Study of the Chemical Reactivity of a Series of Halogen-Substituted ImidazoleThiosemicarbazides Using Density Functional Theory

1 Available online at www.derpharmachemica.com ISSN 0975-413X CODEN (USA): PCHHAX Der Pharma Chemica, 2023, 15(2): 1-10 (http://www.derpharmachemica.com/archive.html) Study of the Chemical Reactivity of a Series of Halogen-Substituted ImidazoleThiosemicarbazides Using Density Functional Theory Mamadou Guy-Richard KONE1,2,3*, Georges Stéphane DEMBELE1,2, Bafétigué OUATTARA4, Adama NIARE4, Panaghiotis KARAMANIS3 and Nahossé ZIAO1,2 1Laboratoire de Thermodynamique et de Physico-Chimie du Milieu, Université NANGUI ABROGOUA, Abidjan, Côte-d’Ivoire 2Groupe Ivoirien de Recherches en Modélisation des Maladies (GIR2M), Université NANGUI ABROGOUA, Abidjan, Côte-d’Ivoire 3E2S UPPA, CNRS, IPREM, Université de Pau et des Pays de l’Adour, 64053 Pau, France 4Laboratoire de Physique Fondamentale et Appliquée, UFR SFA, Université NANGUI ABROGOUA, Abidjan, Côte-d’Ivoire *Corresponding author: Mamadou Guy-Richard KONE, Laboratoire de Thermodynamique et de Physico-Chimie du Milieu, Université NANGUI ABROGOUA, Abidjan, Côte-d’Ivoire, E-mail: [email protected] Received: 30-Jan-2023, Manuscript no: dpc-23-88268, Editor assigned: 01-Feb-2023, PreQC No: dpc-23-88268, Reviewed: 15-Feb-2023, QC No: dpc-23-88268, Revised: 17-Feb-2023, Manuscript No: dpc-23-88268, Published: 24-Feb-2023, DOI: 10.4172/0975-413X.15.2.1-10 ABSTRACT This theoretical reactivity study was conducted on six molecules of a series of halogen-substituted Imidazole-Thiosemicarbazides (ITS) using density functional theory, at the B3LYP/6-31+G (d, p) level. Analysis of the thermodynamic formation quantities confirmed the formation and existence of the series of molecules studied. The study of the boundary molecular orbitals, including the energy gap (ΔE), electronegativity (), chemical hardness (η) and electrophilicity index (ω) provided a better overview of the molecular properties. Thus, the compounds ITS 1 and ITS 4 which have the lowest energy gaps between the boundary orbitals are the most reactive and the least stable. Furthermore, ITS 1 is the softest of the compounds studied. The analysis of the local descriptors and the isodensity map allowed us to identify the N14 nitrogen atom as the preferred electrophilic attack site and the C18 carbon atom as the preferred nucleophilic attack site. These electrophilic and nucleophilic attack sites (N14 and C18) are identical for all compounds according to the dual descriptors. Furthermore, halogen substitution on imidazole-thiosemicarbazides does not change the centres of reactivity. The dendrogram of the Hierarchical Ascending Classification Analysis allowed us to group all the six studied compounds into three categories. The most active one is ITS 3, ITS 2 and ITS 5 the moderately active compounds and ITS 1, ITS 4 and ITS 6, the least active ones. The surface profiler analysis showed us an almost smooth plane connecting the three (3) descriptors that are ΔE, ω and η. This result shows the linearity between these descriptors of reactivity. Keywords: Chemical reactivity; Global descriptors; Local descriptors; Dual descriptors INTRODUCTION Parasites from plants or animals origin, feed themselves at the expense of a host without which they are unable to survive. Parasitism is a universally widespread phenomenon, which affects practically all living creatures. For example, we can quote parasites that attack humans such as lice, fleas and intestinal worms. It is in this context that Agata et al. [1] have synthesized and tested imidazole-thiosemicarbazides with halogens as substitution to fight against infection caused by Toxoplasma gondii. It should be noted that Toxoplasma gondii is a species of intracellular parasites belonging