Malaria is a lethal disease caused by Plasmodium parasites, transmitted through the bites of infected Anopheles mosquitoes. It continues to affect millions of people each year, especially in sub-Saharan Africa, Southeast Asia and South America. These parasites exhibit a wide host range, infecting not only humans but also various vertebrates, including reptiles, birds and mammals. More than 200 species of Plasmodium have been identified, each adapted to infect a specific group of hosts. Among them, only five species are known to naturally infect humans and are responsible for malaria worldwide: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi [1]. Among these species, P. falciparum is recognized as the most virulent and predominant in Africa, while P. vivax is the most widespread species outside Sub-Saharan Africa [2].

Despite the availability of both prophylactic and therapeutic interventions, malaria continues to present a formidable global health burden, especially in underdeveloped nations. In 2023, the estimated global burden rose to approximately 263 million malaria cases and 597,000 deaths with an increase of 11 million cases in comparison to previous year. Alarmingly, about 95 % of malaria-related morbidity and mortality continues to be concentrated within the African Region, where access to essential services for prevention, diagnosis, and treatment remains critically limited. Although the World Health Organization (WHO) has approved two vaccines RTS, S/AS01 and R21/Matrix-M, the implementation of large-scale immunization campaigns is still in early phases across many endemic countries. Given that these vaccines confer only partial protection, there remains a pressing need for early diagnosis, effective therapeutic strategies, and integrated vector control to mitigate disease transmission [3].

Current treatment options for malaria include artemisinin-based combination therapies (ACTs), quinine derivatives, and other antimalarial drugs. However, the growing resistance of P. falciparum to these drugs has emerged as a significant challenge, reducing treatment efficacy and complicating disease control efforts [4]. This alarming trend underscores the urgent need for novel and more effective therapies.

Within this context, heterocyclic compounds have gathered increasing interest due to their versatile biological properties and potential as scaffolds for antimalarial drug development [5]. Defined by ring systems containing at least one non-carbon atom, these compounds are known for their capacity to disrupt multiple stages of the Plasmodium life cycle [[5], [6], [7]]. Their structural diversity allows for the rational design of molecules tailored to target specific parasite stages, thereby offering a promising solution to the problem of drug resistance [5,8]. Heterocyclic compounds, characterized by ring systems containing heteroatoms like nitrogen, oxygen, or sulphur, play a pivotal role in antimalarial drug discovery due to their ability to interact with key biological targets. Nitrogen-based frameworks such as pyrazoles, imidazoles, quinolines, and indoles have demonstrated potent anti-plasmodial effects, while oxygen- and sulphur-containing systems like coumarins, benzofurans, thiazoles, and thiophenes offer additional bioactive potential [9].

Synthetic small molecules with immunomodulatory activity are valuable as lead candidates for novel drug development. Among emerging targets, Indoleamine 2,3-dioxygenase-1 (IDO-1) plays a significant role in regulating immune responses. Though IDO-1 is normally inactive, its expression is induced by proinflammatory signals such as IFN-γ, TNF-α and TLR ligands during pathological conditions like protozoan infections [10]. Additionally, IDO-1 plays a role in vascular relaxation and blood pressure regulation during systemic inflammation, including malaria. Given its immunosuppressive and metabolic effects, IDO-1 has become a promising therapeutic target [11].

In malaria, particularly cerebral malaria, IFN-γ signalling and T-cell activation drive IDO-1 overexpression, which contributes to immune suppression [[12], [13], [14]]. This is evidenced by increased levels of kynurenic acid, picolinic acid and quinolinic acid in the brains of mice infected with both cerebral (P. berghei NK-65) and non-cerebral (P. berghei K-173) malaria strains [14]. IDO-1 catalyzes the rate-limiting step of tryptophan degradation via the kynurenine pathway. This activity alters the kynurenine-to-tryptophan balance, a hallmark observed in human patients with Plasmodium vivax infections [13,15] and inhibition of IDO-1 in mouse malarial models has been shown to protect against cerebral malaria [13,16].

Furthermore, Dos Santos et al. [12] demonstrated that accelerated tryptophan metabolism during acute infection promotes an immunosuppressive environment through induction of regulatory T cells, which contribute to immune tolerance. Complementing this, Tetsutani et al. [16] reported that in vivo inhibition of IDO-1 partially protected mice from lethal malaria, enhancing CD4+ T cell proliferation and interferon-gamma production specific to malaria parasites. These findings collectively highlight IDO-1 as a key enzyme that modulates host immune responses and metabolic pathways during malaria infection, making it a promising therapeutic target for achieving a balanced immune response and reducing malaria-associated pathology. Its inhibition is under investigation for treating cerebral malaria and other diseases such as cancer [11].

In our review, we have summarized that over the last three decades many attempts have been made to develop new IDO-1 inhibitors. Interestingly, the structural diversity of the identified IDO-1 inhibitors is enormous with wide variety of molecules ranging from high molecular mass to ones with low molecular mass [17]. Based on the structure-based design, synthesis, bio-evaluation and docking studies, we have recently identified few novel IDO-1 inhibitors [18]. Based on these insights, two structurally diverse heterocyclic small molecules were identified and subsequently assessed for their biological activity against malaria through targeting IDO-1 enzyme, aiming to identify candidates with potential for future drug development. Recent studies emphasize their multitarget effects on parasite metabolism and resistance strains, supporting their therapeutic promise [19]. Similarly, tryptanthrin derivatives, have also shown potent anti-plasmodial activity, justifying their exploration as antimalarial agents [20]. Heterocyclic small molecules, including β-carboline derivatives, have demonstrated significant antimalarial activity, where structural modifications profoundly influence potency and selectivity, designating this scaffold as a valuable lead for further drug development [21].

Halogenated forms of tryptanthrin are more potent inhibitors of Plasmodium malaria than the parent compound [22]. 8-halogenated tryptanthrin derivatives, including 8-fluoro tryptanthrin, demonstrated potent biological activity with reduced cytotoxicity compared to the parent compound tryptanthrin [23]. Their data indicate a higher therapeutic index for these analogues, suggesting a broad safety margin in vivo. Specifically, the fluorinated derivatives were less cytotoxic among halogen variants, confirming their relative safety profile. This study establishes that such compounds maintain strong efficacy while presenting minimal toxicological risk [23]. Fluorinated tryptanthrin derivatives, including 8-fluoro-2-((4-methyl-piperazin-1-yl)methyl)indolo[2,1-b]quinazoline-6,12-dione,effectively suppressed tumour growth in mice at doses up to 200 mg/kg without causing toxicity or mortality [24]. These results highlight the compound's strong antitumor activity coupled with a favourable safety profile. Such evidence underscores heterocyclic small molecules as promising candidates for antimalarial drug development, guiding our study's focus on IDO1-targeting heterocyclic compounds.