Nigellicine

Nigellicine at a Glance

Nigellicine is a rare indazole alkaloid from the seeds of nigella / black seed (Nigella sativa). It was isolated in 1985 and is one of a small handful of natural products built on an indazole ring — a scaffold that is common in synthetic medicinal chemistry and almost absent from plants ^{1,9Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →Reference 9Mal S et al. · 2022ReviewA review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspectiveView study →}.

That rarity is the most substantive thing that can be said about it. Nigellicine has essentially no pharmacology of its own. It has never been tested in an animal, a cell line, or a person as an isolated compound; the chemistry literature that does exist is about how to make it and how to describe its unusual charge distribution, not about what it does ^{4,5,6Reference 4Elliott EL et al. · 2005Total synthesis of nigellicine and nigeglanine hydrobromideView study →Reference 5Schmidt A et al. · 2003New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicineView study →Reference 6Schmidt A et al. · 2009Quantum mechanical study and vibrational spectra of indazolium-3-carboxylate and its decarboxylation product, the N-heterocyclic carbene indazol-3-ylideneView study →}.

It is important to be blunt about the second point: black seed’s substantial evidence base rests on the quinone fraction — chiefly thymoquinone — and not on these alkaloids ^{7Reference 7Ali BH · 2003Pharmacological and toxicological properties of Nigella sativaView study →}. Nothing here inherits that record. Nigellicine is a marker and a curiosity, not an active principle with a case behind it.

Nigellicine vs. Nigellidine

The two indazole alkaloids of black seed are routinely named in the same breath, which invites the assumption that they are variants of one thing. They share a ring system but are chemically quite different molecules, and the difference matters for how each would behave.

Both are built on the same 6,7,8,9-tetrahydropyridazino[1,2-a]indazole core — a benzene ring fused to a pyrazole (that is the indazole), with a second six-membered nitrogen ring bridged across it. What differs is the substituent at position 11:

Feature	Nigellicine	Nigellidine
Isolated	1985 1Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →	1995 2Reference 2Atta-ur-Rahman et al. · 1995Nigellidine — a new indazole alkaloid from the seeds of Nigella sativaView study →
Formula / mass	C₁₃H₁₄N₂O₃ · 246.3	C₁₈H₁₈N₂O₂ · 294.3
C-11 substituent	carboxylate (–COO⁻)	4-hydroxyphenyl (a phenol)
Charge character	permanently zwitterionic — a pseudo-cross-conjugated mesomeric betaine 5Reference 5Schmidt A et al. · 2003New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicineView study →	neutral phenol; more lipophilic
Reported natural companion	—	also occurs as nigellidine-4-O-sulfite, the first sulfated indazole alkaloid found in nature 8Reference 8Ali Z et al. · 2008Nigellidine-4-O-sulfite, the first sulfated indazole-type alkaloid from the seeds of Nigella sativaView study →

Two consequences follow. First, nigellicine is the smaller, far more polar molecule: the carboxylate and the adjacent quaternised nitrogen give it a fixed internal charge separation that no pH change can neutralise, which is exactly the profile of a compound that crosses membranes badly. Nigellidine’s phenol, by contrast, leaves it lipophilic enough to look drug-like — which is a large part of why it, not nigellicine, dominates the docking literature.

Second, nigellicine is the older discovery, not the junior partner. It was characterised a decade before nigellidine ^{1,2Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →Reference 2Atta-ur-Rahman et al. · 1995Nigellidine — a new indazole alkaloid from the seeds of Nigella sativaView study →}. Neither has been quantified against the other in seed, so there is no verified basis for calling one “the major” alkaloid — a claim worth resisting when you meet it.

The Indazole Scaffold in Plants

Indazole (benzopyrazole) is a fused bicyclic ring bearing two adjacent nitrogen atoms. It is a workhorse of pharmaceutical chemistry — the core of axitinib, entrectinib, niraparib, granisetron and benzydamine — but in nature it is close to a dead end. Plant alkaloid chemistry is overwhelmingly built on indoles, isoquinolines, tropanes, pyridines and quinolizidines; the N–N bond of a pyrazole is rare in secondary metabolism because there is no common biosynthetic route to it.