to the phylum Apicomplexa, and it is the pathogen agent of toxoplasmosis. The Apicomplexa phylum includes many other pathogens of medical or veterinary importance; among them we can quote Plasmodium falciparum which is responsible for malaria in humans. In addition, this parasite affects around 30% of the world population [2]. It causes serious illnesses in people living with HIV/AIDS or in pregnant women creating birth defects [3,4]. Imidazole-thiosemicarbazides are practical precursors that have been widely used in heterocyclic synthesis. One of the most complex branches of organic chemistry is the chemistry of heterocyclic compounds. It is also interesting for its theoretical implications, because of the diversity of its synthesis methods, and because of the physiological and industrial significance of heterocyclic compounds. Studies on heterocyclic compounds have a longtime been an interesting area in medicinal chemistry. For better understanding of the ways how to control these harmeful and mortal parasites, medicinal chemistry or therapeutic chemistry, which is a scientific discipline at the interface of chemistry and pharmacy, including the design of drugs and their development, is on the lookout for new molecular entities with biological or therapeutic activity. Nowadays, computational chemistry gives a lot of information on the electronic structures of molecules and contributes largely to the development of traditionally experimental chemistry [5-7]. In this work, a series of six molecules of Imidazole-Thiosemicarbazides Substituted (ITS) by halogens 2 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 like Chlorine and Fluorine in Ortho, Meta and Para position (ITS 1, ITS 2, ITS 3, ITS 4, ITS 5 and ITS 6) have been used (Figure 1). The aim of this work is to theoretically determine, on the one hand the reactivity of imidazole-thiosemicarbazides substituted by halogens and on the other hand to identify the sites of nucleophilic / electrophilic attacks by different methods of quantum chemistry. Figure 1: Structures and nomenclature of studied Imidazole-Thiosemicarbazides and their codes MATERIAL AND METHODS Calculation theory level The theoretical study of chemical reactivity was carried out based on three theoretical approaches. The first concerns the analysis of molecular isodensity maps. The second one relates to border molecular orbitals. And finally the last approach deals with local indices of reactivity as well as dual descriptors. The geometries of the molecules have been optimized at the DFT calculation level with the functional B3LYP [8-10] in the base 631 + G (d, p) using the Gaussian software 09 [11]. This hybrid functional gives better energies and is in agreement with high calculations level of ab initio methods [12, 13]. As for the base split-valence and double-dzéta (6-31G (d, p)), it is sufficiently extended and the fact of taking into account the functions of polarization is important for the explanation of the free doublets of the heteroatoms. The geometries are kept constant for cationic and anionic systems. The global reactivity indices were obtained from the conceptual DFT model [14-16]. The Hierarchical Ascending Classification (HAC) analysis was carried out using XLSTAT software [17]. As for the local chemical reactivity indices, they were determined using the electronic populations calculated with the Hirshfeld Population Analysis (HPA) [18]. Thermodynamic parameters of formation The thermodynamic quantities of the studied molecules were carried out from optimization and the frequency calculation at the level B3LYP / 6-31 + G (d, p). The magnitudes such as the entropy, the enthalpy and the free enthalpy of ITS’ formation were determined using the following formulas proposed by Otchersky et al. [11]. ∆𝑯𝒇 𝟎(𝑴,𝟎𝑲)= ∑ 𝒙∆𝑯𝒇 𝟎(𝑿,𝟎𝑲) 𝒂𝒕𝒐𝒎𝒔 −∑𝑫𝟎 (1) ∆𝐻𝑓 0(𝑀,298𝐾)= ∆𝐻𝑓 0(𝑀,0𝐾)+(𝐻𝑀 0(298𝐾)−𝐻𝑀 0(0𝐾))− ∑ 𝑥(𝐻𝑋 0(298𝐾)−𝐻𝑋 0(0𝐾)) 𝑎𝑡𝑜𝑚𝑠 (2) With ∑𝑫𝟎=∑𝒙𝜺𝟎−𝜺𝟎(𝑴)−𝜺𝒁𝑷𝑬 (3) 3 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 ∑𝑫𝟎 : Atomization energy; 𝜺𝟎(𝑴) : Total energy of the molecule; 𝜺𝒁𝑷𝑬 : Zero point energy of the molecule; 𝑯𝑿 𝟎(𝟐𝟗𝟖𝑲)−𝑯𝑿 𝟎(𝟎𝑲) : Enthalpy corrections for atomic elements. These values are included in the table of Janaf [19]. 