunic acid [85] (1c), and dihydroartemisinin (1d) [86], [87]. These compounds have depicted enhanced solubility and biological activity than ART itself (Fig. 3) [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99].

Detection of artemisinin has been recently studied in 2022 by Tarabi et al., through bismuth tungstate dressed rGO nanocomposite [100]. Some novel hybrids of artemisinin also tend to show antiplasmodial [101], anti-inflammatory [101], antileishmanial [102], antihelminthic [102], anti-viral [103], anticancer [104], antifungal [105], and ART hybrids also work as anti-tumor agents [106]. ART and derivatives are also capable of showing antibacterial efficacy in Drosophilla systematic infections [107]. The first report on the application of A. sieberi extracts on the treatment of murine malaria was given by Nahrevanian et al in 2012 [108]. Therefore, it won’t be wrong to call ART [109] and derivatives as wonder drugs (Fig. 4) [110], [111].

The parasites are said to be abundant in heme which itself act as a catalyst for the degradation of the endoperoxide bridge and the presence of this peroxide bridge explains as to why 1,2,4-trioxanes and other analogs of ART are fatal to the malarial parasites [112], [113]. 1,2,4-trioxanes are activated reductively by iron (II) heme (Heme is a major ART-reactive agent inside cells) [114] and formation of carbon centered radicals take place which then react with heme and proteins which shows the high reactivity of trioxanes against the asexual erythrocytic stage of malaria [115], [116], [117], [118]. Serum albumin is the primary plasma protein carrier that artemisinin is known to bind with [119]. Endoperoxide-based therapeutic research has remained a fascinating and relevant subject throughout the years, since parasite resistance has increased and clinical efficacy of currently available treatments has decreased [120], [121](a), [121](b). A cure for malarial disorders, from the standpoint of public health, attempts to reduce the spread of infection to others by reducing the infected population and spreading resistance to antimalarial medications [121].

ART in treating Cancer:

Another leading cause of death worldwide is cancer, a complex disease that includes intricate genetic and environmental connections [122], [123]. The main issues with cancer treatment are side effects brought on by medications. Recently, techniques for delivering drugs with nanostructures have been developed to increase therapeutic effectiveness and lessen toxicity [124]. Artemisinin (ART) has been used against many cancer cells [125], its derivatives (especially dihydroartemisinin) [126] and conjugates are more lethal to cancer cells that are iron-rich [127], [128]. Due to greater expression of the transferrin receptor 1 (TFR1) on their cell surface for iron intake, it has been observed that rapidly developing cancer cells have a higher level of iron than normal cells, allowing ART to target cancer cells only. Through endocytosis, these cells take up iron via TFR1, which has a strong affinity for transferrin-bound iron. The onset and spread of several malignancies, including breast, liver, colorectal, and others, are closely correlated with high intracellular iron levels. The effectiveness of ART-transferrin conjugates and the use of nanoparticles in conjunction with ART for specifically targeting breast cancer cells has been investigated in a number of research. Combination therapy have been used to study how ART affects breast cancer cells synergistically [129], [130].

At dosages that have been demonstrated to be safe for people, artesunate consistently causes cell death in vitro in drug-naive as well as drug-resistant MM cells [131]. Docetaxel-resistant prostate cancer cells are inhibited from proliferating by the drug artesunate [132] having half-life less than an hour in vivo [133]. The National Cancer Institute has conducted studies using 55 different cell lines of cancer to observe the response to in vitro treatment with artesunate [134]. p-glycoprotein ABCB5 is inhibited by peroxides, which can then specifically trigger the apoptotic pathway in HepG2 cancer cells. Synthetic ozonides occasionally exhibit greater selectivity than paclitaxel, artemisinin, or artesunic acid. The outcomes show a fresh field of potential use for peroxides in medical chemistry [135].

ART in treating COVID:

An extremely contagious respiratory ailment caused by a coronavirus called COVID-19 that originally appeared in Wuhan, Hubei Province, China, has since spread to 235 different nations [136]. A. annua extracts, artemisinin, and other artemisinin-based treatments have been shown to be effective in preventing SARS-CoV-2 virus infections in human lung cancer A549-hACE2 cells, VeroE6 cells, and human hepatoma Huh7.5 cells in vitro. The highest anti-SARS-CoV-2 action was seen with artesunate (7–12 g/mL), followed by artemether (53–98 g/mL), A. annua extracts (83–260 g/mL), and artemisinin (151–at least 208 g/mL) [137] Fig. 5 briefly explains how does ART and derivatives help in treating COVID.

Artemisinin [138] effectively reduced neutrophil infiltration into the peritoneum and lung in vivo in mouse infection models and decreased the release of cytokines/chemokines and NETs. In situations like sepsis and Covid-19, where an overactive innate immune system results in tissue damage that can be fatal, this research implies that artemisinin may be useful as a treatment [139]. Based on the findings, it was predicted that countries using artemether-lumefantrine or dihydroartemisinin-piperaquine would report more cases and deaths than those using artesunate-amodiaquine or artesunate-mefloquine [140].

The target of this review article is to provide an all-inclusive platform for brief perceptive of 1,2,4‐trioxane hybrids and dimers as antimalarial agents.