Reviews of the indazole scaffold consistently make the same observation: the natural supply of indazoles is limited to a handful of alkaloids from the genus Nigella — nigellicine, nigellidine and nigeglanine — and this scarcity is repeatedly cited as a reason the pharmaceutical work on the ring system is entirely synthetic ^{9,14Reference 9Mal S et al. · 2022ReviewA review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspectiveView study →Reference 14Sharma R et al. · 2026Fused 1H-/2H-indazole as bioactive privileged scaffolds: synthetic strategies and pharmaceutical applicationsView study →}. Nigella sativa is therefore one of the very few plants where an indazole occurs at all.

Two caveats keep this from being over-read. The scaffold’s “privileged” status in drug discovery is a property of synthetic indazoles with deliberately designed substituents; it says nothing about what the plant’s own indazoles do. And the biosynthetic pathway that forms the N–N bond in Nigella has not been established — the origin of these alkaloids remains an open question.

Alongside the indazoles, the seed also carries isoquinoline alkaloids (nigellimine and nigellimine N-oxide) and dolabellane-type diterpene alkaloids, so nigellicine is one member of a chemically mixed minor-alkaloid fraction rather than the seed’s alkaloid ^{3Reference 3Botnick I et al. · 2012Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical usesView study →}.

What It's Used For

There is no primary pharmacology for nigellicine. No enzyme assay, no cell assay, no animal study has used the isolated compound. What follows is a map of the adjacent evidence and an honest statement of what it does and does not license.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. No application clears a meaningful floor for this molecule, because no application has ever been tested on it. The single row below is a read-across from a structural relative and is scored accordingly; molecular-docking papers are deliberately excluded and generate no row.

01Gastrointestinal Anti-Inflammatory (Scaffold Read-Across)Shaky8%A mouse/Caco-2 colitis study of the relative nigeglanine, plus a med-chem review that lists nigellicine among GI-relevant indazoles ^{10,11Reference 10Saha S et al. · 2022Indazole derivatives effective against gastrointestinal diseasesView study →Reference 11Gao XJ et al. · 2019AnimalThe protective effect of nigeglanine on dextran sulfate sodium-induced experimental colitis in mice and Caco-2 cellsView study →}

Mechanisms

The first row is the honest headline. The third row is included so that the docking literature is visible and labelled rather than quietly absorbed.

Pharmacokinetics

No pharmacokinetic data exist for nigellicine — no absorption, bioavailability, distribution, metabolism or half-life figures, in any species. It has never been dosed.

What can be said from structure is that the outlook for oral absorption is poor. Nigellicine is a pseudo-cross-conjugated mesomeric betaine: the carboxylate and the quaternised ring nitrogen hold a permanent, pH-independent charge separation, a state confirmed by X-ray crystallography, negative solvatochromism and calculation on the compound’s close analogues ^{5Reference 5Schmidt A et al. · 2003New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicineView study →}. Permanently charged, highly polar molecules of this kind generally cross lipid membranes badly by passive diffusion. That is an inference from physical chemistry, not a measurement, but it is the reason a docking score against an intracellular human target should be treated with particular scepticism for this molecule — a binding affinity is worthless if the compound never reaches the compartment.

A second structural note with practical edge: the indazolium-3-carboxylate nucleus decarboxylates on heating to a free N-heterocyclic carbene, a reaction studied in detail on model compounds ^{6Reference 6Schmidt A et al. · 2009Quantum mechanical study and vibrational spectra of indazolium-3-carboxylate and its decarboxylation product, the N-heterocyclic carbene indazol-3-ylideneView study →}. Whether roasting or prolonged heating of black seed degrades nigellicine has not been tested, but it is a reasonable question for anyone quantifying it in processed products.

Clinical Trials

There are no clinical trials of nigellicine and none registered. It has never been given to a human as an isolated compound. Human trials of Nigella sativa seed and oil exist in quantity, but they test the whole seed or oil and attribute their effects to thymoquinone ^{7Reference 7Ali BH · 2003Pharmacological and toxicological properties of Nigella sativaView study →}; none was designed around, standardised to, or analysed for the alkaloids.

Last checked: July 2026.

The Molecular-Docking Literature

If you search this molecule you will mostly find computational papers, and it is worth naming the pattern rather than letting it pad the page.