𝑯𝑴 𝟎(𝟐𝟗𝟖𝑲)−𝑯𝑴 𝟎(𝟎𝑲)=𝑯𝒄𝒐𝒓𝒓 −𝜺𝒁𝑷𝑬(𝑴) : Correction of enthalpy of the Molecule 𝐻𝑐𝑜𝑟𝑟 : Thermal correction enthalpy. ∆𝑺𝒇 𝟎(𝑴,𝟐𝟗𝟖𝑲)=𝑺𝑴− ∑ 𝒙∆𝑺(𝟐𝟗𝟖𝑲) 𝒂𝒕𝒐𝒎𝒔 (4) 𝑥 : Number of atoms of X in the Molecule ∆𝑮𝒇 𝟎(𝑴,𝟐𝟗𝟖𝑲)= ∆𝑯𝒇 𝟎(𝑴,𝟐𝟗𝟖𝑲)−𝑻∆𝑺𝒇 𝟎(𝑴,𝟐𝟗𝟖𝑲) (5) Hirshfeld Population Analysis Hirshfeld charges analysis has been used extensively, particularly for the calculation of Fukui coefficients. Before obtaining Hirshfeld charges of a molecule that one must first be decomposed into atomic fragments. A general and natural choice consist to share the charge density at each point between the different atoms in proportion to their densities of free atoms at the corresponding distances from the nuclei [20,8]. This method allows obtaining localized and bound electronic distributions, which is approximately like the molecular electronic density. The integration of the densities surrounding each atom defines its net atomic charge. Reactivity descriptors Global descriptors To predict chemical reactivity, some theoretical descriptors related to conceptual DFT have been determined. In particular, the energy of the lowest unoccupied Molecular Orbital (LUMO), the energy of the Highest Occupied Molecular Orbital (HOMO), electronegativity (χ), global softness (σ) and global electrophilicity index (ω). These descriptors are all determined from the optimized structure of the molecules. It should be noted that, the descriptors related to the molecular orbital boundaries have been calculated in a very simple way within the framework of Koopmans’ approximation [21]. LUMO energy characterizes the sensitivity of the molecule to nucleophilic attack, and HOMO energy characterizes the susceptibility of a molecule to electrophilic attack. The electronegativity (χ) is the parameter that reflects the ability of a molecule not to let its electrons escape. Global softness (σ) expresses the resistance of a system to changes in its number of electrons. The global electrophilicity index characterizes the electrophilic power of the molecule. These different parameters are calculated from equations (6): 𝐼 =−𝐸𝐻𝑂𝑀𝑂 𝐴 = −𝐸𝐿𝑈𝑀𝑂 𝜒 = −𝜇 = −1 2 ⁄ (𝐸𝐿𝑈𝑀𝑂 +𝐸𝐻𝑂𝑀𝑂) 𝜂 =(𝐸𝐿𝑈𝑀𝑂 −𝐸𝐻𝑂𝑀𝑂)2 ⁄ (6) 𝜔 = 𝜒2 2𝜂 𝜎 =1 𝜂 ⁄ Local and dual descriptors The Fukui indices of a molecule inform about the local reactivity in a molecule. The atom with the highest value of Fukui index is more reactive than the other atoms belonging to the molecule [22]. These indices represent the qualitative description of the reactivity of the atoms in the molecule. The Fukui function successfully predicts relative reactivity for most chemical systems. Fukui indices for the selectivity of electrophilic and nucleophilic atoms in Imidazole-Thiosemicarbazides compounds have been determined. Ayers and Parr [23] explained that molecules tend to react where the Fukui function is greatest when they are attacked by soft reagents and similarly where the Fukui function is smallest it is where it will be attacked by hard reagents. Using the Hirshfeld atomic charges of the optimized compounds at the ground state, the Fukui functions (fk +,fk −), the local softness (sk +,sk −) and the local electrophilic indices (ωk +,ωk −) [24] were determined. The Fukui functions are calculated using equations (7) and (8): 𝑓𝑘 +=𝑞𝑘(𝑁+1)−𝑞𝑘(𝑁) (7) 𝑓𝑘 −=𝑞𝑘(𝑁)−𝑞𝑘(𝑁−1) (8) 𝑓𝑘 + for nucleophilic attack 𝑓𝑘 − for electrophilic attack 𝑞𝑘(𝑁) : Electronic population of the k atom in the neutral molecule. 