Mortalities associated with leishmaniasis are skyrocketing at an alarming rate. Lack of vaccine for leishmaniasis treatment is making the fight against the disease an arduous one. Interestingly, apart from the expensive nature of leishmaniasis treatments, the mono- and combinational chemotherapeutic agents suffer drawbacks such as resistance, synergism resistance, systemic toxicity, and ineffectiveness. Due to this, the new paradigm proposed for combating this canker is an efficient therapeutic antileishmanial agent with multitarget inhibitory properties. Though natural products and their derivatives have long been known for their medicinal properties for treating various ailments, little is known for their multimodality antileishmanial effects. A plethora of structurally diverse natural products, their IC50, and their biological targets of inhibition are, therefore, discussed in this book chapter. Structural modifications of these natural products based on pharmacophoric analysis leading to the semi-synthesis of their derivatives are also presented. Additionally, a view on metallodrugs using these versatile natural products and their derivatives coordinated to transition metals geared toward leishmaniasis treatment is proposed.

Steroid 5 alpha-reductase 2 (5αR-2) is a membrane-embedded protein that together with other isoforms plays a key role in the metabolism of steroids. This enzyme catalyzes the reduction of testosterone to the more potent ligand, dihydrotestosterone (DHT) in the prostate. Androgens, testosterone, and DHT play important roles in prostate growth, development, and function. At the same time, both testosterone and DHT have been implicated in the pathogenesis of benign prostate hyperplasia (BPH). Inhibition of the DHT formation, therefore, provides a therapeutic strategy that offers the possibility of preventing, delaying, or treating BPH. Currently, two steroidal drugs that inhibit 5αR-2, dutasteride and finasteride, have been approved for clinical use. These two come at a high cost and also portray undesirable sexual side effects which necessitate the need to find new chemotherapeutic alternatives for the disease. Based on the aforementioned, finasteride and dutasteride were subjected to scaffold hopping, fragment-based de novo design, molecular docking, and molecular dynamics simulations employing databases like ChEMBL, DrugBank, PubChem, ChemSpider, and Zinc15 in the identification of potential hits targeting 5αR-2. Altogether, ten novel compounds targeting 5αR-2 were identified with binding energies lower or comparable to finasteride and dutasteride, the main inhibitors for this target. Molecular docking and molecular dynamics simulations studies identify amino acid residues Glu57, Phe219, Phe223, and Leu224 to be critical for ligand binding and complex stability. The physicochemical and pharmacological profiling suggests the potential of the hit compounds to be drug-like and orally active. Similarly, the quality parameter assessments revealed the hits possess LELP greater than 3 implying their promise as lead-like molecules. The compounds A5, A9, and A10 were, respectively, predicted to treat prostate disorders with Pa (0.188, 0.361, and 0.270) and Pi (0.176, 0.050, and 0.093), while A8 and A9 were found to be associated with BPH treatment with Pa (0.09 and 0.127) and Pi (0.077 and 0.033), respectively. Structural similarity searches via DrugBank identified the drugs faropenem, acemetacin, estradiol valerate, and yohimbine to be useful for BPH treatment suggesting the de novo designed ligands as potential chemotherapeutic agents for treating this disease.

In recent years, the demand for climate-smart policies has taken on a global scale. While much of the emphasis has been on carbon footprints, other non-carbon greenhouse gases, like Nitrous oxide (N2O), seem to be having a substantial effect on climate change. N2O, a natural component of the atmosphere and the 3rd most deleterious greenhouse gas is being detected at concentrations higher enough to impact stratospheric ozone and global warming. Estimates of total atmospheric N2O since the industrial revolution showed a 20% increase by 2010. According to recent predictions, an expected increase from 6.4 to 7.6 Tg of N2O by 2030 is forecasted. Agriculture, fossil burning, energy industry, waste water management and transportation are among the worst culprits. Due to the increased rate of artificial N fertilizer application to meet global nutritional needs, the agricultural sector now accounts for over 70% of total N2O emissions. Though chemical inhibition of NH4+ oxidation and urea hydrolysis to lower N2O emissions from agriculture has been widely hailed, the efficacy of this technology as a smart practice for increasing crop production whilst avoiding environmental consequences has come under a barrage of criticisms. In this review, a broad spatial scale of the effects of various N inhibitors on global N2O budget and climate change based on mitigation trends since 2010 is presented.

The mortality rate of leishmaniasis is increasing at an alarming rate and is currently second to malaria amongst the other neglected tropical diseases. Unfortunately, many governments and key stakeholders are not investing enough in the development of new therapeutic interventions. The available treatment options targeting different pathways of the parasite have seen inefficiencies, drug resistance, and toxic side effects coupled with longer treatment durations. Numerous studies to understand the biochemistry of leishmaniasis and its pathogenesis have identified druggable targets including ornithine decarboxylase, trypanothione reductase, and pteridine reductase, which are relevant for the survival and growth of the parasites. Another plausible target is the sterol biosynthetic pathway; however, this has not been fully investigated. Sterol biosynthesis is essential for the survival of the Leishmania species because its inhibition could lead to the death of the parasites. This review seeks to evaluate how critical the enzymes involved in sterol biosynthetic pathway are to the survival of the leishmania parasite. The review also highlights both synthetic and natural product compounds with their IC50 values against selected enzymes. Finally, recent advancements in drug design strategies targeting the sterol biosynthesis pathway of Leishmania are discussed.

Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.