From 2020 onward, Nigella sativa’s alkaloids — nigellidine especially, nigellicine alongside it — became a favourite input for molecular-docking screens. They have been docked against the SARS-CoV-2 spike protein, nucleocapsid, main protease and RNA-dependent RNA polymerase, against human ACE1/ACE2 and angiotensin receptors, against dengue NS2B/NS3 protease and NS5 polymerase, against SIRT7, and against thyroxine-binding globulin ^{12,13Reference 12Maiti S et al. · 2021In silico nigellidine (N. sativa) bind to viral spike/active-sites of ACE1/2, AT1/2 to prevent COVID-19 induced vaso-tumult/vascular-damage/comorbidityView study →Reference 13Mir SA et al. · 2022Identification of SARS-CoV-2 RNA-dependent RNA polymerase inhibitors from the major phytochemicals of Nigella sativa: an in silico approachView study →}. Several conclude with strong language about patient benefit.

Docking is not evidence of activity. It is a geometric and energetic estimate of how well a molecule might sit in a protein pocket, computed from a static structure. It says nothing about whether the compound is absorbed, reaches the target tissue, survives metabolism, engages the target in a living cell, or produces any effect at achievable concentrations. A favourable docking score is a hypothesis-generating step that belongs before an experiment, not in place of one.

For that reason none of these papers contributes to the support score above, and none is used here to claim an activity. They are cited only as examples of the literature they represent. The practical test to apply: if a paper on a Nigella alkaloid has no enzyme assay, no cell assay and no animal arm, it has not shown that the alkaloid does anything.

Isolate vs. Plant Studies

The usual isolate-versus-plant tension does not apply here, because neither side has been studied for nigellicine.

There is no isolate pharmacology — the pure compound has been made, crystallised, synthesised and used as a structural template, but never assayed biologically ^{1,4,5Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →Reference 4Elliott EL et al. · 2005Total synthesis of nigellicine and nigeglanine hydrobromideView study →Reference 5Schmidt A et al. · 2003New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicineView study →}. And there is no plant study attributable to it: black seed’s large preclinical and clinical literature is built on whole seed, fixed oil and volatile oil, with the activity attributed to thymoquinone and the other quinones and monoterpenes ^{7Reference 7Ali BH · 2003Pharmacological and toxicological properties of Nigella sativaView study →}. Nigellicine sits in the seed at trace level and has never been the variable in any experiment.

The correct reading is therefore not “the isolate underperforms the plant” or the reverse; it is that this molecule is a marker of the seed, not a demonstrated contributor to what the seed does. Anything you read that assigns black seed’s anti-inflammatory, antidiabetic or antimicrobial effects to its alkaloids is running ahead of the data.

Prevalence in Nature

Nigellicine is documented from one plant: Nigella sativa seed ^{1Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →}. It has not been reliably reported outside N. sativa: the indazole alkaloids recovered from the second studied species, Nigella glandulifera, are nigellidine and nigeglanine rather than nigellicine ^{9,11Reference 9Mal S et al. · 2022ReviewA review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspectiveView study →Reference 11Gao XJ et al. · 2019AnimalThe protective effect of nigeglanine on dextran sulfate sodium-induced experimental colitis in mice and Caco-2 cellsView study →}.

Its distribution within the seed is unusually well described for such an obscure compound. Metabolite mapping of dissected seed by UPLC-Q-TOF-MS found that nigellidine and nigellicine accumulate almost exclusively in the seed coat, the same tissue that holds the volatile-oil compounds (thymoquinone, thymohydroquinone, p-cymene, carvacrol, γ-terpinene) — while amino and organic acids sit in the inner tissues and dopamine and the saponin α-hederin are spread across both ^{3Reference 3Botnick I et al. · 2012Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical usesView study →}. Practically, that means the alkaloids ride with the bran/hull fraction: dehulling or fine sieving would be expected to strip them, whereas whole-seed powder retains them.

No absolute content figure has ever been published. The localisation work reports relative content between tissues, not milligrams per gram, and no HPLC or LC-MS assay quantifying nigellicine in seed or oil could be verified. It is described consistently as a minor constituent, and the indazole reviews single out low natural abundance as a defining limitation of these alkaloids ^{9Reference 9Mal S et al. · 2022ReviewA review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspectiveView study →} — but “minor” here is a qualitative statement, not a measured one. See the gaps note for this compound.