𝑞𝑘(𝑁+1) : Electronic population of the k atom in the anionic molecule. 𝑞𝑘(𝑁−1) : Electronic population of the k atom in the cationic molecule. Local softness and electrophilicity indices are calculated using (9-12) 𝑠𝑘 +=𝑠𝑓𝑘 + (9) 𝑠𝑘 −=𝑠𝑓𝑘 − (10) 4 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 𝜔𝑘 +=𝜔𝑓𝑘 + (11) 𝜔𝑘 −=𝜔𝑓𝑘 − (12) The values of the dual descriptors [25,26] are obtained from equations (13-15) ∆𝑓 =𝑓𝑘 +−𝑓𝑘 − (13) ∆𝑠 =𝑠𝑘 +−𝑠𝑘 − (14) ∆𝜔 =𝜔𝑘 +−𝜔𝑘 − (15) RESULTS AND DISCUSSION The study of the reactivity of organic molecules is essential in the pharmaceutical, cosmetic and food-processing fields. In these fields, the prediction of the evolution of product quality under the influence of external factors is important. These factors include temperature, humidity, light, oxygen and pH. They permit to define the storage and transportation conditions and the expiry date of these organic compounds. Analysis of thermodynamic formation quantities The thermodynamic parameters namely enthalpy of formation ΔfHo (kcal/mol), entropy of formation ΔfSo (kcal/molK), and free enthalpy of formation ΔfGo (kcal/mol) were explored. It should be noted that a variation in enthalpy reflects the thermicity of a chemical reaction when that of the entropy provides information about the level of disorder in the system. On the other hand, a variation in free enthalpy reflects the spontaneity with which a chemical reaction occurs. These thermodynamic quantities in our study were obtained after optimization and frequency calculation, at the B3LYP/6-31+G (d, p) level. The values of the thermodynamic parameters are given in Table 1. Table 1: Thermodynamic quantities of ITSs’ formation calculated at B3LYP/6-31+G (d, p) Molecules ∆𝒇𝑯𝟎 𝟐𝟗𝟖(𝒌𝒄𝒂𝒍/𝒎𝒐𝒍) ∆𝒇𝑺𝟎 𝟐𝟗𝟖(𝒌𝒄𝒂𝒍/𝒎𝒐𝒍.𝑲) ∆𝒇𝑮𝟎 𝟐𝟗𝟖(𝒌𝒄𝒂𝒍/𝒎𝒐𝒍) ITS 1 -1219.335 -0.935 -940.438 ITS 2 -1219.502 -0.935 -940.673 ITS 3 -1219.081 -0.935 -940.322 ITS 4 -1177.678 -0.933 -899.421 ITS 5 -1177.422 -0.933 -899.105 ITS 6 -1178.215 -0.933 -899.954 The results show that all the values of the standard thermodynamic quantities for molecule formation are negative. These negative values of enthalpy and free enthalpy reflect an exothermic and spontaneous reaction respectively under the conditions of the study. For entropy, a negative value indicates a decrease in disorder. Thus, the formation of all compounds is spontaneous with a release of heat and a decrease of disorder. At this level, we note that the determined quantities at the level of theory B3LYP/6-31+G (d, p) confirm the formation and the existence of the explored series of Imidazole-Thiosemicarbazides at required conditions of temperature and pressure (298.15K and 1 atm). Global Descriptors The study of the global chemical reactivity of molecules is based on the calculation of global indices deduced from the electronic properties. The global indices of the chemical reactivity of the studied ITSs are recorded in Table 2. Table 2: Energetic values of the orbital boundaries and the gap (eV) of the ITSs, calculated at the B3LYP/6-31+G(d, p) level Molecules 𝑬𝑯𝑶𝑴𝑶 (eV) 𝑬𝑳𝑼𝑴𝑶 (eV) ΔE (eV) (eV) µ(eV) Ƞ(eV) ω(eV) ITS 1 -6.331 -1.701 4.630 4.016 -4.016 2.315 3.483 ITS 2 -6.416 -1.738 4.678 4.077 -4.077 2.339 3.553 ITS 3 -6.38 -1.636 4.744 4.008 -4.008 2.372 3.387 ITS 4 -6.349 -1.716 4.633 4.032 -4.032 2.317 3.510 ITS 5 -6.434 -1.738 4.696 4.086 -4.086 2.348 3.555 ITS 6 -6.37 -1.728 4.643 4.049 -4.049 2.321 3.531 The results in Table 2 show that the ITS 1 compound has the smallest energy gap value (ΔE=4.630 eV), so this compound is more reactive and less stable. In contrast, the ITS 3 compound which has the largest energy gap (ΔE=4.744 eV), is therefore the less reactive and the more stable among studied molecules. Thus, we can establish the following sequence in decreasing order of reactivity: ΔE : ITS 1 > ITS 4>ITS 6> ITS 2> ITS 5> ITS 3 This decreasing order of stability is shown in Figure 2. 