Contribution to the History of Heterocyclic Compounds: H. Antaki From a 1950 Thesis to a Named Synthesis

Hekmat Antaki (1923–1993) was an organic chemist. His doctoral thesis, Contributions to the Chemistry of Heterocyclic Compounds, was completed at Queen Mary College, University of London, in May 1950.

Part 1: What the Thesis Contained

A transferable ring-forming method: The thesis demonstrated that ethyl β-aminocrotonate could replace ethyl acetoacetate in ring closures with amidine-like heterocycles where earlier reactions had stopped at open-chain products. Antaki tested the same strategy across 2-aminopyridines, 2-aminothiazoles, 2-aminobenzothiazoles, 2-aminobenzoxazole, and 2-aminobenzimidazole. The partner changed while the ring-building logic stayed the same.

The fused pyrimidine systems were:

• Pyrido[1,2-a]pyrimidin-4-one: Structure corrected.
• Thiazolo[3,2-a]pyrimidin-5-one: A novel ring system.
• Pyrimido[2,1-b]benzothiazol-4-one: A novel ring system.
• Pyrimido[2,1-b]benzoxazol-4-one: A novel ring system.
• Pyrimido[1,2-a]benzimidazole: An already known system whose chemistry he extended with new 3-alkyl substitution.
• Ultraviolet spectroscopy as structural evidence: He used UV absorption to support his interpretation of the fused pyrido[1,2-a]pyrimidine system.

Three structural reassignments: Each was a correction of a structure, made with the evidence available at the time of the original assignment.

• Pyrido[1,2-a]pyrimidine (1911 assignment): The first compound of the series had been formulated as the 2-oxo compound, and that assignment was repeated in the literature for nearly forty years. An independent synthesis from 2-bromopyridine and ethyl β-aminocrotonate, published with V. Petrow in 1951, established the 4-oxo structure.
• Naphthyridine (1925 assignment): He reproduced an earlier reaction of 2-amino-3-methylpyridine with bromoacetal and compared it with closely analogous condensations. He concluded that the product was a five-membered methylpyrimidazole, not the six-membered dihydronaphthyridine originally assigned.
• Indolo-cholestane (1935 assignment): He revised the structure from angular to linear.

Fused heterocyclic steroids (Part II): He observed that the systematic study of heterocycle formation on steroid frameworks “has not hitherto been attempted,” and then carried it out. He prepared quinolino-, indolo-, pyrrolo-, thiazolo- and diazacarbazolo/triazafluoreno steroid systems and submitted compounds for biological testing.

Part 2: What Antaki Built Afterwards

• 1951 — Three papers (Journal of the Chemical Society): One paper brought together four fused pyrimidine systems from the thesis and corrected the pyrido[1,2-a]pyrimidine structure. A second published the steroid correction. A third described glycosylbenzimidazoles as potential vitamin B₁₂ inhibitors.
• 1958 — Journal of the American Chemical Society: Prepared 3-acetyl and 3-cyano pyrido[1,2-a]pyrimidin-4-ones from 2-aminopyridines.
• 1962 — Journal of Organic Chemistry: Established the ultraviolet chromophore rules for the class, relating molecular structure to absorption and testing the interpretation experimentally.
• 1963 — Journal of the Chemical Society: Reported the first practical three-component synthesis of 4-aryl-hexahydroquinolines, now called the Antaki synthesis.
• 1965 and 1967 — Journal of the Chemical Society: Extended the chemistry to pentacyclic benz[h]indenoquinolines, which showed intense blue fluorescence.
• 1952 and 1968 — Journal of the Medical Association: Published work on polarographic antimony determination in schistosomiasis therapy, and on the metabolism and excretion of niridazole.

What came after: The ring systems he closed and whose structures he corrected were later taken up by others. Pharmaceutical chemists developed derivatives of the pyrido[1,2-a]pyrimidinone framework into medicines. The discovery, development and testing of each drug are their work. His part was the early groundwork, and the chemistry remains in the record.

Medicines

• Risperidone: Antipsychotic; reduced (tetrahydro) ring system.
• Paliperidone (Invega): Antipsychotic; the 9-hydroxy metabolite of risperidone; reduced (tetrahydro) ring system.
• Pemirolast: Antiallergic, used ophthalmically for allergic conjunctivitis, aromatic ring system.
• Risdiplam (Evrysdi): First approved oral therapy for spinal muscular atrophy; aromatic ring system.
• Rimazolium (PROBON®): Non-narcotic analgesic; reduced (tetrahydro) ring system.

The same ring system later reappeared in crop protection. Mesoionic derivatives of the pyrido[1,2-a]pyrimidinone framework were developed into the commercial insecticides triflumezopyrim (marketed as Pyraxalt, for rice planthoppers) and dicloromezotiaz (for lepidopteran pests).

Reach: His work has been cited over a span of 75 years, from 1951 to 2026. It appears in twenty-nine pharmaceutical patents across six countries, from 1970 to 2017. His 1963 synthesis was named the Antaki synthesis.

www.hekmatantaki.org