Discovery & Synthesis

First isolation (1985). Nigellicine was isolated from Nigella sativa seed and its structure determined by Atta-ur-Rahman, Sabira Malik, He Cun-Heng and Jon Clardy, working between Karachi and Cornell, and published in Tetrahedron Letters as “a novel alkaloid” ^{1Reference 1Atta-ur-Rahman et al. · 1985Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativaView study →}. The structure was settled by X-ray crystallography — appropriate for a ring system with no natural precedent. The same group went on to describe the seed’s isoquinoline alkaloids nigellimine and nigellimine N-oxide, and a decade later nigellidine ^{2Reference 2Atta-ur-Rahman et al. · 1995Nigellidine — a new indazole alkaloid from the seeds of Nigella sativaView study →}; nigellidine-4-O-sulfite, the first sulfated indazole alkaloid known from nature, was added by Ali and colleagues in 2008 ^{8Reference 8Ali Z et al. · 2008Nigellidine-4-O-sulfite, the first sulfated indazole-type alkaloid from the seeds of Nigella sativaView study →}. The name follows the genus, as the whole Nigella alkaloid series does.

First total synthesis (2005). Elliott, Bushell, Cavero, Tolan and Kelly at Boston College reported the first syntheses of nigellicine and nigeglanine hydrobromide in Organic Letters, reaching both pyridazinoindazolium alkaloids through a common intermediate by ortho-lithiation/acylation and direct amination of an isatin ring system ^{4Reference 4Elliott EL et al. · 2005Total synthesis of nigellicine and nigeglanine hydrobromideView study →}. The route is the reason the compound is available at all for chemical study — there is no commercial isolation from seed.

Chemical afterlife. Rather than becoming a pharmacological lead, nigellicine became a reference structure in physical organic chemistry. It is one of the few natural examples of a pseudo-cross-conjugated mesomeric betaine, and Schmidt’s group built synthetic pyrazolium-carboxylate analogues explicitly as relatives of “the betainic alkaloid Nigellicine” to probe how the charge separation works ^{5Reference 5Schmidt A et al. · 2003New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicineView study →}, later showing that the underlying indazolium-3-carboxylate nucleus thermally decarboxylates to an N-heterocyclic carbene ^{6Reference 6Schmidt A et al. · 2009Quantum mechanical study and vibrational spectra of indazolium-3-carboxylate and its decarboxylation product, the N-heterocyclic carbene indazol-3-ylideneView study →}. Manufacture today: none. Nigellicine is not produced commercially, not sold as an ingredient, and not used to standardise any black-seed product.

Patents: not yet researched.

Toxicity & Safety

Nigellicine carries a low flag, and the basis for that badge should be stated precisely, because it is not an isolate dataset.

There is no toxicology for nigellicine at all — no acute, repeat-dose, genotoxicity, reproductive or interaction data, in any species. The low badge rests on two indirect arguments. First, exposure: the only route by which anyone encounters this molecule is eating whole Nigella sativa seed, a culinary spice with a very long history of food use, and reviews of the seed report a very low degree of toxicity, with adverse reports confined to occasional contact dermatitis and no significant liver or kidney effects on extended dosing in animals ^{7Reference 7Ali BH · 2003Pharmacological and toxicological properties of Nigella sativaView study →}. Second, dose: nigellicine is a trace seed-coat constituent, so dietary intake is minute even at generous culinary or supplemental seed doses. Neither argument would survive if the compound were ever concentrated or given as an isolate — at which point the badge would need revisiting on real data.

Safety at a Glance

✅ Low / no toxicity

• Dietary exposure only, in a food with a good record. Nigellicine is a trace constituent of a spice eaten for millennia; whole black seed is characterised as having a very low order of toxicity ^{7Reference 7Ali BH · 2003Pharmacological and toxicological properties of Nigella sativaView study →}.
• No isolate safety data of any kind. Acute toxicity, genotoxicity, reproductive effects and drug interactions are entirely uncharacterised for the pure compound; the badge is an exposure argument, not a measurement.
• Do not read black seed’s safety or efficacy record onto this molecule. That record belongs to the whole seed and to thymoquinone; the cautions that matter for black-seed products (additive blood-sugar and blood-pressure lowering, pregnancy) are decided on the herb page, not here.
• Nothing supports isolated or concentrated use. No product is standardised to nigellicine and no dose has ever been studied; a purified alkaloid is a different exposure from a spice.

Dosage

There is no dose. Nigellicine has never been administered to a human or an animal as an isolated compound, no supplement is standardised to it, and no assay has established how much of it a given amount of seed delivers.

Human exposure is entirely incidental and dietary — trace quantities inside whole black seed, concentrated in the seed coat and therefore reduced by dehulling ^{3Reference 3Botnick I et al. · 2012Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical usesView study →}. Black-seed products are dosed as seed powder or cold-pressed oil and, where standardised at all, are standardised to thymoquinone; the dosing that has actually been studied belongs on the nigella herb page. No figure here is a recommendation, and no number could be, because none has been measured.