5 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 Figure 2: Representation of the energy gap of the imidazole-thiosemicarbazide series by increasing gap value. The other interpreted parameter is chemical hardness (η). Compounds ITS 1 and ITS 4 have the lowest values (2.315 eV and 2.317 eV) respectively compared to the other compounds, indicating that they are the least hard (soft) of the studied compounds. In summary, the overall descriptors revealed that ITS 1 and ITS 4 were the most reactive, least stable and softest compounds. On the other hand, ITS 1 was the softest of the studied compounds. Local Descriptors In the study of the isodensity map, a site is likely to be nucleophilic or electrophilic if it belongs to a larger lobe [27]. The isodensity maps showing the probable nucleophilic and electrophilic attack sites using the large lobes of the six (6) studied compounds are shown below in Figures 3-8. Figure 3: HOMO and LUMO isodensity maps of the ITS 1 compound. Figure 4: HOMO and LUMO isodensity maps of the ITS 2 compound. Figure 5: HOMO and LUMO isodensity maps of the ITS 3 compound. 6 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 Figure 6: HOMO and LUMO isodensity maps of the ITS 4 compound. Figure 7: HOMO and LUMO isodensity maps of the ITS 5 compound. Figure 8: HOMO and LUMO isodensity maps of the ITS 6 compound. Analysis of the maps through HOMO indicates that the largest lobe entirely containing the C28, C1 and N14 atoms would be the probable nucleophilic sites of the series of six (6) studied compounds. With respect to the electrophilic sites of attack obtained from LUMO; atoms C18, C12, and S21 have the largest lobes. These would appear to be the likely electrophilic sites of the studied series of halogenated ITSs. In order to predict accurately the sites of electrophilic and nucleophilic attack, local and dual descriptors of reactivity were determined for each compound according to equations 7 to 15. Only heavy atoms are taken into account in this study. These different descriptors of reactivity are grouped in Tables 3-8. Table 3: Descriptors of the reactivity of Compound 1 (ITS 1) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0908 0.0910 0.0388 0.0389 0.3225 0.3235 -0.0003 -0.0001 -0.0009 C2 0.0134 0.0366 0.0057 0.0157 0.0478 0.1301 -0.0232 -0.0099 -0.0823 C3 0.0388 0.0407 0.0166 0.0174 0.1379 0.1448 -0.0019 -0.0008 -0.0068 C6 0.0508 0.0531 0.0217 0.0227 0.1804 0.1885 -0.0023 -0.0010 -0.0081 N10 0.0337 0.0361 0.0144 0.0154 0.1198 0.1284 -0.0024 -0.0010 -0.0086 N11 0.0436 0.0344 0.0186 0.0147 0.1549 0.1223 0.0092 0.0039 0.0327 C12 0.0625 0.0156 0.0267 0.0067 0.2219 0.0553 0.0469 0.0201 0.1667 O13 0.0655 0.0386 0.0280 0.0165 0.2328 0.1373 0.0269 0.0115 0.0955 N14 0.0234 0.0744 0.0100 0.0318 0.0831 0.2644 -0.0510 -0.0218 -0.1813 N16 0.0406 0.0833 0.0174 0.0356 0.1442 0.2958 -0.0427 -0.0182 -0.1516 C18 0.0687 0.0050 0.0294 0.0021 0.2440 0.0176 0.0637 0.0272 0.2264 N19 0.0328 0.0701 0.0140 0.0300 0.1164 0.2490 -0.0373 -0.0160 -0.1326 S21 0.1480 0.0848 0.0633 0.0363 0.5257 0.3013 0.0632 0.0270 0.2244 C22 0.0195 0.0283 0.0083 0.0121 0.0693 0.1006 -0.0088 -0.0038 -0.0312 C23 0.0209 0.0343 0.0089 0.0147 0.0743 0.1218 -0.0134 -0.0057 -0.0475 C24 0.0394 0.0434 0.0168 0.0185 0.1398 0.1541 -0.0040 -0.0017 -0.0143 C25 0.0575 0.0534 0.0246 0.0228 0.2043 0.1896 0.0041 0.0018 0.0146 C26 0.0457 0.0566 0.0195 0.0242 0.1624 0.2011 -0.0109 -0.0047 -0.0387 C28 0.0860 0.0928 0.0367 0.0397 0.3054 0.3296 -0.0068 -0.0029 -0.0242 F32 0.0184 0.0275 0.0078 0.0117 0.0652 0.0976 -0.0091 -0.0039 -0.0324 7 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 Table 4: Descriptors of the