References

1. Atta-ur-Rahman, Malik S, Cun-Heng H, Clardy J (1985). Isolation and structure determination of nigellicine, a novel alkaloid from the seeds of Nigella sativa. Tetrahedron Letters. https://doi.org/10.1016/S0040-4039(00)94904-9
2. Atta-ur-Rahman, Malik S, Hasan SS, Choudhary MI, Ni CZ, Clardy J (1995). Nigellidine — a new indazole alkaloid from the seeds of Nigella sativa. Tetrahedron Letters. https://doi.org/10.1016/0040-4039(95)00210-4
3. Botnick I, Xue W, Bar E, Ibdah M, Schwartz A, Joel DM, Lev E, Fait A, Lewinsohn E (2012). Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical uses. Molecules. https://pubmed.ncbi.nlm.nih.gov/22922285/
4. Elliott EL, Bushell SM, Cavero M, Tolan B, Kelly TR (2005). Total synthesis of nigellicine and nigeglanine hydrobromide. Organic Letters. https://pubmed.ncbi.nlm.nih.gov/15932220/
5. Schmidt A, Habeck T, Kindermann MK, Nieger M (2003). New pyrazolium-carboxylates as structural analogues of the pseudo-cross-conjugated betainic alkaloid nigellicine. The Journal of Organic Chemistry. https://pubmed.ncbi.nlm.nih.gov/12868936/
6. Schmidt A, Snovydovych B, Casado J, Quirante JJ, Navarrete JT, Ramírez FJ (2009). Quantum mechanical study and vibrational spectra of indazolium-3-carboxylate and its decarboxylation product, the N-heterocyclic carbene indazol-3-ylidene. Physical Chemistry Chemical Physics. https://pubmed.ncbi.nlm.nih.gov/19088990/
7. Ali BH, Blunden G (2003). Pharmacological and toxicological properties of Nigella sativa. Phytotherapy Research. https://pubmed.ncbi.nlm.nih.gov/12722128/
8. Ali Z, Ferreira D, Carvalho P, Avery MA, Khan IA (2008). Nigellidine-4-O-sulfite, the first sulfated indazole-type alkaloid from the seeds of Nigella sativa. Journal of Natural Products. https://pubmed.ncbi.nlm.nih.gov/18471018/
9. Mal S, Malik U, Mahapatra M, Mishra A, Pal D, Paidesetty SK (2022). A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective. Drug Development Research. https://pubmed.ncbi.nlm.nih.gov/35971890/
10. Saha S, Pal D, Nimse SB (2022). Indazole derivatives effective against gastrointestinal diseases. Current Topics in Medicinal Chemistry. https://pubmed.ncbi.nlm.nih.gov/34886775/
11. Gao XJ, Tang B, Liang HH, Yi L, Wei ZG (2019). The protective effect of nigeglanine on dextran sulfate sodium-induced experimental colitis in mice and Caco-2 cells. Journal of Cellular Physiology. https://pubmed.ncbi.nlm.nih.gov/31169313/
12. Maiti S, Banerjee A, Kanwar M (2021). In silico nigellidine (N. sativa) bind to viral spike/active-sites of ACE1/2, AT1/2 to prevent COVID-19 induced vaso-tumult/vascular-damage/comorbidity. Vascular Pharmacology. https://pubmed.ncbi.nlm.nih.gov/33746069/ (cited as an example of the in-silico literature; no wet-lab arm)
13. Mir SA, Firoz A, Alaidarous M, Alshehri B, Dukhyil AAB, Banawas S, Alsagaby SA, Alturaiki W, Bhat GA, Kashoo F, Abdel-Hadi AM (2022). Identification of SARS-CoV-2 RNA-dependent RNA polymerase inhibitors from the major phytochemicals of Nigella sativa: an in silico approach. Saudi Journal of Biological Sciences. https://pubmed.ncbi.nlm.nih.gov/34518755/ (cited as an example of the in-silico literature; no wet-lab arm)
14. Sharma R, Mahajan AT, Shrivastava V, Husain IFBZ, Chaudhary S (2026). Fused 1H-/2H-indazole as bioactive privileged scaffolds: synthetic strategies and pharmaceutical applications. Current Drug Discovery Technologies. https://pubmed.ncbi.nlm.nih.gov/42163609/

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