reactivity of Compound 2 (ITS 2) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0889 0.0939 0.0380 0.0401 0.3158 0.3335 -0.0050 -0.0021 -0.0177 C2 0.0128 0.0396 0.0055 0.0169 0.0456 0.1406 -0.0268 -0.0114 -0.0951 C3 0.0378 0.0423 0.0161 0.0181 0.1341 0.1503 -0.0046 -0.0019 -0.0162 C6 0.0494 0.0549 0.0211 0.0235 0.1755 0.1950 -0.0055 -0.0023 -0.0195 N10 0.0331 0.0371 0.0141 0.0159 0.1175 0.1318 -0.0040 -0.0017 -0.0143 N11 0.0425 0.0359 0.0182 0.0154 0.1508 0.1276 0.0065 0.0028 0.0233 C12 0.0605 0.0155 0.0259 0.0066 0.2150 0.0551 0.0450 0.0192 0.1599 O13 0.0633 0.0393 0.0271 0.0168 0.2248 0.1397 0.0240 0.0102 0.0852 N14 0.0231 0.0745 0.0099 0.0319 0.0819 0.2647 -0.0515 -0.0220 -0.1828 N16 0.0417 0.0824 0.0178 0.0352 0.1480 0.2926 -0.0407 -0.0174 -0.1446 C18 0.0679 0.0057 0.0290 0.0025 0.2412 0.0204 0.0622 0.0266 0.2208 N19 0.0452 0.0697 0.0193 0.0298 0.1604 0.2477 -0.0246 -0.0105 -0.0873 S21 0.1490 0.0886 0.0637 0.0379 0.5292 0.3146 0.0604 0.0258 0.2146 C22 0.0198 0.0242 0.0084 0.0103 0.0702 0.0860 -0.0044 -0.0019 -0.0157 C23 0.0376 0.0370 0.0161 0.0158 0.1336 0.1316 0.0006 0.0002 0.0020 C24 0.0456 0.0587 0.0195 0.0251 0.1621 0.2087 -0.0131 -0.0056 -0.0466 C25 0.0226 0.0265 0.0097 0.0113 0.0802 0.0941 -0.0039 -0.0017 -0.0139 C26 0.0564 0.0533 0.0241 0.0228 0.2003 0.1894 0.0031 0.0013 0.0109 C28 0.0810 0.0921 0.0346 0.0394 0.2877 0.3272 -0.0111 -0.0047 -0.0395 F32 0.0220 0.0287 0.0094 0.0123 0.0781 0.1020 -0.0067 -0.0029 -0.0239 Table 5: Descriptors of the reactivity of Compound 3 (ITS 3) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Table 6: Descriptors of the reactivity of Compound 4 (ITS 4) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0891 0.0900 0.0385 0.0389 0.3127 0.3160 -0.0009 -0.0004 -0.0033 C2 0.0129 0.0358 0.0056 0.0154 0.0454 0.1255 -0.0228 -0.0099 -0.0801 C3 0.0381 0.0401 0.0164 0.0173 0.1336 0.1408 -0.0020 -0.0009 -0.0072 C6 0.0494 0.0520 0.0213 0.0224 0.1735 0.1824 -0.0026 -0.0011 -0.0090 N10 0.0332 0.0358 0.0143 0.0154 0.1164 0.1255 -0.0026 -0.0011 -0.0092 N11 0.0427 0.0339 0.0184 0.0147 0.1498 0.1191 0.0087 0.0038 0.0306 C12 0.0615 0.0155 0.0266 0.0067 0.2159 0.0545 0.0460 0.0199 0.1614 O13 0.0644 0.0386 0.0278 0.0167 0.2261 0.1356 0.0258 0.0111 0.0905 N14 0.0220 0.0736 0.0095 0.0318 0.0771 0.2583 -0.0516 -0.0223 -0.1812 N16 0.0402 0.0814 0.0174 0.0352 0.1412 0.2858 -0.0412 -0.0178 -0.1447 C18 0.0688 0.0053 0.0297 0.0023 0.2414 0.0186 0.0635 0.0274 0.2228 N19 0.0308 0.0672 0.0133 0.0290 0.1081 0.2360 -0.0364 -0.0157 -0.1279 Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0931 0.0913 0.0393 0.0385 0.3153 0.3091 0.0018 0.0008 0.0062 C2 0.0147 0.0380 0.0062 0.0160 0.0499 0.1287 -0.0233 -0.0098 -0.0788 C3 0.0397 0.0407 0.0167 0.0171 0.1345 0.1377 -0.0009 -0.0004 -0.0032 C6 0.0524 0.0528 0.0221 0.0223 0.1773 0.1790 -0.0005 -0.0002 -0.0016 N10 0.0344 0.0362 0.0145 0.0152 0.1165 0.1225 -0.0018 -0.0007 -0.0060 N11 0.0451 0.0350 0.0190 0.0148 0.1527 0.1186 0.0101 0.0042 0.0341 C12 0.0629 0.0153 0.0265 0.0065 0.2131 0.0519 0.0476 0.0201 0.1612 O13 0.0653 0.0388 0.0275 0.0163 0.2210 0.1313 0.0265 0.0112 0.0898 N14 0.0254 0.0694 0.0107 0.0293 0.0862 0.2350 -0.0440 -0.0185 -0.1489 N16 0.0403 0.0788 0.0170 0.0332 0.1365 0.2667 -0.0384 -0.0162 -0.1302 C18 0.0652 0.0075 0.0275 0.0032 0.2209 0.0254 0.0577 0.0243 0.1955 N19 0.0545 0.0699 0.0230 0.0295 0.1845 0.2368 -0.0154 -0.0065 -0.0523 S21 0.1453 0.1003 0.0613 0.0423 0.4921 0.3399 0.0450 0.0190 0.1523 C22 0.0152 0.0283 0.0064 0.0119 0.0515 0.0960 -0.0131 -0.0055 -0.0445 C23 0.0276 0.0419 0.0116 0.0177 0.0935 0.1419 -0.0143 -0.0060 -0.0484 C24 0.0542 0.0491 0.0229 0.0207 0.1836 0.1664 0.0051 0.0021 0.0172 C25 0.0464 0.0510 0.0195 0.0215 0.1570 0.1728 -0.0047 -0.0020 -0.0158 C26 0.0481 0.0611 0.0203 0.0258 0.1630 0.2069 -0.0130 -0.0055 -0.0439 C28 0.0398 0.0501 0.0168 0.0211 0.1349 0.1696 -0.0102 -0.0043 -0.0347 F31 0.0302 0.0444 0.0127 0.0187 0.1022 0.1505 -0.0143 -0.0060 -0.0484 8 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 S21 0.1479 0.0884 0.0638 0.0382 0.5190 0.3104 0.0594 0.0257 0.2086 C22 0.0204 0.0250 0.0088 0.0108 0.0716 0.0879 -0.0046 -0.0020 -0.0162 C23 0.0202 0.0282 0.0087 0.0122 0.0710 0.0991 -0.0080 -0.0034 -0.0280 C24 0.0335 0.0398 0.0145 0.0172 0.1176 0.1397 -0.0063 -0.0027 -0.0221 C25 0.0493 0.0489 0.0213 0.0211 0.1729 0.1716 0.0004 0.0002 0.0012 C26 0.0465 0.0519 0.0201 0.0224 0.1630 0.1820 -0.0054 -0.0023 -0.0190 C28 0.0835 0.0879 0.0361 0.0380 0.2931 0.3085 -0.0044 -0.0019 -0.0154 Cl31 0.0455 0.0604 0.0196 0.0261 0.1595 0.2120 -0.0150 -0.0065 -0.0525 Table 7: Descriptors of the reactivity of Compound 5 (ITS 5) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0863 0.0926 0.0368 0.0395 0.3070 0.3294 -0.0063 -0.0027 -0.0224 C2 0.0122 0.0394 0.0052 0.0168 0.0435 0.1400 -0.0271 -0.0116 -0.0965 C3 0.0366 0.0418 0.0156 0.0178 0.1301 0.1485 -0.0052 -0.0022 -0.0184 C6 0.0480 0.0542 0.0204 0.0231 0.1707 0.1928 -0.0062 -0.0026 -0.0221 N10 0.0322 0.0366 0.0137 0.0156 0.1145 0.1300 -0.0044 -0.0019 -0.0155 N11 0.0411 0.0355 0.0175 0.0151 0.1461 0.1262 0.0056 0.0024 0.0199 C12 0.0585 0.0152 0.0249 0.0065 0.2078 0.0539 0.0433 0.0184 0.1539 O13 0.0612 0.0385 0.0261 0.0164 0.2175 0.1370 0.0226 0.0096 0.0805 N14 0.0226 0.0730 0.0096 0.0311 0.0805 0.2595 -0.0504 -0.0214 -0.1790 N16 0.0414 0.0807 0.0176 0.0344 0.1472 0.2869 -0.0393 -0.0167 -0.1397 C18 0.0663 0.0059 0.0282 0.0025 0.2356 0.0209 0.0604 0.0257 0.2148 N19 0.0465 0.0680 0.0198 0.0290 0.1653 0.2418 -0.0215 -0.0092 -0.0765 S21 0.1458 0.0864 0.0621 0.0368 0.5183 0.3072 0.0594 0.0253 0.2112 C22 0.0211 0.0232 0.0090 0.0099 0.0751 0.0825 -0.0021 -0.0009 -0.0074 C23 0.0299 0.0297 0.0127 0.0127 0.1062 0.1056 0.0001 0.0001 0.0005 C24 0.0491 0.0574 0.0209 0.0244 0.1747 0.2040 -0.0082 -0.0035 -0.0293 C25 0.0192 0.0212 0.0082 0.0090 0.0684 0.0752 -0.0019 -0.0008 -0.0069 C26 0.0535 0.0510 0.0228 0.0217 0.1903 0.1814 0.0025 0.0011 0.0089 C28 0.0802 0.0863 0.0342 0.0368 0.2852 0.3069 -0.0061 -0.0026 -0.0217 Cl32 0.0480 0.0634 0.0205 0.0270 0.1707 0.2255 -0.0154 -0.0066 -0.0548 Table 8: Descriptors of the reactivity of Compound 6 (ITS 6) calculated using Hirshfeld Population Analysis at B3LYP/6-31+G (d, p). Local descriptors Dual descriptors Atoms f+ fS+ Sω+ ωΔf(r) ΔS(r) ΔW(r) C1 0.0866 0.0854 0.0228 0.0225 0.2993 0.2950 0.0012 0.0003 0.0043 C2 0.0125 0.0347 0.0033 0.0091 0.0432 0.1198 -0.0222 -0.0058 -0.0766 C3 0.0367 0.0378 0.0097 0.0099 0.1270 0.1305 -0.0010 -0.0003 -0.0036 C6 0.0481 0.0490 0.0127 0.0129 0.1664 0.1694 -0.0009 -0.0002 -0.0031 N10 0.0323 0.0338 0.0085 0.0089 0.1115 0.1169 -0.0016 -0.0004 -0.0054 N11 0.0413 0.0325 0.0109 0.0086 0.1428 0.1123 0.0088 0.0023 0.0306 C12 0.0586 0.0144 0.0154 0.0038 0.2026 0.0498 0.0442 0.0116 0.1528 O13 0.0612 0.0359 0.0161 0.0094 0.2116 0.1239 0.0254 0.0067 0.0876 N14 0.0228 0.0649 0.0060 0.0171 0.0786 0.2244 -0.0422 -0.0111 -0.1458 N16 0.0406 0.0724 0.0107 0.0191 0.1404 0.2503 -0.0318 -0.0084 -0.1099 C18 0.0652 0.0058 0.0172 0.0015 0.2253 0.0200 0.0594 0.0156 0.2052 N19 0.0473 0.0698 0.0124 0.0184 0.1634 0.2413 -0.0225 -0.0059 -0.0778 S21 0.1439 0.0874 0.0379 0.0230 0.4974 0.3020 0.0565 0.0149 0.1954 C22 0.0198 0.0298 0.0052 0.0079 0.0684 0.1031 -0.0101 -0.0026 -0.0347 C23 0.0323 0.0435 0.0085 0.0115 0.1118 0.1505 -0.0112 -0.0029 -0.0387 C24 0.0515 0.0510 0.0136 0.0134 0.1780 0.1763 0.0005 0.0001 0.0017 C25 0.0455 0.0476 0.0120 0.0125 0.1571 0.1646 -0.0022 -0.0006 -0.0075 C26 0.0497 0.0554 0.0131 0.0146 0.1717 0.1914 -0.0057 -0.0015 -0.0197 C28 0.0395 0.0451 0.0104 0.0119 0.1365 0.1558 -0.0056 -0.0015 -0.0194 Cl32 0.0645 0.1038 0.0170 0.0273 0.2228 0.3586 -0.0393 -0.0103 -0.1359 Analysis of the local descriptors in Table 3 shows that the sulphur atom S21 is the nucleophilic site of attack and the carbon atom C28 is the electrophilic site of attack. Also, the analysis of the local descriptors in Table 4 indicates that the sulphur atom S21 is the nucleophilic site of attack but the carbon atom C1 becomes the electrophilic site of attack. In addition, Table 5 shows that the sulphur atom S21 is the nucleophilic and electrophilic site of attack. The values of the local descriptors in Tables 6 and 7 show that the sulphur atom S21 is the nucleophilic site of attack and the carbon atom C1 is the electrophilic site of attack. Also, Table 8 shows that the sulphur atom S21 is the nucleophilic site of attack and the chlorine atom Cl32 is the 9 Mamadou Guy-Richard KONE, et al Der Pharma Chemica, 2023, 15(2): 1-10 electrophilic site of attack. The observation made when analyzing the data in Tables 3 to 8 is that the results are mixed, for example Table 7 where the sulphur atom is both a nucleophilic and an electrophilic site. This result does not allow us to identify the electrophilic and nucleophilic sites. This leads us to the use of dual descriptors that will be used as ideal descriptors of the regioselectivity of the different sites of attack. The values of the dual descriptors of the series of halogenated imidazole-thiosemicarbazides, calculated at the B3LYP/6-31+G level (d, p), show that the nitrogen atom N14 is the preferred site of electrophilic attack. According to this same level of calculation, nucleophilic attack will preferentially take place on the C18 atom. These electrophilic and nucleophilic attack sites (N14 and C18) are identical for all compounds according to the dual descriptors. It is thus retained that the substitution of halogens on imidazole-thiosemicarbazides does not modify the centres of reactivity. Hierarchical Ascending Classification Analysis (HAC) The Ascending Hierarchical Classification (AHC) of ITSs was illustrated by the dendrogram in Figure 9. The purpose of the dendrogram is to partition a set of compounds into homogeneous groups or classes [28,29]. It assembles molecules by aggregation the molecules that are most similar to each other using measures of dissimilarity or distance between compounds to form classes. The horizontal lines represent the compounds. Vertical lines represent similarity values between pairs of compounds, a compound and a group of compounds, and among groups of compounds. Figure 9: Dendrogram obtained for the studied ITSs. From this analysis, we can see that the studied compounds have been grouped into three categories: the most active, which is ITS 3, the moderately active compounds ITS 2 and ITS 5, and the less active compounds ITS 1, ITS 4 and ITS 6. Surface profiler The surface profiler is a three-dimensional plot with one or more dependent variables represented by a readable surface. The surface plot from JMP Pro 13 software [30] of few global descriptors ΔE, ω, and η is shown in Figure 10. Figure 10: Surface profile of ITSs from a few descriptors. The analysis of the surface profiler shows a nearly smooth plane connecting the three (3) descriptors. This result shows the linearity between the descriptors of reactivity. CONCLUSION In this work, Quantum Chemistry and Molecular Modelling methods were used on six (6) molecules of the family of halogenated imidazolethiosemicarbazides in order to study their chemical reactivity. This theoretical study was carried out using the DFT method with the B3LYP/6-31+G (d, p) level. Global and local descriptors were used to study the reactivity of different nucleophilic and electrophilic sites and their influence on molecular interaction in a qualitative and quantitative manner. The obtained descriptors could also provide more information and contribute to a